|Número de publicación||US7740851 B2|
|Tipo de publicación||Concesión|
|Número de solicitud||US 10/657,363|
|Fecha de publicación||22 Jun 2010|
|Fecha de presentación||8 Sep 2003|
|Fecha de prioridad||27 Ene 2000|
|También publicado como||CA2398466A1, DE60142614D1, EP1265928A1, EP1265928B1, EP2289550A2, EP2289550A3, US6656467, US20020164326, US20040131609, US20100266614, US20120135006, WO2001055217A1|
|Número de publicación||10657363, 657363, US 7740851 B2, US 7740851B2, US-B2-7740851, US7740851 B2, US7740851B2|
|Inventores||James F. Young, Leslie S. Johnson, William D. Huse, Herren Wu, Jeffry D. Watkins|
|Cesionario original||Medimmune, Llc|
|Exportar cita||BiBTeX, EndNote, RefMan|
|Citas de patentes (133), Otras citas (329), Citada por (17), Clasificaciones (20), Eventos legales (7)|
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet|
This application is a continuation of U.S. Ser. No. 09/771,415, filed Jan. 26, 2001 (now U.S. Pat. No. 6,656,467), which claims the benefit of U.S. Provisional Application Ser. No. 60/178,426, filed Jan. 27, 2000, the disclosure of each of which is hereby incorporated by reference in its entirety.
The present invention relates to novel ultra high affinity neutralizing antibodies.
The current incidence of infection caused by resistant or difficult to control microbes has created a need for newer approaches to controlling such organisms, as well as to treating those already infected.
Among the more difficult infectious agents to control and treat are the viruses. For example, respiratory syncytial virus (RSV) is the major cause of acute respiratory illness in young children admitted to hospitals and the major cause of lower respiratory tract infection in young children. A major obstacle to producing an effective vaccine against such agents as RSV has been the issue of safety. Conversely, the use of immunoglobulins against such viral agents has proven of some value. For example, studies have shown that high-titred RSV immunoglobulin was effective both in prophylaxis and therapy for RSV infections in animal models.
An alternative approach has been the development of antibodies, especially neutralizing monoclonal antibodies, with high specific neutralizing activity. One drawback to this route has been the need to produce human antibodies rather than those of mouse or rat and thus minimize the development of human anti-mouse or anti-rat antibody responses, which potentially results in further immune pathology.
An alternative approach has been the production of human-murine chimeric antibodies in which the genes encoding the mouse heavy and light chain variable regions have been coupled to the genes for human heavy and light chain constant regions to produce chimeric, or hybrid, antibodies.
In some cases, mouse CDRs have been grafted onto human constant and framework regions with some of the mouse framework amino acids being substituted for correspondingly positioned human amino acids to provide a “humanized” antibody. [Queen, U.S. Pat. Nos. 5,693,761 and 5,693,762]. However, such antibodies contain intact mouse CDR regions and have met with mixed effectiveness, producing affinities often no higher than 107 to 108 M−1.
A humanized anti-RSV antibody with good affinity has been prepared and is currently being marketed. [See: Johnson, U.S. Pat. No. 5,824,307]
The production of ultra high affinity antibodies would be desirable from the point of view of both the neutralizing ability of such an antibody as well as from the more practical aspects of needing to produce less antibody in order to achieve a desirable degree of clinical effectiveness, thereby cutting costs of production and/or allowing a greater degree of clinical effectiveness for administration in the same volume.
The present invention relates to high affinity neutralizing antibodies and active fragments thereof exhibiting affinity constants of at least 1010 M−1, and even 1011 M−1, and more specifically to such a neutralizing monoclonal immunoglobulin, including antibodies and/or active fragments thereof, wherein the antibody and/or fragment has human constant regions.
The present invention solves the above-mentioned problems by providing high affinity neutralizing antibodies without the presence of intact mouse CDR regions that cause human anti-mouse antibody reactions (HAMA) and with sufficiently high affinity neutralizing activity to reduce cost and efficacy of overall production.
One aspect of the present invention relates to high affinity neutralizing antibodies with affinity constants of at least 1010 M−1, and even 1011 M−1, and with specificity towards specific antigenic determinants, such as those exhibited by virus-expressed proteins.
One object of the present invention is to provide such high affinity neutralizing antibodies with specificity toward antigens produced by viruses, such as where such antigens are expressed by virus-infected cells in a mammal, especially a human.
In one such embodiment, the high affinity neutralizing immunoglobulin, including antibodies and/or active fragments thereof, of the present invention, and active fragments thereof, are specific for respiratory syncytial virus (RSV), most especially for the F antigen expressed by said RSV and also expressed on the surfaces of cells infected with RSV (the presence of which antigen on the cell surface causes fusion of the cells into syncytia),
Thus, in one embodiment, a high affinity neutralizing immunoglobulin, including antibodies and/or active fragments thereof, of the present invention binds to the same epitope on RSV as the antibody whose light chain variable chain has the sequence of SEQ ID NO: 1 (shown in
It is an object of the present invention to provide ultra high affinity neutralizing antibodies having substantially the framework regions of the immunoglobulin disclosed in
In a preferred embodiment of the present invention, the novel immunoglobulins of the present invention will differ from the antibody of
Especially preferred embodiments of the present invention have the framework sequences depicted in
In one embodiment, the high affinity neutralizing antibodies of the invention include a human constant region.
In a preferred embodiment, a high affinity RSV-neutralizing antibody of the invention, including active fragments thereof, with an affinity constant (Ka) of at least as high as 1010 M−1, and even 1011 M−1, is a recombinant immunoglobulin, such as an antibody or active fragment thereof, that includes a human constant region and framework regions for the heavy and light chains wherein at least a portion of the framework is derived from a human antibody (or from a consensus sequence of a human antibody framework), an example of said framework regions depicted for the antibody sequences of
In one embodiment, all of the framework is derived from a human antibody (or a human consensus sequence).
In another highly specific embodiment, a high affinity RSV-neutralizing antibody, with an affinity of at least 1010 M−1, is a recombinant antibody having a human constant region, one or more CDRs that are derived from a non-human antibody in which at least one of the amino acids in at least one of the CDRs is changed and in which all or a portion of the framework is derived from a human antibody (or a consensus sequence of a human antibody framework).
In a separate embodiment, a humanized neutralizing immunoglobulin that binds to the same epitope as the basic or reference antibody or immunoglobulin whose variable chains are shown in
It is another object of the present invention to provide compositions comprising the immunoglobulins disclosed herein wherein said structures are suspended in a pharmacologically acceptable diluent or excipient.
It is a still further object of the present invention to provide methods of preventing and/or treating respiratory syncytial virus comprising the administering to a patient at risk thereof, or afflicted therewith, of a therapeutically effective amount of a composition containing an immunoglobulin of the invention, such as where said antibodies or active fragments thereof exhibit the specificity and affinity properties disclosed herein for the immunoglobulins of the invention.
The term “antigen” refers to a structure, often a polypeptide or protein, present on the surface of a microorganism, such as a virus, for which an antibody has affinity and specificity.
The term “antigenic determinant” refers to a specific binding site on an antigenic structure for which an immunoglobulin, such as an antibody, has specificity and affinity. Thus, a particle, such as a virus, may represent an antigen but may have on its surface a number of separate, and different, antigenic sites such as where the virus has a number of different surface proteins and each represents a distinct potential binding site for an immunoglobulin.
The term “immunoglobulin” refers to a protein or polypeptide having specificity and affinity for an antigen or antigenic determinant. This term includes antibodies, commonly depicted as tetrameric, as well as active fragments thereof, such fragments having specificity and affinity for antigens or antigenic determinants. Thus, “immunoglobulin” as used herein includes antibodies and all active fragments thereof.
The term “antibody” refers to a protein or polypeptide having affinity for an antigenic determinant, usually one found on the surface of a microorganism, especially a virus. Such an antibody is commonly composed of 4 chains and is thus tetrameric.
The term “neutralizing immunoglobulin” or “neutralizing antibody” refers to the ability of the immunoglobulins, including antibodies, of the present invention to reduce the replication of microorganisms, especially viruses, in organisms as well as in cell cultures. An indication of such ability is the data from the microneutralization assays disclosed hereinbelow. Such a structure usually has both variable and constant regions whereby the variable regions are mostly responsible for determining the specificity of the antibody and will comprise complementarity determining regions (CDRs).
The term “complementarity determining region” or “CDR” refers to variable regions of either H (heavy) or L (light) chains contains the amino acid sequences capable of specifically binding to antigenic targets. These CDR regions account for the basic specificity of the antibody for a particular antigenic determinant structure. Such regions are also referred to as “hypervariable regions.”
The term “active fragment” refers to a portion of an antibody that by itself has high affinity for an antigenic determinant and contains one or more CDRs accounting for such specificity. Non-limiting examples include Fab, F(ab)′2, heavy-light chain dimers, and single chain structures, such as a complete light chain or complete heavy chain.
The term “specificity” refers to the ability of an antibody to bind preferentially to one antigenic site versus a different antigenic site and does not necessarily imply high affinity.
The term “affinity” refers to the degree to which an antibody binds to an antigen so as to shift the equilibrium of antigen and antibody toward the presence of a complex formed by their binding. Thus, where an antigen and antibody are combined in relatively equal concentration, an antibody of high affinity will bind to the available antigen so as to shift the equilibrium toward high concentration of the resulting complex.
The term “affinity constant” refers to an association constant used to measure the affinity of an antibody for an antigen. The higher the affinity constant the greater the affinity of the immunoglobulin for the antigen or antigenic determinant and vice versa. An affinity constant is a binding constant in units of reciprocal molarity. Such a constant is readily calculated from the rate constants for the association-dissociation reactions as measured by standard kinetic methodology for antibody reactions.
The present invention is directed to ultra high affinity neutralizing antibodies and active fragments thereof having affinity constants of at least 1010 M−1. Active fragments of these antibodies are fragments containing at least one high affinity complementarity determining region (CDR).
With the advent of methods of molecular biology and recombinant technology, it is now possible to produce antibody molecules by recombinant means and thereby generate gene sequences that code for specific amino acid sequences found in the polypeptide structure of the antibodies. Such antibodies can be produced by either cloning the gene sequences encoding the polypeptide chains of said antibodies or by direct synthesis of said polypeptide chains, with in vitro assembly of the synthesized chains to form active tetrameric (H2L2) structures with affinity for specific epitopes and antigenic determinants. This has permitted the ready production of antibodies having sequences characteristic of neutralizing antibodies from different species and sources.
Regardless of the source of the immunoglobulins, or how they are recombinantly constructed, or how they are synthesized, in vitro or in vivo, using transgenic animals, such as cows, goats and sheep, using large cell cultures of laboratory or commercial size, in bioreactors or by direct chemical synthesis employing no living organisms at any stage of the process, all immunoglobulins have a similar overall 3 dimensional structure. In the case of an antibody, this structure is often given as H2L2 and refers to the fact that antibodies commonly comprise 2 light (L) amino acid chains and 2 heavy (H) amino acid chains. Both chains have regions capable of interacting with a structurally complementary antigenic target. The regions interacting with the target are referred to as “variable” or “V” regions and are characterized by differences in amino acid sequence from antibodies of different antigenic specificity.
The variable region of either H or L chains contains the amino acid sequences capable of specifically binding to antigenic targets. Within these sequences are smaller sequences dubbed “hypervariable” because of their extreme variability between antibodies or active fragments of differing specificity. Such hypervariable regions are also referred to as “complementarity determining regions” or “CDR” regions. These CDR regions account for the basic specificity of the antibody for a particular antigenic determinant structure.
The CDRs represent non-contiguous stretches of amino acids within the variable regions but, regardless of species, the positional locations of these critical amino acid sequences within the variable heavy and light chain regions have been found to have similar locations within the amino acid sequences of the variable chains. The variable heavy and light chains of all canonical antibodies each have 3 CDR regions, each non-contiguous with the others (termed L1, L2, L3, H1, H2, H3) for the respective light (L) and heavy (H) chains. The accepted CDR regions have been described by Kabat et al, J. Biol. Chem. 252:6609-6616 (1977). The numbering scheme is shown in the figures, where the CDRs are underlined and the numbers follow the Kabat scheme.
In all mammalian species, antibody polypeptides contain constant (i.e., highly conserved) and variable regions, and, within the latter, there are the CDRs and the so-called “framework regions” made up of amino acid sequences within the variable region of the heavy or light chain but outside the CDRs.
The immunoglobulins disclosed according to the present invention afford extremely high affinity (on the order of 1010 M−1, and even 1011 M−1, for the affinity constant, or Ka, defined as an association constant describing the binding of antibody and antigen as the ligands) for epitopes, or antigenic determinants, found in macromolecules, especially proteins, and most especially proteins expressed by viruses and other microorganisms, such as proteins expressed on the surfaces of viruses as well as the surfaces of cells infected with a virus. The high affinity antibodies of the present invention are neutralizing antibodies and thus reduce the replication of viruses in organisms as well as in cell cultures while maintaining sufficient homology to the antibody amino acid sequences of the recipient so as to prevent adverse immunological pathology. The latter feature is achieved through the use of constant regions similar to those of the recipient organism, such as a mammal and most especially a human. This feature is also achieved through the use of framework amino acid sequences similar, if not identical, to those found in antibodies from the recipient organism. In the latter case, some amino acid replacements may be made in the framework sequences so as to facilitate and maintain the high affinity interaction between the novel CDRs of the present invention and the antigen for which said antibodies show specificity.
As used herein, terms such as “antibody” and “active fragment” or “fragment” are not to be considered limiting in determining the full extent of the present invention. Thus, the fact that the term “antibody” is used rather than “active fragment” or “immunoglobulin” is not to be taken as a limitation on the invention or its uses so long as the requisite properties of specificity and affinity are exhibited by said structure.
In accordance with the invention disclosed herein, the affinity constants characterizing the affinities of the high affinity neutralizing antibodies, and active fragments thereof, of the present invention are association constants and were measured by the kinetics of antigen-antibody complex formation, with the rate constant for association to form the complex being denoted as kassoc or kon and the dissociation constant being denoted as kdiss or koff. Measurement of such constants is well within the ordinary skill in the art and the details will not be described further herein except for general methodology and specific conditions, where appropriate, as recited in the examples given herein to further describe the invention.
The high affinity antibodies of the present invention can be achieved, as already described, through genetically engineering appropriate antibody gene sequences, i.e., amino acid sequences, by arranging the appropriate nucleotide sequences and expressing these in a suitable cell line. Any desired nucleotide sequences can be produced using the method of codon based mutagenesis, as described, for example, in U.S. Pat. Nos. 5,264,563 and 5,523,388. Such procedures permit the production of any and all frequencies of amino acid residues at any desired codon positions within an oligonucleotide. This can include completely random substitutions of any of the 20 amino acids at an desired position or in any specific subset of these. Alternatively, this process can be carried out so as to achieve a particular amino acid a desired location within an amino acid chain, such as the novel CDR sequences according to the invention. In sum, the appropriate nucleotide sequence to express any amino acid sequence desired can be readily achieved and using such procedures the novel CDR sequences of the present invention can be reproduced. This results in the ability to synthesize polypeptides, such as antibodies, with any desired amino acid sequences. For example, it is now possible to determine the amino acid sequences of any desired domains of an antibody of choice and, optionally, to prepare homologous chains with one or more amino acids replaced by other desired amino acids, so as to give a range of substituted analogs.
In applying such methods, it is to be appreciated that due to the degeneracy of the genetic code, such methods as random oligonucleotide synthesis and partial degenerate oligonucleotide synthesis will incorporate redundancies for codons specifying a particular amino acid residue at a particular position, although such methods can be used to provide a master set of all possible amino acid sequences and screen these for optimal function as antibody structures or for other purposes. Such methods are described in Cwirla et al, Proc. Natl. Acad. Sci. 87:6378-6382 (1990) and Devlin et al., Science 249:404-406 (1990).
In accordance with the invention disclosed herein, enhanced antibody variants can be generated by combining in a single polypeptide structure one, two or more novel CDR sequences according to the invention, each shown to independently result in enhanced binding activity. In this manner, several novel amino acids sequences can be combined into one antibody, in the same or different CDRs, to produce high affinity antibodies within the present invention. For example, 3 such novel CDR sequences may be employed and the resulting antibodies screened for affinity for a particular antigenic structure, such as the F antigen or RSV. The overall result would thus be an iterative process of combining various single amino acid substitutions and screening the resulting antibodies for antigenic affinity in a step by step manner. Such methods were used to prepare some of the antibodies embodied within the present invention. Such methods also represent a convenient, if tedious, means of optimizing the antibody sequences of the present invention, especially the sequences of the CDR regions of said antibodies.
Using the novel sequences and methods of the present invention, such an approach avoids the time and expense of generating and screening all possible permutations and combinations of antibody structure in an effort to find the antibody with the maximum efficiency. Conversely, complete randomization of a single 10 amino acid residue CDR would generate over 10 trillion variants, a number virtually impossible to screen.
This iterative method can be used to generate double and triple amino acid replacements in a stepwise process so as to narrow the search for antibodies having higher affinity.
Conversely, it should be recognized that not all locations within the sequences of the different antibody domains may be equal. Substitutions of any kind in a particular location may be helpful or detrimental. In addition, substitutions of certain kinds of amino acids at certain locations may likewise be a plus or a minus as it affects affinity for the particular antigen. For example, it may not be necessary to try all possible hydrophobic amino acids at a given position. It may be that any hydrophobic amino acid will do as well. Alternatively, an acidic or basic amino acid at a given location may provide large swings in measured affinity. It is therefore necessary also to learn the “rules” of making such substitutions but the determination of such “rules” may not require the study of all possible combinations and substitutions—trends may become apparent after examining fewer than the maximum number of substitutions.
In accordance with the foregoing, the antibodies of the present invention are ultra high affinity neutralizing antibodies, such as anti-RSV antibodies, and in the latter case most preferably antibodies with specificity toward the same epitope of RSV as the antibody of U.S. Pat. No. 5,824,307.
In addition, the affinities of the ultra high affinity antibodies of the invention typically are at least 1010 M−1. Because such high affinities are not easily measured, except by the procedures described herein, such value may commonly be considered as part of a range and may, for example, be within 2 fold of 1010 M−1 or be greater than 1010 M−1 or may even be numerically equal to 1010 M−1. In such cases, the affinity is denoted by an affinity constant, which is in the nature of a binding constant so as to give units of reciprocal molarity. As such, the affinity of the antibody for antigen is proportional to the value of this constant (i.e., the higher the constant, the greater the affinity). Such a constant is readily calculated from the rate constants for the association-dissociation reactions as measured by standard kinetic methodology for antibody reactions.
In a specific embodiment, the high affinity neutralizing antibodies of the present invention, and active fragments thereof, have affinity constants for their respective antigens of at least at least 1011 M−1, in some cases being in excess of this value, a range at the very upper region of measurability.
The high affinity neutralizing antibodies of the present invention, and active fragments thereof, may be advantageously directed to any antigenic determinants desired, such as epitopes present on any type of macromolecule, especially peptide epitopes present as part of the three dimensional structure of protein and polypeptide molecules. Such peptide epitopes may commonly be present on the surfaces, or otherwise be part of the structure of, microorganisms and cells, such as cancer cells. Microorganisms expressing such peptide epitopes includes bacteria and viruses. In the latter case, the proteins and polypeptides exhibiting peptide epitopes may be molecules expressed on the surfaces of the virus or may be expressed by cells infected with a virus. For purposes of evaluating the efficacy of the rules and methods disclosed according to the present invention, a virus was chosen as one available antigenic source for developing antibodies within the present invention. The virus chosen for further analysis was the respiratory syncytial virus (RSV). This latter virus was chosen because it is well characterized with respect to its replicative cycle as well as with respect to the antigenic determinants found on its surface. In addition, antigens known to be expressed by cells infected with this virus are well characterized. Thus, the virus exhibits both a surface G antigen and a surface F antigen, both proteins. The G antigen facilitates binding of the virus to cell surfaces and the F proteins facilitates the fusion of the virus with cells. The cells so infected also express the F antigen on their surfaces and the latter result induces fusion of the cells to form a syncytium, hence the name of the virus. In addition, this virus is a convenient subject for analysis in that cell lines readily infected by this virus are well known and well characterized, thereby making it an easy virus to grow and culture in vitro. Further, antibodies available for treatment of this virus are known and are commercially available (for example, the antibodies disclosed in U.S. Pat. No. 5,824,307). For these reasons, the antibody disclosed in said patent, the disclosure of which patent is hereby incorporated by reference in its entirety, contains the amino acid sequences of the “reference antibody” disclosed in
A high affinity neutralizing antibody according to the present invention, including active fragments thereof, comprises at least one high affinity complementarity determining region (CDR) wherein said CDR has an amino acid sequence selected to result in an antibody having an affinity constant (Ka) of at least 1010 M−1. In preferred embodiments, such antibody, or active fragment, comprises at least 2 high affinity CDRs, or at least 3 high affinity CDRs or even at least 4 high affinity CDRs. In highly preferred embodiments, such antibodies or active fragments comprise 3 or 4 high affinity CDRs. In one preferred embodiment, such active fragment is an Fab fragment.
The high affinity antibodies of the present invention commonly comprise a mammalian, preferably a human, constant region and a variable region, said variable region comprising heavy and light chain framework regions and heavy and light chain CDRs, wherein the heavy and light chain framework regions are derived from a mammalian antibody, preferably a human antibody, and wherein the CDRs are derived from an antibody of some species other than a human, preferably a mouse. Where the framework amino acids are also derived from a non-human, the latter is preferably a mouse.
In addition, high affinity antibodies of the invention bind the same epitope as the antibody from which the CDRs are derived, and wherein at least one of the CDRs of said ultra high affinity antibody contains amino acid substitutions, and wherein said substitutions comprise the replacement of one or more amino acids in the CDR regions by non-identical amino acids, preferably the amino acids of the correspondingly aligned positions of the CDR regions of the human antibody contributing the framework and constant domains.
The high affinity CDRs may be produced by amino acid substitutions in non-high affinity CDRs to produce such high affinity CDRs or such high affinity CDRs may be synthesized directly to form such high affinity CDRs. Thus, the ultra high affinity neutralizing antibodies of the present invention may have amino acid substitutions in only one of the CDR regions, preferably more than one CDR region, and most preferably 3 or even 4 such regions, with possibly as many as 5 or even all 6 of the CDRs containing at least one substituted amino acid.
In applying the methods disclosed herein to produce antibodies of the present invention, the method of preparing the antibodies is not a limiting factor. Thus, the high affinity neutralizing antibodies of the present invention may be prepared by generating polynucleotide sequences coding for the polypeptides of the antibodies and using vectors to insert said polynucleotide sequences into permissive cells capable of not only expressing such polypeptides but also of assembling them into characteristic tetrameric antibody structures that are then retrieved from the cells or cell cultures, possibly being secreted into the medium by such cells. Technologies for such manufacturing procedures are already known and patented and are not essential to practicing the present invention. [see: Morrison et al, U.S. Pat. No. 5,807,715]. In addition, the polypeptide chains of the antibodies of the present invention may be synthesized chemically, with or without the addition of enzymes, and then chemically joined to form tetrameric structures of the usual H2L2 configuration. Thus, any method of preparing the antibodies disclosed herein can be utilized.
The present invention is also directed to the formation of high affinity neutralizing antibodies, with the properties already enumerated, having high affinity as a result predominantly of having high affinity CDR sequences. In accordance with the present invention, the CDR sequences of the antibodies disclosed herein have been optimized so as to confer upon the antibody molecule the ultra high affinities characteristic of the antibodies of the present invention. Such CDR sequences, together with the framework sequences disclosed herein, especially those taught by the sequences of
To produce immunoglobulins, such as antibodies and/or active fragments thereof, within the present invention, e.g., high affinity neutralizing antibodies, the rules taught by the present invention are used advantageously to produce antibody molecules whose structures incorporate the sequences of the high affinity CDR sequences disclosed according to the present invention. Thus, the high affinity neutralizing antibodies of the present invention are, in essence, not truly “monoclonal” antibodies as that term is commonly used, since they do not have to be produced by cloning anything. As already mentioned, the sequences of the antibodies of the invention may be directly synthesized and thus may not be identical to any antibody sequences, especially not to any CDR sequences, presently known. The sequences themselves can be wholly novel ab initio and not be exactly represented in any antibody produced by any living organism. Thus, the high affinity CDR sequences disclosed herein are found, or achieved, by optimization, as disclosed herein, and then, once said high affinity CDR sequences are known, can be used to synthesize fully functional antibody molecules, whether dimeric or tetrameric, bifunctional or monofunctional, by any and all means known to science.
In keeping with the foregoing, and in order to better describe the sequences disclosed according to the invention, including their optimization, the sequence of the light and heavy chain variable regions of a reference antibody (here, the anti-RSV antibody of U.S. Pat. No. 5,824,307) are shown in
In accordance with the forgoing, changes were made in first one CDR sequence to optimize that sequence and determine the “critical” residue, or residues, than said position(s) was optimized through a series of amino acid substitutions limited to that position alone. Each of the 6 CDRs of the antibody clone was studied in turn until the “critical” CDRs were determined (wherein “critical CDRs” means CDRs having a substantial effect on antibody binding, such as the beneficial or high affinity CDRs of Table 3). No all CDRs were found to be critical. For the antibody used in this particular study, only CDRs H1, H3, L2, and L3 were found to be critical but the results may be different for a different antibody. Once a “high affinity” CDR was determined (i.e., a “beneficial CDR”) then combinations of the CDRs were studied to optimize the combination of CDR sequences resulting in a high affinity neutralizing antibody of the invention.
As a very specific embodiment, the invention disclosed herein relates to a high affinity neutralizing antibody against respiratory syncytial virus (RSV) having an affinity constant of at least 1010 M−1, wherein said affinity constant could be within at least 2 fold of this value because of the variability of such determinations and the variability of affinity of the different cloned antibodies for the antigen (here, F antigen of RSV). Some of the resulting optimized structures within this embodiment had Ka greater than 1011 M−1 (for example, clones numbered 22 and 23 in Table 4).
This high affinity neutralizing antibody is also an antibody that binds to the same epitope on RSV as the antibody whose light chain variable region has the sequence of SEQ ID NO: 1 (
In general, the approach used to identify antibodies of the invention, based on the specific example of anti-RSV just described, was to generate nucleotide sequences for the genes expressing the desired antibody chains and insert these into vectors then used to transform Escherichia coli cells by standard protocols. The cells were grown in wells and the supernatant sampled and measured for antigen binding using capture lift and ELISA techniques. [See: Watkins et al, (1997) Anal. Biochem. 253, 37-45; Watkins et al, (1998) Anal. Biochem. 256, 169-177 (the specifications of which are incorporated herein by reference)] These polynucleotides were designed so as to provide single amino acid replacements in the CDRs that could then be screened for increased affinity, with beneficial replacements (those yielding increased affinity) being selectively combined for increased affinity. These were then screened for binding affinity for F antigen of RSV versus the basic or reference antibody.
Using this protocol, ELISA data indicated that no single amino acid replacements in CDRs L1 or H2 produced any increase in the affinity of the antibody clone for the epitope used as antigen (here, the F antigen of RSV). Therefore, the antibodies of the present invention all contain CDR sequences that differ from the reference antibody only in CDRs L2, L3, H1 and H3 (here, the reference antibody with sequences in
The antibodies thus disclosed herein with respect to RSV also commonly have framework regions derived from a human antibody but, where not so derived, preferably from a mouse.
For the CDRs of the reference antibody, the amino acid sequence of each CDR (as given in the sequences of
Sequences of Basic or Reference CDRs
SEQ ID NO.
DT S KLAS
FQGS G YPFT
T S GMSVG
SMITN W YFDV
With respect to the sequences disclosed herein, the CDR regions as defined for purposes of the present invention are those segments corresponding to residues 24-33 (CDR L1), 49-55 (CDR L2) and 88-95 (CDR L3) of the light chain variable regions and residues 31-37 (CDR H1), 52-67 (CDR H2) and 100-109 (CDR H3) of the heavy chain variable regions of the antibodies disclosed herein.
In producing the antibodies of the present invention, whether by generating clones or cloning the polypeptide chains composing said antibodies, or by direct synthesis of the polypeptide sequences, with or without the use of polynucleotide sequences coding therefor, or by whatever method the user may choose, since no method of producing said antibodies results in a limitation of the teaching of the present invention, the basic or reference antibody (heavy and light chain variable regions (CDRs plus Framework) shown in
Libraries were initially screened by capture lift to identify the highest affinity variants. Subsequently, these clones were further characterized using capture ELISA and by titration on immobilized antigen.
DNA from the highest affinity variants was sequenced to determine the nature of the beneficial or high affinity replacements. After screening, it was determined that eight beneficial or high affinity replacements, occurring in only four of the CDRs, had been observed. These are summarized as the CDR sequences in Table 3 with differences versus the reference or basic CDRs of Table 1 being bold and underlined. Thus, the CDR sequences of Table 3 can be considered a CDR library of cassettes available for use in producing a high affinity neutralizing antibody of the present invention where specificity is directed toward the F antigen of RSV.
Analysis of the data indicated that replacement of amino acids at selected locations had greatly increased epitope binding, especially where the nature of the replacement was the insertion of an amino acid selected from the group phenylalanine, alanine, proline, tryptophan and tyrosine, most especially phenylalanine, all such beneficial or high affinity replacements again being at selected positions.
For the optimization experiment described herein and employing the RSV/anti-RSV system, the most beneficial of high affinity CDRs were found to result from amino acid replacements in 3 or 4 of the 6 CDRs, and in just 4 amino acid locations overall. Thus, the high affinity neutralizing antibodies of the present invention contain amino acid sequences differing from that of the base or reference antibody only in complementarity determining regions, or in such regions as well as in surrounding framework regions, unlike previously known man-made antibodies. Thus, the antibodies of the present invention are high affinity neutralizing antibodies containing one or more CDR sequences selected so as to produce high affinity in the antibody molecule. In the specific embodiment using RSV as the target such differences are found only in L2 (or CDRL2), L3 (or CDRL3), H1 (or CDRH1) and H3 (or CDRH3). As noted, the greatest affinities for this antibody occurred only at selected amino acid positions of these CDRs, and in some of the embodiments of the present invention just one amino acid location in each CDR was preferred for giving high affinity.
Thus, for CDR H1, substitution at amino acid 2 of the CDR (counting from the amino terminal end of the particular underlined CDR sequence of
In accordance with the invention, by combining such amino acid substitutions so that more than one occurred in the same antibody molecule, it was possible to greatly increase the affinity of the antibodies disclosed herein for the epitope of the F antigen of RSV.
Table 2 shows the results of using the novel CDR sequences (for H1, H3, L2, and L3, respectively) of a number of clones according to the present invention. As shown in Table 2, a particular antibody may have incorporated therein as many as 1, 2, or 3 novel CDRs of the invention versus the basic or reference antibody chains shown in
The total number of clones examined in this experiment was 37, with some duplicates (indicated by the “n” value in parenthesis, for example, “n=4” for clone No. 7 indicates that 4 duplicate clones were examined).
In general, the data showed that there is a correlation between affinity and the number of beneficial or high affinity CDRs, with all of the higher affinity variants having more than one beneficial or high affinity CDR. Further, all of the best clones had an F (Phe) at position 6 within CDR H3. Also, the beneficial or high affinity CDRs were those wherein a hydrophobic, especially an aromatic, amino acid was inserted in place of the residue found in the basic or reference antibody.
The antibody titration assay employed varying concentrations of antibody using 500 ng of RSV F antigen for each measurement. A graph of comparison data for a number of the combinatorial clones of Table 2 is shown in
In sum, Table 2 shows a number of clones evaluated by the procedures described herein along with the amino acids occurring at the key locations (underlined and bold-faced in Tables 1 and 3) of CDRs H1, H3, L2, and L3. The Table also summarizes the number of differences between the CDRs of these clones versus the corresponding CDRs of the reference antibody (See Table 1 and
Summary of Clone Data
(n = 3)
(n = 3)
(n = 3)
(n = 4)
(n = 2)
(n = 2)
(n = 3)
(n = 2)
(n = 2)
(n = 2)
Table 2 also shows the number of novel CDRs for each antibody clone (meaning the number of CDRs in the antibody with at least one amino acid difference with respect to the corresponding CDR of the reference antibody—see Table 1). The number of novel CDRs is also the number of “beneficial” or “high affinity” CDRs present in that antibody molecule. The amino acid differences in the novel CDR would occur at the position bold and underlined in Table 1 for the reference antibody so that the amino acid bold and underlined in Table 1 has been replaced by the amino acid indicated for the respective CDR in Table 2 (using standard single letter amino acid designations).
The novel CDRs represented in each of the clones is readily determined by locating the clone in the table, and matching the indicated amino acid for each CDR with the corresponding amino acid for the same CDR next to the basic or reference clone. For convenience, where an amino acid is different in a particular CDR of one of the clones, the new amino acid is indicated in bold face. In addition, for all clones shown in the table, replacements occur only at the selected locations recited above as yielding a novel CDR. Thus, all substitutions in CDR H1 relative to the basic or reference antibody are at position 2 of the CDR (meaning, again, the second amino acid from the N-terminal end of CDR H1 as underlined and bold-faced in
Thus, the novel and beneficial CDRs according to the present invention (i.e., high affinity CDRs or CDR sequences whose presence in the basic or reference antibody in place of the corresponding basic or reference CDR served to greatly increase the affinity of said antibody for the same RSV epitope) which are present in the antibody structures produced in the supernatants tested for the clones of Table 2 are summarized in Table 3. In each case, the bold face indicates how the novel and beneficial, or high affinity, CDRs of the invention differ from the corresponding CDRs of the basic or reference anti-RSV antibody.
Sequences for High Affinity CDRs
SEQ ID NO:
T A GMSVG
T P GMSVG
SMITN F YFDV
DT F KLAS
DT Y KLAS
FQGS F YPFT
FQGS Y YPFT
FQGS W YPFT
While the CDR sequences of Table 3 represent the sequences for the high affinity CDRs disclosed according to the invention, it is understood that one or more of these CDRs may be present in the same antibody and the sequences of the table indicate the set from which appropriate sequences for each of the high affinity CDRs may be selected. Thus, as shown in Table 3, when a high affinity H1 CDR is present in a high affinity neutralizing antibody of the invention disclosed herein, it has a sequence corresponding to the sequence of SEQ ID NO: 9 or 10. When a neutralizing antibody of the claimed invention contains a high affinity H3 CDR, said CDR has the sequence of SEQ ID NO: 12. When a high affinity neutralizing antibody of the invention contains a high affinity L2 CDR, said high affinity L2 CDR has an amino acid sequence selected from the group consisting of the sequences of SEQ ID NO: 12 and 13. Finally, when a high affinity neutralizing antibody of the present invention contains a high affinity L3 CDR, said CDR has an amino acid sequence selected from the group consisting of the sequences of SEQ ID NO: 14, 15 and 16.
As already stated, in one embodiment, the high affinity neutralizing antibodies are antibodies that include a human constant region.
Thus, in a preferred embodiment, the high affinity neutralizing antibody of the invention, with an affinity of at least 1010 M−1, or even at least 1011 M−1, is a grafted antibody that includes a human constant region and a framework for the heavy and light chains wherein at least a portion of the framework is derived from a human antibody (or from a consensus sequence of a human antibody framework).
In another embodiment, all of the framework is derived from a human antibody (or a human consensus sequence).
Thus, an RSV-neutralizing antibody, with an affinity of at least 1010 M−1, is a grafted antibody having a human constant region, one or more CDRs that are derived from a non-human antibody in which at least one of the amino acids in at least one of said CDRs is changed and in which all or a portion of the framework is derived from a human antibody (or a consensus sequence of a human antibody framework).
Because the combination of CDR sequences of one antibody with non-CDR regions of another antibody results from a form of “grafting” of CDRs onto the remainder of the molecule, these have been referred to as “CDR grafted” antibodies. Today, using the techniques of genetic engineering the same product can be formed without isolating any sequences from actual antibodies. So long as the desired CDR sequences, and the constant and framework sequence are known, genes with the desired sequences can be assembled and, using a variety of vectors, inserted into appropriate cells for expression of the functional tetrameric antibody molecules. Coupling this with the methodology already described permits the assembly of single mutation libraries wherein the antibodies possess the same sequences as corresponding grafted antibodies and, therefore, the same structure and binding affinities.
The high affinity antibodies of the invention can be present in a relatively pure or isolated form as well as in a supernatant drawn from cells grown in wells or on plates. Such supernatants were used to generate the data of Table 1. The antibodies of the invention can thus also be present in the form of a composition comprising the antibody of the invention and wherein said antibody is suspended in a pharmacologically acceptable carrier, or excipient. The antibodies of the invention may be present in such a composition at a concentration, or in an amount, sufficient to be of therapeutic or pharmacological value in treating diseases, such as RSV. Said antibodies may also be present in a composition in a more dilute form.
Consequently, the invention is also directed to providing a method of preventing and/or treating respiratory syncytial virus infections comprising the administering to a patient at risk thereof, or afflicted therewith, of a therapeutically (including prophylactically) effective amount of the antibody composition described herein.
One preferred embodiment of the high affinity antibodies of the present invention is the antibody whose heavy and light chain CDR regions have sequences as follows: CDR H1 has the sequence of SEQ ID NO: 9, CDR H3 has the sequence of SEQ ID NO: 11, CDR L2 has the sequence of SEQ ID NO: 4 (no change from CDR L2 of the reference sequence of
Another preferred embodiment of the high affinity antibodies of the present invention is the antibody whose heavy and light chain CDR regions have the sequences as follows: CDR H1 has the sequence of SEQ ID NO: 9, CDR H3 has the sequence of SEQ ID NO: 11, CDR L2 has the sequence of SEQ ID NO: 12, and CDR L3 has the sequence of SEQ ID NO: 5 (see Table 2, clone 2—no difference from the reference sequence of CDR L3 of
An additional preferred embodiment of the high affinity antibodies of the present invention is the antibody whose heavy and light chain CDR regions have the sequences as follows: CDR H1 has the sequence of SEQ ID NO: 10, CDR H3 has the sequence of SEQ ID NO: 11, CDR L2 has the sequence of SEQ ID NO: 12, and CDR L3 has the sequence of SEQ ID NO: 14 (see Table 3 for CDR sequences) which clone is designated number 3 in Table 2. In this preferred embodiment, the affinity constant is about 8.13×1010 (or about 12.3 pM as a dissociation constant) as shown in Table 4 (clone 3). The heavy and light chain variable regions of an antibody comprising this embodiment, along with framework sequences, is shown in
A most preferred embodiment of the high affinity antibodies of the present invention is the antibody whose heavy and light chain CDR regions have the sequences as follows: CDR H1 has the sequence of SEQ ID NO: 9, CDR H3 has the sequence of SEQ ID NO: 11, CDR L2 has the sequence of SEQ ID NO: 12, and CDR L3 has the sequence of SEQ ID NO: 14 (see Table 3). In this preferred embodiment, the affinity constant is about 3.6×1011 (or about 2.8 pM as a dissociation constant) as shown in Table 4 (clone 22). The heavy and light chain variable regions of an antibody comprising this embodiment, along with framework sequences, is shown in
Another most preferred embodiment of the present invention is the antibody whose heavy and light chain CDR regions include the following sequences: CDR H1 has the sequence of SEQ ID NO: 9, CDR H3 has the sequence of SEQ ID NO: 11, CDR L2 has the sequence of SEQ ID NO: 12, and CDR L3 has the sequence of SEQ ID NO: 15 (see Table 3). In this latter preferred embodiment, the affinity constant is about 4×1011 (about 2.5 pM as a dissociation constant) as shown in Table 4 (clone 23). The heavy and light chain variable regions of an antibody comprising this embodiment, along with framework sequences, is shown in
In particularly preferred embodiments, the antibodies of the present invention will have the framework regions of the sequences depicted for the framework regions shown in
It should be kept in mind that while the high affinity neutralizing antibodies of the present invention can be assembled from CDR regions and non-CDR regions derived from actual neutralizing antibodies by splicing amino acid segments together (and antibodies so assembled would be within the invention disclosed herein) the antibodies of the present invention are most conveniently prepared by genetically engineering appropriate gene sequences into vectors that may then be transfected into suitable cell lines for eventual expression of the assembled antibody molecules by the engineered cells. In fact, such recombinant procedures were employed to prepare the antibodies disclosed herein. In addition, because the sequences of the chains of the high affinity antibodies are known from the disclosure herein, such antibodies could also be assembled by direct synthesis of the appropriate chains and then allowed to self-assemble into tetrameric (H2L2) bivalent antibody structures.
The method of preparing the high affinity neutralizing antibodies of the invention involved the creation of a combinatorial library which was used to prepare clones producing antibodies comprising the beneficial CDRs of the invention that could then be screened for affinity for RSV epitopes (for Example,
The kinetics of interaction between high affinity anti-RSV Mabs and the RSV F protein was studied by surface plasmon resonance using a Pharmacia BIAcore™ biosensor. A recombinant baculovirus expressing a C-terminal truncated F protein provided an abundant source of antigen for kinetic studies. The supernatant, which contained the secreted F protein, was enriched approximately 20-fold by successive chromatography on concanavalin A and Q-sepharose columns. The pooled fractions were dialyzed against 10 mM sodium citrate (pH 5.5), and concentrated to approximately 0.1 mg/ml. In a typical experiment, an aliquot of the F-protein (100 ml) was amine-coupled to the BIAcore sensor chip. The amount immobilized gave approximately 2000 response units (Rmax) of signal when saturated with the mouse monoclonal antibodies H1129 or H1308F (prepared as in U.S. Pat. No. 5,824,307, whose disclosure is hereby incorporated by reference). This indicated that there was an equal number of “A” and “C” antigenic sites on the F-protein preparation following the coupling procedure. Two unrelated irrelevant Mabs (RVFV 4D4 and CMV H758) showed no interaction with the immobilized F protein. A typical kinetic study involved the injection of 35 ml of Mab at varying concentrations (25-300 nM) in PBS buffer containing 0.05% Tween-20 (PBS/Tween). The flow rate was maintained at 5 ml/min, giving a 7 min binding phase. Following the injection of Mab, the flow was exchanged with PBS/Tween buffer for 30 min for determining the rate of dissociation. The sensor chip was regenerated between cycles with a 2 min pulse of 10 mM HCl. The regeneration step caused a minimal loss of binding capacity of the immobilized F-protein (4% loss per cycle). This small decrease did not change the calculated values of the rate constants for binding and dissociation (also called the kon and koff, respectively).
More specifically, for measurement of kassoc (or kon), F protein was directly immobilized by the EDC/NHS method (EDC=N-ethyl-N′-[3-diethylamino-propyl]carbodiimide; NHS=N-hydroxysuccinimide) with the F-protein being injectedover the EDC/NHS activated sensor chip. Briefly, 4 μg/ml of F protein in 10 mM NaOAc, pH 4.0 was prepared and about a 30 μl injection gives about 500 RU (response units) of immobilized F protein under the above referenced conditions. The blank flow cell (VnR immobilized-CM dextran surface) was subtracted for kinetic analysis. The column could be regenerated using 100 mM HCl (with 72 seconds of contact time being required for full regeneration). This treatment removed bound Fab completely without damaging the immobilized antigen and could be used for over 40 regenerations. For kon measurements, Fab concentrations were 12.5 nM, 25 nM, 50 nM, 100 nM, 200 nM, and 400 nM. The dissociation phase was analyzed from 230 seconds (30 seconds after start of the dissociation phase) to 900 seconds. Kinetics were analyzed by 1:1 Langmuir fitting (global fitting). Measurements were done in HBS-EP buffer (10 mM HEPES, pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.005% (v/v) Surfactant P20.
For measurements of combinatorial clones, as disclosed herein, the kon and koff were measured separately. The kon was measured at conditions that were the same as those for the single mutation clones and was analyzed similarly.
For measuring kdissoc (or koff), the following conditions were employed. Briefly, 4100 RU of F protein were immobilized (as above) with CM-dextran used as the blank. Here, 3000 RU of Fab was bound (with dissociated Fab high enough to offset machine fluctuation). HBS plus 5 nM F protein (about 350-2000 times higher than the Kdissoc or Kd—the dissociation equilibrium constant) was used as buffer. The dissociation phase was 6-15 hours at a flow rate of 5 μl/min. Under the conditions used herein, re-binding of the dissociated Fab was minimal. For further details, see the manual with the biosensor.
The binding of the high affinity anti-RSV antibodies to the F protein, or other epitopic sites on RSV, disclosed herein was calculated from the ratio of the first order rate constant for dissociation to the second order rate constant for binding or association (Kd=kdiss/kassoc). The value for kassoc was calculated based on the following rate equation:
dR/dt=k assoc [Mab]R max−(k assoc [Mab]+k diss)R
where R and Rmax are the response units at time t and infinity, respectively. A plot of dr/dt as a function of R gives a slope of (kassoc[Mab]+kdiss)—Since these slopes are linearly related to the [Mab], the value kassoc can be derived from a replot of the slopes versus [Mab]. The slope of the new line is equal to kassoc. Although the value of kdiss can be extrapolated from the Y-intercept, a more accurate value was determined by direct measurement of kdiss. Following the injection phase of the Mab, PBS/Tween buffer flows across the sensor chip. From this point, [Mab]=0. The above stated equation for dR/dt thus reduces to:
dr/dt=k or dR/R=k diss dt
Integration of this equation then gives:
ln(R 0 /R t)=k diss t
where R0/Rt) are the response units at time 0 (start of dissociation phase) and t, respectively. Lastly, plotting ln(R0/Rt) as a function of t gives a slope of kdiss.
In the preferred embodiment herein, the numerical values from such antibody variants were as follows:
Summary of Kinetic Constants from
Ultra-high Affinity Antibodies.
1.13 × 105
1.62 × 10−6
6.98 × 1010
1.33 × 105
1.82 × 10−6
7.31 × 1010
1.10 × 105
1.35 × 10−6
8.15 × 1010
1.34 × 105
3.70 × 10−7
3.62 × 1011
1.22 × 105
3.03 × 10−7
4.03 × 1011
Here, the CDRs represent the amino acids replacing the reference amino acids at the key positions (or critical positions) of the CDRs shown in Table 1 (in bold and underlined) for a reference antibody. Thus, for example, clone 22 has an alanine at position 2 of CDR H1 (residue 32 of the heavy chain variable region—SEQ ID NO: 24) in place of the serine shown at that position in Table 1 (SEQ ID NO: 6), a phenylalanine at position 6 of CDR H3 (residue 105 of the heavy chain variable region—SEQ ID NO: 24) in place of the tryptophan shown at that position in Table 1 (SEQ ID NO: 8), a phenylalanine at position 3 of CDR L2 (residue 51 of the light chain variable region—SEQ ID NO: 23) in place of the serine shown at that position in Table 1 (SEQ ID NO: 4), and a phenylalanine at position 5 of CDR L3 (residue 92 of the light chain variable region —SEQ ID NO: 23) in place of the glycine shown at that position in Table 1 (SEQ ID NO: 5).
Of course, in forming such clones, Table 3 represents a pool of potential CDRs from which the high affinity CDRs of the antibodies of the present invention are to be drawn. For example, clone 23 of Table 4 uses the same CDRs as clone 22 with the exception of CDR L3, which has a tyrosine at position 5 of CDR L3 (Table 3—SEQ ID NO: 15) in place of the glycine shown in that position in Table 1 (SEQ ID NO: 5). The substitutions at the corresponding critical positions are likewise shown in Table 2.
Neutralization of the antibodies of the present invention were determined by microneutralization assay. This microneutralization assay is a modification of the procedures described by Anderson et al (1985). Antibody dilutions were made in triplicate using a 96-well plate. Ten TCID50 of respiratory syncytial virus (RSV—Long strain) were incubated with serial dilutions of the antibody (or Fabs) to be tested for 2 hours at 37° C. in the wells of a 96-well plate. RSV susceptible HEp-2 cells (2.5×104) were then added to each well and cultured for 5 days at 37° C. in 5% CO2. After 5 days, the medium was aspirated and cells were washed and fixed to the plates with 80% methanol and 20% PBS. RSV replication was then determined by F protein expression. Fixed cells were incubated with a biotin-conjugated anti-F protein monoclonal antibody (pan F protein, C-site-specific MAb 133-1H) washed and horseradish peroxidase conjugated avidin was added to the wells. The wells were washed again and turnover of substrate TMB (thionitrobenzoic acid) was measured at 450 nm. The neutralizing titer was expressed as the antibody concentration that caused at least 50% reduction in absorbency at 450 nm (the OD450) from virus-only control cells. Results for several antibodies of the present invention are shown by the graph in
|Patente citada||Fecha de presentación||Fecha de publicación||Solicitante||Título|
|US4517304||29 Jun 1981||14 May 1985||National Research Development Corporation||Production of viral antigens|
|US4526938||15 Abr 1983||2 Jul 1985||Imperial Chemical Industries Plc||Continuous release formulations|
|US4659563||27 Ene 1986||21 Abr 1987||Miles Laboratories, Inc.||High titer anti-respiratory syncytial virus intravenous immune globulin|
|US4717766||9 Mar 1987||5 Ene 1988||Miles Laboratories, Inc.||Method of preparing high titer anti-respiratory syncytial virus intravenous immune globulin|
|US4760026||17 Nov 1986||26 Jul 1988||Celltech Limited||Monoclonal antibody|
|US4800078||28 May 1987||24 Ene 1989||The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services||Immunotherapeutic method of treating respiratory disease by intranasal administration of Igb|
|US4853326||18 Nov 1986||1 Ago 1989||Cytogen Corporaton||Carbohydrate perturbations of viruses or viral antigens and utilization for diagnostic prophylactic and/or therapeutic applications|
|US4917893||30 Sep 1987||17 Abr 1990||Takeda Chemical Industries, Ltd.||Prolonged release microcapsules|
|US5071758||27 Ene 1989||10 Dic 1991||National Research Development Corporation||Production of cell strains capable of propagating respiratory syncytial virus, compositions containing such virus and their use in diagnosis of respiratory syncytial virus infection|
|US5128326||23 Jul 1990||7 Jul 1992||Biomatrix, Inc.||Drug delivery systems based on hyaluronans derivatives thereof and their salts and methods of producing same|
|US5137804||10 May 1988||11 Ago 1992||E. I. Du Pont De Nemours And Company||Assay device and immunoassay|
|US5149650||13 Jul 1988||22 Sep 1992||University Of North Carolina At Chapel Hill||Vaccines for human respiratory virus|
|US5183657||13 Mar 1989||2 Feb 1993||Celltech Limited||Antibodies for use in antilymphocyte antibody therapy|
|US5194595||31 Oct 1988||16 Mar 1993||The Upjohn Company||Chimeric glycoproteins containing immunogenic segments of the glycoproteins of human respiratory syncytial virus|
|US5219996||5 Sep 1988||15 Jun 1993||Celltech Limited||Recombinant antibodies and methods for their production in which surface residues are altered to cysteine residues for attachment of effector or receptor molecules|
|US5223254||20 Sep 1988||29 Jun 1993||Praxis Biologics, Inc.||Respiratory syncytial virus: vaccines|
|US5223409||1 Mar 1991||29 Jun 1993||Protein Engineering Corp.||Directed evolution of novel binding proteins|
|US5240694||19 Nov 1991||31 Ago 1993||University Of Virginia||Combined antiviral and antimediator treatment of common colds|
|US5271927||18 Mar 1993||21 Dic 1993||Celltech Limited||Antibody conjugates with macrocyclic ligands|
|US5279935||1 Mar 1990||18 Ene 1994||Becton, Dickinson And Company||Method of immunossay including deactivation of endogenous alkaline phosphatase|
|US5288630||20 Nov 1992||22 Feb 1994||The Upjohn Company||Expression system for RSV glycoprotein F and G|
|US5290540||1 May 1992||1 Mar 1994||Henry M. Jackson Foundation For The Advancement Of Military Medicine||Method for treating infectious respiratory diseases|
|US5332567||22 Mar 1993||26 Jul 1994||Immunomedics||Detection and treatment of infections with immunoconjugates|
|US5332805||29 Mar 1991||26 Jul 1994||Celltech Limited||Process for the recovery of recombinantly produced chymosin from insoluble aggregate|
|US5340926||5 Ago 1993||23 Ago 1994||Celltech, Limited||Process for the recovery of recombinantly produced protein from insoluble aggregate|
|US5354554||22 Ene 1992||11 Oct 1994||Celltech Limited||Crosslinked antibodies and processes for their preparation|
|US5391478||21 Feb 1992||21 Feb 1995||E. I. Du Pont De Nemours And Company||Assay device and immunoassay|
|US5403484||26 Ene 1993||4 Abr 1995||Protein Engineering Corporation||Viruses expressing chimeric binding proteins|
|US5411749||23 Dic 1992||2 May 1995||Systemix, Inc.||Human lymphoid tissue in an immunocompromised host|
|US5412077||4 Ago 1993||2 May 1995||Massachusetts Health Research Institute, Inc.||Effective antibody titers against respiratory viruses|
|US5418136||10 Jun 1993||23 May 1995||Biostar, Inc.||Devices for detection of an analyte based upon light interference|
|US5422097||26 Ago 1993||6 Jun 1995||University Of Virginia||Combined antiviral and antimediator treatment of common colds|
|US5424189||5 Mar 1993||13 Jun 1995||Kansas State University Research Foundation||Bovine respiratory syncytial virus detection and primers|
|US5468606||31 Jul 1992||21 Nov 1995||Biostar, Inc.||Devices for detection of an analyte based upon light interference|
|US5470736||28 Mar 1994||28 Nov 1995||The Salk Institute For Biological Studies||Transdominant negative proto-oncogene|
|US5476997||17 May 1994||19 Dic 1995||Systemix, Inc.||Extended human hematopoiesis in a heterologous host|
|US5484893||21 Jun 1993||16 Ene 1996||Celltech Limited||Tri-aza macrocycles and metal complexes thereof|
|US5496703||5 Oct 1993||5 Mar 1996||Cornell Research Foundation, Inc.||Indirect immunoassay for dioxinlike compounds|
|US5506209||26 May 1994||9 Abr 1996||Abbott Laboratories||Product for inhibition of infection of mammalian cells by respiratory syncytial virus|
|US5518725||9 Sep 1993||21 May 1996||University Of Utah Research Foundation||Vaccine compositions and method for induction of mucosal immune response via systemic vaccination|
|US5530102||15 May 1995||25 Jun 1996||Gristina; Anthony G.||Methods and compositions for the direct concentrated delivery of passive immunity|
|US5534411||28 Mar 1995||9 Jul 1996||Oravax, Inc.||Monoclonal IgA antibody specific for respiratory syncytial virus, a hybridoma cell line that produces this antibody amd methods of using the antibody to diagnose RSV infection|
|US5538733||7 Jul 1994||23 Jul 1996||Willmar Poultry Company, Inc.||Method of priming an immune response in a one-day old animal|
|US5538952||26 May 1994||23 Jul 1996||Abbott Laboratories||Inhibition of infection of mammalian cells by respiratory syncytial virus|
|US5571698||18 Jun 1993||5 Nov 1996||Protein Engineering Corporation||Directed evolution of novel binding proteins|
|US5585089||7 Jun 1995||17 Dic 1996||Protein Design Labs, Inc.||Humanized immunoglobulins|
|US5624821||7 Jun 1995||29 Abr 1997||Scotgen Biopharmaceuticals Incorporated||Antibodies with altered effector functions|
|US5648260||7 Jun 1995||15 Jul 1997||Scotgen Biopharmaceuticals Incorporated||DNA encoding antibodies with altered effector functions|
|US5667988||2 Sep 1994||16 Sep 1997||The Scripps Research Institute||Methods for producing antibody libraries using universal or randomized immunoglobulin light chains|
|US5679377||17 Jun 1994||21 Oct 1997||Alkermes Controlled Therapeutics, Inc.||Protein microspheres and methods of using them|
|US5693762||7 Jun 1995||2 Dic 1997||Protein Design Labs, Inc.||Humanized immunoglobulins|
|US5762905||16 Sep 1993||9 Jun 1998||The Scripps Research Institute||Human neutralizing monoclonal antibodies to respiratory syncytial virus|
|US5811524||7 Jun 1995||22 Sep 1998||Idec Pharmaceuticals Corporation||Neutralizing high affinity human monoclonal antibodies specific to RSV F-protein and methods for their manufacture and therapeutic use thereof|
|US5824307 *||15 Ago 1994||20 Oct 1998||Medimmune, Inc.||Human-murine chimeric antibodies against respiratory syncytial virus|
|US5840298 *||18 Abr 1996||24 Nov 1998||Idec Pharmaceuticals Corporation||Neutralizing high affinity human monoclonal antibodies specific to RSV F-protein and methods for their manufacture and therapeutic use thereof|
|US5855913||16 Ene 1997||5 Ene 1999||Massachusetts Instite Of Technology||Particles incorporating surfactants for pulmonary drug delivery|
|US5866125||18 Abr 1996||2 Feb 1999||Idec Pharmaceuticals Corporation||Neutralizing high affinity human monoclonal antibodies specific to RSV F-protein and methods for their manufacture and therapeutic use thereof|
|US5874064||29 Oct 1996||23 Feb 1999||Massachusetts Institute Of Technology||Aerodynamically light particles for pulmonary drug delivery|
|US5912015||7 Abr 1998||15 Jun 1999||Alkermes Controlled Therapeutics, Inc.||Modulated release from biocompatible polymers|
|US5916597||29 Ago 1996||29 Jun 1999||Alkermes Controlled Therapeutics, Inc.||Composition and method using solid-phase particles for sustained in vivo release of a biologically active agent|
|US5929212||3 Sep 1993||27 Jul 1999||Celltech Therapeutics Limited||CD3 specific recombinant antibody|
|US5934272||27 Oct 1995||10 Ago 1999||Aradigm Corporation||Device and method of creating aerosolized mist of respiratory drug|
|US5939068||18 Abr 1996||17 Ago 1999||Idec Pharmaceuticals Corporation|
|US5955364||18 Abr 1996||21 Sep 1999||Idec Pharmaceuticals Corporation|
|US5958765||19 Dic 1996||28 Sep 1999||Idec Pharmaceuticals Corporation|
|US5985309||17 Nov 1997||16 Nov 1999||Massachusetts Institute Of Technology||Preparation of particles for inhalation|
|US5985320||3 Mar 1997||16 Nov 1999||The Penn State Research Foundation||Materials and methods for enhancing cellular internalization|
|US5989463||24 Sep 1997||23 Nov 1999||Alkermes Controlled Therapeutics, Inc.||Methods for fabricating polymer-based controlled release devices|
|US6019968||16 Oct 1997||1 Feb 2000||Inhale Therapeutic Systems, Inc.||Dispersible antibody compositions and methods for their preparation and use|
|US6096551||16 Sep 1997||1 Ago 2000||The Scripps Research Institute||Methods for producing antibody libraries using universal or randomized immunoglobulin light chains|
|US6117980||21 Feb 1997||12 Sep 2000||Genentech, Inc.||Humanized anti-IL-8 monoclonal antibodies|
|US6121022||14 Abr 1995||19 Sep 2000||Genentech, Inc.||Altered polypeptides with increased half-life|
|US6194551||31 Mar 1999||27 Feb 2001||Genentech, Inc.||Polypeptide variants|
|US6277375||3 Mar 1997||21 Ago 2001||Board Of Regents, The University Of Texas System||Immunoglobulin-like domains with increased half-lives|
|US6413771||18 Jun 1999||2 Jul 2002||Idec Pharmaceuticals Corporation|
|US6519948||3 May 2001||18 Feb 2003||Ipv Inheidener Produktions-Und Vertriebagesellschaft Mbh||Insulated container|
|US6528624||31 Mar 1999||4 Mar 2003||Genentech, Inc.||Polypeptide variants|
|US6537809||20 Dic 2000||25 Mar 2003||Xenerex Biosciences|
|US6538124||3 Oct 2000||25 Mar 2003||Genentech, Inc.||Polypeptide variants|
|US6565849||2 Mar 2001||20 May 2003||Medimmune, Inc.||Methods of enhancing activity of vaccines and vaccine compositions|
|US6565888||23 Ago 2000||20 May 2003||Alkermes Controlled Therapeutics, Inc.||Methods and compositions for the targeted delivery of biologically active agents|
|US6572856||28 Nov 2000||3 Jun 2003||The University Of Virginia Patent Foundation||Methods for the prevention and treatment of cancer using anti-C3b(i) antibodies|
|US6656467 *||26 Ene 2001||2 Dic 2003||Medimmune, Inc.||Ultra high affinity neutralizing antibodies|
|US6685942||26 Ago 1997||3 Feb 2004||The Scripps Research Institute||Human neutralizing monoclonal antibodies to respiratory syncytial virus|
|US6737056||14 Ene 2000||18 May 2004||Genentech, Inc.||Polypeptide variants with altered effector function|
|US6818216||28 Nov 2001||16 Nov 2004||Medimmune, Inc.||Anti-RSV antibodies|
|US6855493||28 Nov 2001||15 Feb 2005||Medimmune, Inc.||Methods of administering/dosing anti-RSV antibodies for prophylaxis and treatment|
|US7083784||12 Dic 2001||1 Ago 2006||Medimmune, Inc.||Molecules with extended half-lives, compositions and uses thereof|
|US7132100||13 Jun 2003||7 Nov 2006||Medimmune, Inc.||Stabilized liquid anti-RSV antibody formulations|
|US7179900||31 Mar 2003||20 Feb 2007||Medimmune, Inc.||Methods of administering/dosing anti-RSV antibodies for prophylaxis and treatment|
|US7208162||3 May 2001||24 Abr 2007||Medimmune, Inc.||Combination therapy of respiratory diseases using antibodies and anti-inflammatory agents|
|US7229619||28 Nov 2000||12 Jun 2007||Medimmune, Inc.||Methods of administering/dosing anti-RSV antibodies for prophylaxis and treatment|
|US7294336||24 Feb 2006||13 Nov 2007||Medimmune, Inc.||Stabilized liquid anti-RSV antibody formulations|
|US7323172||8 Oct 2004||29 Ene 2008||Medimmune, Inc.||Methods of administering/dosing anti-RSV antibodies for prophylaxis and treatment|
|US7416726||13 Abr 2001||26 Ago 2008||The Rockefeller University||Enhancement of antibody-mediated immune responses|
|US7425618 *||13 Jun 2003||16 Sep 2008||Medimmune, Inc.||Stabilized anti-respiratory syncytial virus (RSV) antibody formulations|
|US7553489||20 Dic 2006||30 Jun 2009||Medimmune, Llc||Methods of administering/dosing anti-RSV antibodies for prophylaxis and treatment|
|US20010026798||2 Mar 2001||4 Oct 2001||Scott Koenig||Methods of enhancing activity of vaccines and vaccine compositions|
|US20010034062||9 Feb 2001||25 Oct 2001||Scott Koenig||Antibody gene therapy with adeno-associated viral vectors|
|US20020001798||20 Dic 2000||3 Ene 2002||Idec Pharmaceuticals Corporation|
|US20020004046||3 May 2001||10 Ene 2002||Johnson Leslie S.||Combination therapy of respiratory diseases using antibodies|
|US20020018780||25 May 2001||14 Feb 2002||Scott Koenig||Epitope-based vaccine for respiratory syncytial virus F-protein|
|US20020051787||3 May 2001||2 May 2002||Gregory Prince||Combination therapy of respiratory diseases using antibodies and anti-inflammatory agents|
|US20020098189||1 Mar 2001||25 Jul 2002||Young James F.||High potency recombinant antibodies and method for producing them|
|US20020102257||21 Sep 1998||1 Ago 2002||Leslie Sid Johnson||Human-murine chimeric antibodies against respiratory syncytial virus|
|US20020164326 *||26 Ene 2001||7 Nov 2002||Young James F.||Ultra high affinity neutralizing antibodies|
|US20040002587||20 Feb 2003||1 Ene 2004||Watkins Jeffry D.||Fc region variants|
|US20040005323||10 Mar 2003||8 Ene 2004||Idec Pharmaceuticals Corporation|
|US20040005324||30 Abr 2003||8 Ene 2004||Pilkington Glenn R.||Neutralizing monoclonal antibodies to respiratory syncytial virus|
|US20040076631||19 Dic 2002||22 Abr 2004||Peter Brams|
|US20040131609||8 Sep 2003||8 Jul 2004||Young James F.||Ultra high affinity neutralizing antibodies|
|US20050002926||26 Jul 2004||6 Ene 2005||Medimmune, Inc.||Methods of administering/dosing anti-RSV antibodies for prophylaxis and treatment|
|US20060099220||21 Sep 2005||11 May 2006||Medimmune, Inc.||Antibodies against and methods for producing vaccines for respiratory syncytial virus|
|US20060115485||31 Oct 2005||1 Jun 2006||Medimmune, Inc.||Methods of preventing and treating RSV infections and related conditions|
|US20060198840||3 Abr 2006||7 Sep 2006||Medimmune, Inc.||Molecules with extended half-lives, compositions and uses thereof|
|US20070122403||3 Ene 2007||31 May 2007||Medimmune, Inc.||Molecules with extended half-lives, compositions and uses thereof|
|US20070196916||20 Dic 2006||23 Ago 2007||Medimmune, Inc.||Methods of administering/dosing anti-RSV antibodies for prophylaxis and treatment|
|US20080286270||1 Oct 2007||20 Nov 2008||Medimmune, Inc.||Stabilized liquid anti-RSV antibody formulations|
|US20090175883||10 Mar 2008||9 Jul 2009||Medimmune, Inc.||Stabilized anti-respiratory syncytial virus (RSV) antibody formulations|
|AU713113B2||Título no disponible|
|AU2002219944B2||Título no disponible|
|CA2197684C||9 Ago 1995||31 Oct 2000||Leslie Sid Johnson||Human-murine chimeric antibodies against respiratory syncytial virus|
|EP0327378B1||3 Feb 1989||11 Dic 1996||The Trustees Of Columbia University In The City Of New York||Domain-modified constant region antibodies|
|EP0368684B2||13 Nov 1989||29 Sep 2004||Medical Research Council||Cloning immunoglobulin variable domain sequences.|
|EP0413622B1||2 Ago 1990||11 Feb 1998||Rhone-Poulenc Rorer S.A.||Albumin derivatives with therapeutic functions|
|EP0451216B1||28 Dic 1989||24 Ene 1996||Protein Design Labs, Inc.||Humanized immunoglobulins and their production and use|
|EP0671927B1||16 Sep 1993||15 Ene 2003||The Scripps Research Institute||Human neutralizing monoclonal antibodies to respiratory syncytial virus|
|EP0682040B1||28 Dic 1989||25 Ago 1999||Protein Design Labs, Inc.||Production of Humanized Immunoglobulins and Corresponding Polynucleotiodies|
|EP0699756B1||3 Ago 1995||17 Mar 2004||Bristol-Myers Squibb Company||Mutant BR96 antibodies reactive with human carcinomas|
|EP1265928B1||26 Ene 2001||21 Jul 2010||Medimmune, LLC||Ultra high affinity rsv neutralizing antibodies|
|FR2758331B1||Título no disponible|
|JPH01268646A||Título no disponible|
|WO2001055217A1 *||26 Ene 2001||2 Ago 2001||Medimmune Inc||Ultra high affinity neutralizing antibodies|
|1||Abbas et al., 1991. Cellular and Molecular Immunology- Chapter 3- Antibodies and Antigens, p. 45-47; W.B Saunders Company.|
|2||Abman et al., 1988, "Role of Respiratory Syncytial Virus in Early Hospitalizations for Respiratory Distress of Young Infants With Cystic Fibrosis", J Pediatr. 113(5):826-30.|
|3||Adams et al, 1998. Prolonged in vivo tumor retention of a human diabody targeting the extracellular domain of human HER2/neu, Br J Cancer; 77(9): 1405-12.|
|4||Adams et al., 1998. Increased affinity leads to improved selective tumor delivery of single-chain Fv antibodies, Cancer Res. 58(3):485-90.|
|5||American Academy of Pediatrics Committee on Infectious Diseases: Use of Ribavirin in the Treatment of Respiratory Syncytial Virus Infection. Pediatrics. Sep. 1993;92(3):501-4.|
|6||Ames et al., 1995. Conversion of murine Fabs isolated from a combinatorial phage display library to full length immunoglobulins. J. Immunol Methods.184(2):177-86.|
|7||Anderson et al., 1985, "Microneutralization test for respiratory syncytial virus based on an enzyme immunoassay," J. Clin. Microbiol. 22:1050-1052.|
|8||Arbiza et al., "Characterization of two antigenic sites recognized by neutralizing monoclonal antibodies directed against the fusion glycoprotein of human respiratory syncytial virus," J. Gen. Virol. 73: 2225-2234 (1992).|
|9||Balint et al., Gene 137, 109-118 (1993).|
|10||Barbas et al., "Selection and evolution of high-affinity human anti-viral antibodies," Trends Biotech. 14(7):230-234 (1996).|
|11||Beeler et al., 1989, "Neutralization Epitopes of the F Glycoprotein of Respiratory Syncytial Virus: Effect of Mutation Upon Fusion Function", J Virol. 63(7):2941-50.|
|12||Bennett et al., 2007, Immunopathogenesis of Respiratory Syncytial Virus Bronchiolitis, J Infect Dis; 195(10):1532-1540.|
|13||Bennett et al., 2007. Immunopathogenesis of Respiratory Syncytial Virus Bronchiolitis, JID, 195:1532-1540.|
|14||Bentley and Rabbits, 1980. Human immunoglobulin variable region genes— DNA Sequences of Two V Kappa Genes and a Pseudogene, Nature 288: 730-733.|
|15||Berzofsky and Berkower, 1993. In Paul, W.E., Fundamental Immunology (Raven Press), Chapter 8: Immunogenicity and antigen structure. p. 242.|
|16||Berzofsky and Berkower, 1993. In Paul, W.E., Fundamental Immunology (Raven Press), Chapter 9: Structure and Function of Immunoglobulins, p. 292-295.|
|17||Better et al., 1988. Escherichia coli secretion of an active chimeric antibody fragment. Science. 240(4855):1041-3.|
|18||Blake et al., "Automated Kinetic Exclusion Assays to Quantify Protein Binding Interactions in Homogeneous Solution," Analytical Biochemistry 272: 123-134 (1999).|
|19||Boder et al., 2000, "Directed evolution of antibody fragments with monovalent femtomolar antigen-binding affinity," Proc. Natl. Acad. Sci. U. S. A. 97(20):10701-5.|
|20||Boeckh et al., 2001, "Phase 1 Evaluation of the Respiratory Syncytial Virus-Specific Monoclonal Antibody Palivizumab in Recipients of Hematopoietic Stem Cell Transplants." J. of Infect. Dis. 184:350-354.|
|21||Boulianne et al., 1984. Production of functional chimaeric mouse/human antibody, Nature 312(5995):643-646.|
|22||Brinkmann et al., 1995. Phage display of disulfide-stabilized Fv fragments. J Immunol Methods. 182(1):4150.|
|23||Burton and Barbas, 1994. Human antibodies from combinatorial libraries. Adv. Immunol. 57:191-280.|
|24||Cao et al., 2003. Bispecific antibody conjugates in therapeutics; Adv Drug Deliv Rev. 55(2):171-97.|
|25||Carlsson et al., 1992. Human peripheral blood lymphocytes transplanted into SCID mice constitute an in vivo culture system exhibiting several parameters found in a normal humoral immune response and are a source of immunocytes for the production of human monoclonal antibodies. J Immunol. 1992; 148(4):1065-71.|
|26||Carson and Freimark, 1986. Human lymphocyte hybridomas and monoclonal antibodies, Adv. Immunol. 38:275-311.|
|27||Casset et al., 2003. A peptide mimetic of an anti-CD4 monoclonal antibody by rational design. Biochem Biophys Res Commun. 307(1):198-205.|
|28||Chamat et al., "Human Monoclonal Antibodies Isolated from Spontaneous Epstein-Barr Virus-Transformed Tumors of Hu-SPL-SCID Mice and Specific for Fusion Protein Display broad Neturalizing Activity Toward respiratory Syncytial Virus," The Journal of Infectious Diseases, 180:268-77 (1999).|
|29||Chamat et al., "Human Monoclonal Antibodies Isolated from Spontaneous Epstein-Barr Virus—Transformed Tumors of Hu-SPL-SCID Mice and Specific for Fusion Protein Display broad Neturalizing Activity Toward respiratory Syncytial Virus," The Journal of Infectious Diseases, 180:268-77 (1999).|
|30||Chanock et al., "Respiratory syncytial virus," Viral Infections of Humans, Epidemiology and Control, 3rd Evans, ed., A.S. Chapter 20:525-544 (1989).|
|31||Chmura et al., 2001, "Antibodies with infinite affinity." Proc. Natl. Acad. Sci. U.S.A. 98(15):8480-8484.|
|32||Chothia et al., 1998. Structural determinants in the sequences of immunoglobulin variable domain. J Mol Biol. 278(2):457-79.|
|33||Chowdhury et al., 2005, "Tailor-made antibody therapeutics." Methods 36: 11-24.|
|34||Cleek et al., 1997. Biodegradable Polymeric Carriers for a bFGF Antibody for Cardiovascular Application, Pro. Int'l Symp. Control. Rel Bioact. Mater. 24: 853-854.|
|35||Colman, 1994. Effects of amino acid sequence changes on antibody-antigen interactions; Res Immunol. 145(1):33-6.|
|36||Connors, 1990. Chemical Kinetics: The Study of Reaction Rates in Solution, p. 152.|
|37||Conrad et al., 1987, "Aerosolized ribavirin treatment of respiratory syncytial virus infection in infants hospitalized during an epidemic," Pediatr. Infect. Dis. J. 6(2):152-158.|
|38||Crowe et al., 1993, Recombinant human respiratory syncytial virus (RSV) monoclonal antibody Fab is effective therapeutically when introduced directly into the lungs of RSV-infected mice, Proc Natl Acad Sci USA; 91:1386-1390.|
|39||Crowe et al., 1994. Recombinant human respiratory syncytial virus (RSV) monoclonal antibody Fab is effective therapeutically when introduced directly into the lungs of RSV-infected mice, Proc. Natl. Acad. Sci. USA, 91:1386-1390.|
|40||Crowe et al., 1998, "Monoclonal antibody-resistant mutants selected with a respiratory syncytial virus-neutralizing human antibody fab fragment (Fab 19) define a unique epitope on the fusion (F) glycoprotein," Virology.252(2):373-5.|
|41||*||Cruse et al. Illustrated Dictionary of Immunology. 1995. Boca Raton: CRC Press, pp. 18-19.|
|42||Dall'Acqua Declatation (dated Oct. 3, 2005)—Filed in U.S. Appl. No. 10/202,354 (U.S. Patent No. 7,083,784) on Oct. 8, 2005.|
|43||Dall'Acqua, 2002, "Increasing the Affinity of a Human IgG1 for the Neonatal Fc Receptor: Biological Consequences." J. of Immunol. 169: 5171-5180.|
|44||David G. Myszka, "Survey of the 1998 Optical Biosensor Literature", Journal of Molecular Recognition, (1999).|
|45||De Vincenzo et al., 2005, Factors Predicting Childhood RespiratorySyncytial Virus Severity - What They Indicate About Pathogenesis, Ped Inf Dis; 24:S177-S183.|
|46||Delagrave et al., 1999, "Effects of humanization by variable domain resurfacing on the antiviral activity of a single-chain antibody against respiratory syncytial virus". Protein Eng. 12(4):357-62.|
|47||DeVincenzo, 2005. Factors Predicting Childhood Respiratory Syncytial Virus Severity. What They Indicate About Pathogenesis. The Pediatric Infectious Disease Journal, 24(11):S177-S183.|
|48||*||Dorland's Illustrated Medical Dictionary. 1994. 28th ed. Philadelphia: WB Saunders. p. 874.|
|49||Downham et al., 1976. Breast-feeding protects against respiratory syncytial virus infections. Br Med J. 2(6030):274-6.|
|50||Duenas, et al., "In vitro Immunization of Naive Human B cells Yields High Affinity Immunoglobulin G Antibodies as Illustrated by Phage Display", pp. 1-7, Blackwell Science Ltd., (1996).|
|51||Duenas, et al., "Selection of Phage Displayed Antibodies Based on Kinetic Constants", vol. 33, No. 3, pp. 279-285 (1996).|
|52||Edelman et al., 1969. The Covalent Structure of an Entire gammaG Immunoglobulin Molecule. PNAS 63:78-85.|
|53||Egan et al, Drug Res. 49 (II), 779-790 (1999).|
|54||EP Serial No. 01903352 (EP 1265928) - Examination Report dated Aug. 10, 2009.|
|55||EP Serial No. 01903352 (EP 1265928) - Examination Report dated May 12, 2006.|
|56||EP Serial No. 01903352 (EP 1265928) - Examination Report dated Sep. 25, 2007.|
|57||EP Serial No. 01903352 (EP 1265928) - Interview Summary dated Aug. 3, 2009.|
|58||EP Serial No. 01903352 (EP 1265928) - Response to Examination Report dated Apr. 7, 2008.|
|59||EP Serial No. 01903352 (EP 1265928) - Response to Examination Report dated Jul. 10. 2009.|
|60||EP Serial No. 01903352 (EP 1265928) - Response to Examination Report dated Nov. 17, 2006.|
|61||EP Serial No. 01903352 (EP 1265928) - Response to Examination Report dated Oct. 20, 2009.|
|62||EP Serial No. 01903352 (EP 1265928) - Summons to Oral Proceedings and Preliminary Opinion dated Apr. 3, 2009.|
|63||Evans et al., eds., 1989, Viral Infections of Humans: Epidemiology and Control, 3rd ed., Plenum Medical Book, New York, pp. 525-544.|
|64||Everitt, et al., "The Pharmacokinetics, Antigenicity, and Fusion-Inhibition Activity of RSHZ19, a Humanized Monoclonal Antibody to Respiratory Syncytial Virus, in Healthy Volunteers," The Journal of Infectious Diseases, (1996).|
|65||Fahy and O'Byrne, 2001. Reactive Airways Disease. Am J Respir Crit Care Med. 163(4):822-3.|
|66||Falsey et al., 1991, "Noninfluence Respiratory Virus Infection in Long-Term Care Facilities", Infect Control Hosp Epidemiol. 12(10):602-8.|
|67||Feigen et al., 1987, Textbook of Pediatric Infectious Diseases, WB Saunders, Philadelphia, pp. 1653-1675.|
|68||Fields et al., 1990, Fields Virology, 2nd Ed., vol. 1, Raven Press, NY p. 1045-1072.|
|69||Fields et al., 1996, "Crystal Structure of the V-alpha domain of a T cell antigen receptor," Immunotechnology 2(4):270.|
|70||Foecking and Hofstetter, 1986. Powerful and versatile enhancer-promoter unit for mammalian expression vectors. Gene. 45:101-105.|
|71||Foote, et al., "Kinetic and Affinity Limits on Antibodies Produced During Immune Response," Proc. Nat'l. Acad. Science USA, vol. 92, pp. 1254-1256 (Feb. 1995).|
|72||Foote, et al., "Kinetic Maturation of an Immune Response", Nature, vol. 352, (Aug. 8, 1991).|
|73||Garcia-Barreno, B. et al., "Marked Differences in the Antigenic Structure of Human Respiratory Syncytial Virus F and G Glycoproteins," J. Virology. 925-932 (1989).|
|74||Garvie and Gray, 1980. Outbreak of Respiratory Syncytial Virus Infection in the Elderly, Br Med J. 281(6250):1253-4.|
|75||Gilchrist, et al. 1994 "National surveillance for respiratory syncytial virus, United States, 1985-1990," J. Infect. Dis. 170:986-990.|
|76||Gillies et al., 1989. High-level expression of chimeric antibodies using adapted cDNA variable region cassettes. J. Immunol Methods. 125:191-202.|
|77||Glaser, et al., "Antibody Engineering by Codon-Based Mutagenesis in a Filamentous Phage Vector System," The Journal of Immunology, vol. 149, pp. 3903-3913 (Dec. 1992).|
|78||Glezen et al., 1981, "Risk of Respiratory Syncytial Virus Infection for Infants From Low-Income Families in Relationship to Age, Sex, Ethnic Group, and Maternal Antibody Level", J Pediatr. 98(5):708-15.|
|79||*||Greenspan et al. Nature Biotechnology. 1999; 7:936-937.|
|80||Groothuis et al., 1988, "Respiratory Syncytial Virus Infection in Children with Bronchopulmonary Dysplasia", Pediatrics. 82(2):199-203.|
|81||Groothuis et al., 1993, "Prophylactic Administration of Respiratory Syncytial Virus Immune Globulin to High-risk Infants and Young Children", The Respiratory Syncytial Virus Immune Globulin Study Group. N Engl J Med. 329(21):1524-30.|
|82||*||Groves et al. Hybridoma. 1987; 6: 71-76.|
|83||Hacking et al., 2002, "Respiratory syncytial virus-viral biology and the host response," J. Infection 45:18-24.|
|84||Hacking et al., 2002, "Respiratory syncytial virus—viral biology and the host response," J. Infection 45:18-24.|
|85||Hall et al., 1975, "Nosocomial respiratory syncytial virus infections," N. Engl. J. Med. 293(26):1343-1346.|
|86||Hall et al., 1979, "Neonatal Respiratory Syncytial Virus Infection", N Engl J Med. 300(8):393-6.|
|87||Hall et al., 1983, "Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection. A randomized double-blind study," N. Engl. J. Med. 308(24):1443-1447.|
|88||Hall et al., 1985, "Ribavarin treatment of respiratory syncytial viral infection in infants with underlying cardiopulmonary disease," JAMA 254(21):3047-3051.|
|89||Hall et al., eds., 1995, Principles and Practice of Infectious Diseases 4th ed., Churchill Livingstone, New York, pp. 1501-1519.|
|90||Hall, 1987, "Respiratory syncytial virus", Textbook of Pediatric Infectious Diseases, Feigin and Cherry, eds., WB Saunders, Philadelphia, 1653-1676.|
|91||Hall, C.B., 1993, Respiratory Syncytial: What We Know Now, Contemp. Pediatrics, 10: 92-110.|
|92||Hammerling et al., 1981. Production of Antibody-Producing Hybridomas in the Rodent Systems, in Monoclonal antibodies and T-cell hybridomas, Elsevier, NY. p. 563-587.|
|93||*||Haynes et al. Journal of Virology. 2002; 76 (14): 6873-6881.|
|94||Heard et al., "Two Neutralizing Human Anti-RSV Antibodies: Cloning, Expression, and Characterization," Molecular Medicine 5:35-45 (1999).|
|95||Heard et al., 1999, "Two neutralizing human RSV antibodies: cloning, expression, and characterization," Mol. Med. 5:35-45.|
|96||Hefta et al, 1998, "Kinetic and affinity constants of epitope specific anti-carcinembryonic antigen (CEA) monoclonal antibodies for CEA and engineered CEA domain constructs," Immunotechnology 4:49-57.|
|97||Hellstrom et al., 1987. Antibodies for drug delivery, in Controlled Drug Delivery, Fundamentals and Applications 2nd edition. Chapter 15: p. 623-653.|
|98||Hemming et al., 1985, "Studies of Passive Immunotherapy for Infections of Respiratory Syncytial Virus in the Respiratory Tract of a Primate Model", J Infect Dis. 152(5):1083-7.|
|99||Hemming et al., 1986, "Immunoglobulins in respiratory syncytial virus infections," Clinical Use of Intravenous Immunoglobulins, Morell and Nydegger., eds., Academic Press, London, pp. 285-294.|
|100||Hemming et al., 1988, Topically Administered Immunoglobulin Reduces PulmonaryRespiratory Syncytial Virus Shedding in Owl Monkeys, Antimicrob Agents Chemother; 32(8):1269-1270.|
|101||Hemming et al., 1988. Topically Administered Immunoglobulin Reduces Pulmonary Respiratory Syncytial Virus Shedding in Owl Monkeys, Antimicrobial Agents and Chemotherapy, 32(8):1269-1270.|
|102||Henderson et al., 1979, "Respiratory Syncytial Virus Infections, Reinfections and Immunity. A Prospective, Longitudinal Study in Young Children", N Engl J Med. 300(10):530-4.|
|103||Hertz et al., 1989, "Respiratory Syncytial Virus-Induced Acute Lung Injury in Adult Patients With Bone Marrow Transplants: a Clinical Approach and Review of the Literature", Medicine (Baltimore). 68(5):269-81.|
|104||Howard et al., 1989. Intracerebral Drug Delivery in Rats with Lesion-Induced Memory Deficits, J Neurosurg. 71(1):105-12.|
|105||Hudson and Souriau, 2003. Engineered Antibodies. Nature Medicine 9(1):129-34.|
|106||Ichiyoshi et al., 1995. A human anti-insulin IgG autoantibody apparently arises through clonal selection from an insulin-specific "germ-line" natural antibody template. Analysis by V gene segment reassortment and site-directed mutagenesis, J. Immunol. 154(1):226-38.|
|107||Ifverson and Borrebaeck, 1996. SCID-hu-PBL: A model for making human antibodies? Semin Immunol. 8(4):243-8.|
|108||International Preliminary Examination Report for WO 01/555217 (including Annex) dated Apr. 10, 2002.|
|109||International Search Report for WO 01/555217 dated Jun. 6, 2001.|
|110||Jackson et al 1998. Antigen specificity and tumour targeting efficiency of a human carcinoembryonic antigen-specific scFv and affinity-matured derivatives, Br. J. Cancer 78(2):181-8.|
|111||Johnson et al., 1987. The G Glycoprotein of Human Respiratory Syncytial Viruses of Subgroups A and B: Extensive Sequence Divergence Between Antigenically Related Proteins, Proc Natl Acad Sci U S A.|
|112||Johnson et al., 1991. Development of humanized monoclonal antibodies which neutralize respiratory syncytial virus. J. Cellular Biochem. Suppl. 15E. P.120, Abstract No. 108.|
|113||*||Johnson et al., J of Infectious Dis. 1999 vol. 180, pp. 35-40.|
|114||*||Johnson et al., Journal of Infectious Diseases 1999, vol. 180, pp. 35-40.|
|115||Johnson, et al., "A Direct Comparison of the Activities of Two Humanized Respiratory Syncytal Virus Monoclonal Antibodies: MEDI-493 and RSHZ19," The Journal of Infectious Diseases, Vo. 180, No. 1 (Jul. 1999).|
|116||Johnson, et al., "Development of a Humanized Monoclonal Antibody (MEDI-493) with Potent InVitro and InVivo Activity against Respiratory Syncytial Virus," The Journal of Infectious Diseases, vol. 176, No. 5 (Nov. 1997).|
|117||Kapikian et al., 1969. An Epidemiologic Study of Altered Clinical Reactivity to Respiratory Syncytial (RS) Virus Infection in Children Previously Vaccinated With an Inactivated RS Virus Vaccine, Am J Epidemiol. 89(4):405-21.|
|118||Karlsson, et al., "Experimental Design for Kinetic Analysis of Protein-Protein Interactions with Surface Plasmon Resonance Biosensors," The Journal of Immunological Methods, (1997).|
|119||Karlsson, et al., "Experimental Design for Kinetic Analysis of Protein—Protein Interactions with Surface Plasmon Resonance Biosensors," The Journal of Immunological Methods, (1997).|
|120||Kettleborough et al., 1994. Isolation of tumor cell-specific single-chain Fv from immunized mice using phage-antibody libraries and the re-construction of whole antibodies from these antibody fragments. Eur J Immunol. 24(4):952-8.|
|121||*||Kevin Shreder, Synthetic Haptens as Probes of Antibody Response and Immunorecognition, Methodsvol. 20, Issue 3, , Mar. 2000, pp. 372-379.|
|122||*||Kevin Shreder, Synthetic Haptens as Probes of Antibody Response and Immunorecognition, MethodsVolume 20, Issue 3 Mar. 2000, pp. 372-379.|
|123||Kim et al., 1969, "Respiratory Syncytial Virus Disease in Infants Despite Prior Administration of Antigenic Inactivated Vaccine", Am J Epidemiol. 89(4):422-34.|
|124||Knappik, et al., "Fully Synthetic Human Combinatorial Antibody Libraries (HuCAL) Based on Modular Consensus Frameworks and CDRs Randomized with Trinucleotides", Academic Press, pp. 57-86, (2000).|
|125||Krishnan et al., 2008, Therapeutic addition of motavizumab, a monoclonal antibody against respiratory syncytial virus (RSV), modulates epithelial cell responses to RSV infection., Annual Interscience Conf Antimicrobial Agents Chemotherapy/Annual Meed Infect Dis Soc Am; 48/46 Oct. 28 Abstract V-4147.|
|126||Kudo et al., 1992. New strategies to establish human monoclonal antibodies; Tohoku J Exp Med. 168(2):323-327.|
|127||Kudo et al., 1993. Production of a human monoclonal antibody to a synthetic peptide by active in vivo immunization using a SCID mouse grafted with human lymphocytes; Tohoku J Exp Med. 171:327-338.|
|128||Kunkel et al., 1987, "Rapid and efficient site-specific mutagenesis without phenotypic selection," Methods Enzymol. 154:367-382.|
|129||Lagos et al., 2005, Administration of the anti-RSV monoclonal antibody (Mab) Numax™ is associated with a reduction in upper airway (UA) RSV load, World Congress Pediatr Infect Disease; Sep. 1-4.|
|130||Lam et al., 1997, "Microencapsulation of Recombinant Humanized Monoclonal Antibody for Local Delivery", Proc. Int'l. Symp. Control Rel. Bioact. Mater. 24:759-760.|
|131||Lamprecht et al., 1976, "Role of Maternal Antibody in Pneumonia and Bronchiolitis Due to Respiratory Syncytial Virus", J Infect Dis. 134(3):211-7.|
|132||Landry et al., "Evaluation of reconstituted lyophilized palivizumab given intravenously at 15 and 30 mg/kg," Poster Session, Tuesday, Infect. Dis. 166A: 969.|
|133||Langer and Peppas, 1983. Chemical and physical structure of polymers as carriers for controlled release of bioactive agents: A review. J Macromol. Sci.- Rev. Macromol. Chem. Phys.C23(1):61-126.|
|134||Langer, 1990. New methods of drug delivery. Science. 249:1527-1533.|
|135||Lee et al., 1998. Demonstration of IgM antibodies of high affinity within the anti-Galalphal-3Gal antibody repertoire. Transplantation; 66(8):1117-9.|
|136||Levy et al., 1985. Inhibition of Calcification of Bioprosthetic Heart Valves by Local Controlled-release Diphosphonate, Science. 228(4696):190-2.|
|137||Liu et al., 1987. Expression of mouse::human immunoglobulin heavy-chain cDNA in lymphoid cells, Gene 54(1):33-40.|
|138||LoBuglio et al., 1989, "Mouse/human chimeric monoclonal antibody in man: kinetics and immune response," Proc. Natl. Acad. Sci. USA 86(11):4220-4224.|
|139||Lonberg and Huszar, 1995. Human antibodies from transgenic mice. Int. Rev. Immunol. 13:65-96.|
|140||Love et al, Biochemistry 32, 10950-10959 (1993).|
|141||Maccallum et al., 1996. Antibody-antigen interactions: contact analysis and binding site topography. J Mol Biol. 262(5):732-45.|
|142||MacDonald et al., 1982, "Repiratory Syncytial Viral Infection in Infants With Congenital Heart Disease", N Engl J Med. 307(7):397-400.|
|143||Malley et al., 1998, "Reduction of Respiratory Syncytial Virus (RSV) in Tracheal Aspirates in Intubated Infants by Use of Humanized Monoclonal Antibody to RSV F Protein." J. of Infect. Dis. 178:1555-1561.|
|144||Marks et al., 1992, "By-passing immunization: building high affinity human antibodies by chain shuffling," Biotechnology (N Y) 10(7):779-83.|
|145||Maynard et al., 2002. Protection against anthrax toxin by recombinant antibody fragments correlates with antigen affinity, Nat. Biotechnol. 20(6):597-601.|
|146||McArthur-Vaughan et al., 2002, "A rhesus monkey model of respiratory syncytial virus infection," J. Med. Primatol. 31(2):61-73.|
|147||McCall et al., 1999. Isolation and characterization of an anti-CD 16 single-chain Fv fragment and construction of an anti-HER2/neu/anti-CD16 bispecific scFv that triggers CD16-dependent tumor cytolysis. Mol Immunol. May 1999;36(7):433-45.|
|148||Medimmune, Inc. (MEDI) Release: Numax achieves primary endopoint in preliminary analysis of data from comparative phase 3 trial with Synagis (Nov. 6, 2006) BioSpace Beat, biospace.com (www.biospace.com/news-story.aspx?StoryID=36114&full=1).|
|149||Medimmune, Inc. (MEDI) Release: Numax achieves primary endopoint in preliminary analysis of data from comparative phase 3 trial with Synagis (Nov. 6, 2006) BioSpace Beat, biospace.com (www.biospace.com/news—story.aspx?StoryID=36114&full=1).|
|150||MedImmune, Inc. Annual Report (2001).|
|151||Medimmune, Inc., 1999, "SYNAGIS(TM). package insert", revised Dec. 2, 1999.|
|152||Medimmune, Inc., 1999, "SYNAGIS™. package insert", revised Dec. 2, 1999.|
|153||Medimmune, Inc.'s (MEDI) phase I Numax study shows potential to reduce RSV disease in upper airway of children. (Sep. 1, 2005) BioSpace Beat, Biospace.com (www.biospace.com/news-story.aspx?StoryID=21014020).|
|154||Medimmune, Inc.'s (MEDI) phase I Numax study shows potential to reduce RSV disease in upper airway of children. (Sep. 1, 2005) BioSpace Beat, Biospace.com (www.biospace.com/news—story.aspx?StoryID=21014020).|
|155||Medimmune, SYNAGIS(TM), 2002, package insert, revised Oct. 23, 2002.|
|156||Medimmune, SYNAGIS™, 2002, package insert, revised Oct. 23, 2002.|
|157||Meissner et al., "Safety and Pharmacokinetics of an Intramuscular Monoclonal Antibody (SB 209763) Against Respiratory Syncytial Virus (RSV) in Infants and Young Children at Risk for Severe RSV Disease", Antimicrob Agents Chemother 43:1183-1188 (1999).|
|158||Mejias et al., 2005. Comparative Effects of Two Neutralizing Anti-Respiratory Syncytial Virus (RSV) Monoclonal Antibodies in the RSV Murine Model: Time versus Potency, Antimicrobial Agents and Chemotherapy vol. 49, No. 11: 4700-4707.|
|159||Mejias et al., 2005. Respiratory syncytial virus infections: Old challenges and new opportunities, Ped. Infect. Dis. J. 24: S189-S197.|
|160||Morrison et al., 1984. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains, Proc. Natl. Acad. Sci. USA 81(21):6851-6855.|
|161||Morrison et al., 1985. Transfectomas provide novel chimeric antibodies, Science 229(4719):1202-1207.|
|162||Motavizumab vs. palivizumab for RSV infections in infants (Nov. 11, 2006) Inpharma vol. 1 No. 1563, p. 5.|
|163||Mullinax et al., 1992. Expression of a heterodimeric Fab antibody protein in one cloning step. Bio Techniques. 12:864-869.|
|164||Murphy et al., 1988, "Passive Transfer of Respiratory Syncytial Virus (RSV) Antiserum Suppressed The Immune Response to the RSV Fusion (F) and Large (G) Glycoproteins Expressed By Recombinant Vaccinia Viruses", J Virol. 62(10):3907-10.|
|165||Murphy et al., 1991, "Effect of Passive Antibody on the Immune Response of Cotton Rats to Purified F and G HG Glycoproteins of Respiratory Syncytial Virus (RSV)", Vaccine. 9(3):185-9.|
|166||Murphy et al., 1994. An Update on Approaches to the Development of Respiratory Syncytial Virus (RSV) and Paraintluenza Virus Type 3 (PIV3) Vaccines, Virus Res. 32(1):13-36.|
|167||Myszka, et al., "Kinetic Analysis of a Protein Antigen-Antibody Interaction Limited by Mass Transport on an Optical Biosensor", Elsevier Science, pp. 127-137 (1997).|
|168||Navas et al., 1992 , "Improved Outcome of Respiratory Syncytial Virus Infection in a High-Risk Hospitalized Population of Canadian children. Pediatric Investigators Collaborative Network on Infections in Canada", J Pediatr. 121(3):348-54.|
|169||Newman, et al., "Primatization" of Recombinant Antibodies for Immunotherapy of Human Diseases: A Macaque/Hunab Chimeric Antibody Against Human CD4, vol. 10, pp. 1455-1460, Nov. 1992.|
|170||Nguyen et al., 2000 "Efficient generation of respiratory syncytial virus (RSV)-neutralizing human MoAbs via human peripheral blood lymphocyte (hu-PBL)-SCID mice and scFv phage display libraries," Clin. Exp. Immunol. 122:85-93.|
|171||Ning et al., 1996. Intratumoral Radioimmunotherapy of a Human Colon Cancer Xenograft Using a Sustained Release Gel, Radiotherapy and Oncology 39: 179-89.|
|172||O'Byrne and Postma, 1999. The Many Faces of Airway Inflammation. Am J Respir Crit Care Med. May 1999;159(5 Pt 2):S41-63.|
|173||Ogra et al., 1988. Respiratory Syncytial Virus Infection and the Immunocompromised Host, Pediatr Infect Dis J. Apr. 1988;7(4):246-9.|
|174||Orkin and Motulsky, Report and recommendations of the panel to assess the NIH investment in research on gene therapy, available from http://www.nih.gov/news/panelrep.html (1995).|
|175||Padlan, 1991. A possible procedure for reducing the immunogenicity of antibody variable domains while preserving their ligand-binding properties. Mol. Immunol. 28(4/5):489-498.|
|176||Palomo et al., "Induction of a Neutralizing Immune Response to Human Respiratory Syncytial Virus with Anti-Idiotypic Antibodies" J. Virology 64(9):4199-4206 (1990).|
|177||Persic et al., 1997. An integrated vector system for the eukaryotic expression of antibodies or their fragments after selection from phage display libraries. Gene. 187(1):9-18.|
|178||Physician's Desk Reference, 2001, 55th ed. p. 1863-1864.|
|179||Pohl et al., 1992. Respiratory Syncytial Virus Infections in Pediatric Liver Transplant Recipients, J Infect Dis. 165(1):166-9.|
|180||Press et al., 1970. The Amino Acid Sequences of the Fd Fragments of Two Human Gamma-1 Heavy chains, Biochem J. I 17(4):641-60.|
|181||Prince (2001) "An update of respiratory syncytial virus antiviral agents." Expert Opin Investig Drugs. 10(2):297-308.|
|182||Prince et al., 1983, "Mechanisms of Immunity to Respiratory Syncytial Virus in Cotton Rats", Infect Immun. 42(1):81-7.|
|183||Prince et al., 1985, "Immunoprophylaxis and Immunotherapy of Respiratory Syncytial Virus Infection in the Cotton rat", Virus Res. 3(3):193-206.|
|184||Prince et al., 1987, Effectiveness of Topically Administered Neutralizing Antibodies inExperimental Immunotherapy of Respiratory Syncytial Virus Infection in Cotton Rats, J Virol; 61(6):1851-1854.|
|185||Prince et al., 1987. Effectiveness of Topically Administered Neutralizing Antibodies in Experimental Immunotherapy of Respiratory Syncytial Virus Infection in Cotton Rats, Journal of Virology, 61(6);1851-1854.|
|186||Prince et al., 1990, "Mechanism of Antibody-mediated Viral Clearance in Immunotherapy of Respiratory Syncytial Virus Infection of Cotton Rats", J Virol. 64(6):3091-2.|
|187||Prince et al., 2000, "Treatment of Respiratory Syncytial Virus Bronchiolitis and Pneumonia in a Cotton Rat Model with Systematically Administered Monoclonal Antibody (Palivizumab) and Glucocorticosteroid," J Inf Diseases 182:1326-1330.|
|188||Prince, 1975, "The Pathogenesis of Respiratory Syncytial Virus Infection in Infant Ferrets" Ph.D. Dissertation, University of California-Los Angeles.|
|189||Prince, et al., "Quantitative Aspects of Passive Immunity to Respiratory Syncytkal Virus Infection in Infant Cotton Rats," Journal of Virology, pp. 517-520, vol. 55, No. 3 (1985).|
|190||Prince, et al., "Treatment of Parainfluenza Virus Type 3 Bronchiolitis and Pneumonia in a Cotton Rat Model Using Topical Antibody and Glucocorticosteroid," The Journal of Infectious Diseases, pp. 598-608 (1996).|
|191||Raman, et al., "Diffusion-Limited Rates for Monoclonal Antibody Binding to Cytochrome," Biochemistry (1992).|
|192||Richter et al., 2008, Respiratory syncytial virus (RSV) therapy utilizing intranasally delivered motavizumab, a monoclonal antibody against F protein, Annual Interscience Conf Antimicrobial Agents Chemotherapy/Annual Meed Infect Dis Soc Am; 48/46 Oct. 28 Abstract V-4145.|
|193||Riechmann et al., 1988. Reshaping human antibodies for therapy. Nature. 332(6162):323-7.|
|194||Roguska et al., "Humanization of murine monoclonal antibodies through variable domain resurfacing," Proc. Natl. Acad. Sci. U.S.A. 91(3):969-973 (1994).|
|195||Roost, et al., "Early High-Affinity Neutralizing Anti-Viral IgG Responses Without Further Overall Improvements of Affinity," Proc. Nat'l. Acad. Sci. USA, vol. 92, pp. 1257-1261 (Feb. 1995).|
|196||Rosok, et al., "A Combinatorial Library Strategy for the Rapid Humanization of Anticarcinoma BR 96 Fab," The Journal of Biological Chemistry, vol. 271, No. 27 pp. 22611-22618 (Sep. 1995).|
|197||*||Rudikoff et al. Proc Natl Acad Sci USA. 1982; 79: 1979-1983.|
|198||Ruther and Muller-Hill, 1983. Easy identification of cDNA clones. EMBO J. 2:1791-1794.|
|199||Ruuskanen et al., 1993. Respiratory syncytial virus, Curr Probl Pediatr. 23(2):50-79.|
|200||Saez-Llorens et al., 1997, "Phase I/II open label multi dose escalation trial of a humanized respiratory syncytial virus (RSV) monoclonal antibody (Medi-493) administered intramuscularly (IM) in high risk children," Abstract in Non HIV virology, ICAAC Toronto.|
|201||Saez-Llorens et al., 1998, "Safety and Pharmacokinetics of an Intramuscular Humanized Monoclonal Antibody to Respiratory Syncytial Virus in Premature infants, and infants with Bronchopulmonary Dysplasia", The MEDI-493 Study Group, Pediatric Infect Dis J. 17(9):787-91.|
|202||Sahagan et al., 1986, "A genetically engineered murine/human chimeric antibody retains specificity for human tumor-associated antigen," J. Immunol. 137(3):1066-1074.|
|203||Sakurai et al., 1999, "Human antibody responses to mature and immature forms of viral envelope in respiratory syncytial virus infection: significance for submit vaccines." J. Virol. 73(4):2956-2962.|
|204||Saudek et al., 1989. A Preliminary Trial of the Programmable Implantable Medication System for Insulin Delivery. N. Engl J Med. 321(9):574-9.|
|205||Schier et al.,. 1996, "Isolation of high-affinity monomeric human anti-c-erbB-2 single chain Fv using affinity-driven selection." J Mol Biol. 255(1):28-43.|
|206||Schier, et al., Isolation of Picomolar Affinity Anti-c-erbB-2 Single-chain Fv by Molecular Evolution of the Complementarity Determining Regions . . . :, Academic Press Limited, pp. 551-567 (1996).|
|207||Scott et al., 1985. Cellular reactivity to respiratory syncytial virus in human colostrum and breast milk. J Med Virol. 17(1):83-93.|
|208||Seaver, 1994. Monoclonal antibodies in industry: More difficult than originally thought; Genetic Engineering News, vol. 14, No. 14, p. 10 and 21.|
|209||Sefton, 1987. Implantable Pumps, CRC Crit. Rev. Biomed. Eng. 14:201-240.|
|210||*||Sequence alignment of SEQ ID No. 12 with Geneseq database. Accession No. AAW70933. entry date: Oct. 1998 from patent No. FR2758331-A1 of Bourgeois et al.|
|211||Sevier et al., 1981. Monoclonal antibodies in clinical immunology. Clin Chem. 27(11):1797-806.|
|212||Smith et al., 1991, "A Controlled Trial of Aerosolized Ribavirin in Infants Receiving Mechanical Ventilation for Severe Respiratory Syncytial Virus Infection", N Engl J Med. 325(1):24-9.|
|213||Song et al., 1995. Antibody Mediated Lung Targeting of Long-Circulating Emulsions, PDA Journal of Pharmaceutical Science & Technology 50: 372-77.|
|214||Sorbera et al., 1998, "Palivizumab," Drugs Data Report 20:702-703.|
|215||Sorbera et al., 1998, "Palivizumab," Drugs of the Future 23:970-976.|
|216||Steplewski et al., 1988, "Biological activity of human-mouse IgG1, IgG2, IgG3, and IgG4 chimeric monoclonal antibodies with antitumor specificty," Proc. Natl. Acad. Sci. USA 85(13):4852-4856.|
|217||Stott et al., 1984. The characterization and uses of monoclonal antibodies to respiratory syncytial virus. Dev Biol Stand. 57:237-44.|
|218||Studnicka et al., 1994. Human-engineered monoclonal antibodies retain full specific binding activity by preserving non-CDR complementarity-modulating residues. Protein Eng. 7:805-814.|
|219||Subramanian et al., "Safety, Tolerance and Pharmacokinetics of a Humanized Monoclonal Antibody to Respiratory Syncytial Virus in Premature Infants and Infants with Bronchopulmonary Dysplasia", Pediatric Infect Dis J. 17:110-115.|
|220||Subramanian et al., 1997, "Randomized double blind placebo controlled dose escalation trial of a humanized repiratory syncytial virus monoclonal antibody in high risk infants," Poster session infect. dis. 130A:768.|
|221||Sun et al., 1987, "Chimeric antibody with human constant regions and mouse variable regions directed against carcinoma-associated antigen 17-1A," Proc. Natl. Acad. Sci. USA 84(1):214-218.|
|222||Takahashi et al. 1984. Rearranged immunoglobulin heavy chain variable region (VH) pseudogene that deletes the second complementarity-determining region. PNAS 81: 5194-198.|
|223||Takeda et al., 1985, "Construction of chimaeric processed immunoglobulin genes containing mouse variable and human constant region sequences," Nature 314(6010):452-454.|
|224||*||Talwar et al. PNAS. 1976; 73 (1): 218-222, abstract only.|
|225||Taylor et al., 1984. Monoclonal antibodies protect against respiratory syncytial virus infection in mice. Immunology. 52(1):137-42.|
|226||Taylor et al., 1992. Protective epitopes on the fusion protein of respiratory syncytial virus recognized by murine and bovine monoclonal antibodies. J Gen Virol. 73 ( Pt 9):2217-23.|
|227||The Impact-RSV Study Group, "Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants." Pediatrics. Sep. 1998; 102(3 Pt 1):531-537.|
|228||Thompson et al., 1996, "Affinity maturation of a high-affinity human monoclonal antibody against the third hypervariable loop of human immunodeficiency virus: use of phage display to improve affinity and broaden strain reactivity," J. Mol. Biol. 256(1):77-88.|
|229||U.S. Appl. No. 09/724,396, filed Nov. 28, 2000, Young.|
|230||U.S. Appl. No. 09/724,396—Office Action dated Apr. 5, 2004.|
|231||U.S. Appl. No. 09/724,396—Office Action dated Dec. 3, 2002.|
|232||U.S. Appl. No. 09/724,396—Office Action dated Jul. 28, 2003.|
|233||U.S. Appl. No. 09/724,396—Office Action dated Jun. 3, 2003.|
|234||U.S. Appl. No. 09/724,396—Office Action dated Mar. 26, 2002.|
|235||U.S. Appl. No. 09/724,531 (U.S. Patent No. 7,229,619)—Office Action dated Apr. 4, 2006.|
|236||U.S. Appl. No. 09/724,531 (U.S. Patent No. 7,229,619)—Office Action dated Aug. 22, 2006.|
|237||U.S. Appl. No. 09/724,531 (U.S. Patent No. 7,229,619)—Office Action dated Feb. 21, 2003.|
|238||U.S. Appl. No. 09/724,531 (U.S. Patent No. 7,229,619)—Office Action dated Feb. 9, 2005.|
|239||U.S. Appl. No. 09/724,531 (U.S. Patent No. 7,229,619)—Office Action dated Jan. 30, 2007.|
|240||U.S. Appl. No. 09/724,531 (U.S. Patent No. 7,229,619)—Office Action dated Jun. 15, 2005.|
|241||U.S. Appl. No. 09/724,531 (U.S. Patent No. 7,229,619)—Office Action dated Jun. 4, 2004.|
|242||U.S. Appl. No. 09/724,531 (U.S. Patent No. 7,229,619)—Office Action dated Oct. 21, 2003.|
|243||U.S. Appl. No. 09/771,415 (U.S. Patent No. 6,656,467)—Office Action / Notice of Allowability dated May 6, 2003.|
|244||U.S. Appl. No. 09/771,415 (U.S. Patent No. 6,656,467)—Office Action dated Feb. 10, 2003.|
|245||U.S. Appl. No. 09/771,415 (U.S. Patent No. 6,656,467)—Office Action dated Jun. 18, 2002.|
|246||U.S. Appl. No. 09/796,848 (U.S. Publ. No. 2002/0098189) - Office Action dated Jan. 22, 2009.|
|247||U.S. Appl. No. 09/796,848 (U.S. Publ. No. 2002/0098189)—Office Action dated Apr. 14, 2008.|
|248||U.S. Appl. No. 09/796,848 (U.S. Publ. No. 2002/0098189)—Office Action dated Apr. 4, 2006.|
|249||U.S. Appl. No. 09/796,848 (U.S. Publ. No. 2002/0098189)—Office Action dated Dec. 29, 2003.|
|250||U.S. Appl. No. 09/796,848 (U.S. Publ. No. 2002/0098189)—Office Action dated Jul. 13, 2005.|
|251||U.S. Appl. No. 09/796,848 (U.S. Publ. No. 2002/0098189)—Office Action dated Jul. 27, 2007.|
|252||U.S. Appl. No. 09/796,848 (U.S. Publ. No. 2002/0098189)—Office Action dated Jun. 18, 2002.|
|253||U.S. Appl. No. 09/796,848 (U.S. Publ. No. 2002/0098189)—Office Action dated Oct. 29, 2004.|
|254||U.S. Appl. No. 09/996,265 (U.S. Patent No. 6,855,493)—Office Action dated Aug. 12, 2003.|
|255||U.S. Appl. No. 09/996,265 (U.S. Patent No. 6,855,493)—Office Action dated Jul. 13, 2004.|
|256||U.S. Appl. No. 09/996,265 (U.S. Patent No. 6,855,493)—Office Action dated Mar. 31, 2004.|
|257||U.S. Appl. No. 09/996,288 (U.S. Patent No. 6,818,216)—Office Action dated Jan. 29, 2004.|
|258||U.S. Appl. No. 09/996,288 (U.S. Patent No. 6,818,216)—Office Action dated Jul. 14, 2003.|
|259||U.S. Appl. No. 09/996,288 (U.S. Patent No. 6,818,216)—Office Action dated Jun. 30, 2004.|
|260||U.S. Appl. No. 10/020,354 (U.S. Patent No. 7,083,784)—Office Action / Notice of Allowability dated Dec. 15, 2005.|
|261||U.S. Appl. No. 10/020,354 (U.S. Patent No. 7,083,784)—Office Action dated Apr. 7, 2004.|
|262||U.S. Appl. No. 10/020,354 (U.S. Patent No. 7,083,784)—Office Action dated Jun. 1, 2005.|
|263||U.S. Appl. No. 10/020,354 (U.S. Patent No. 7,083,784)—Office Action dated Nov. 17, 2004.|
|264||U.S. Appl. No. 10/403,180 (U.S. Patent No. 7,179,900)—Office Action dated Apr. 4, 2005.|
|265||U.S. Appl. No. 10/403,180 (U.S. Patent No. 7,179,900)—Office Action dated Mar. 30, 2006.|
|266||U.S. Appl. No. 10/403,180 (U.S. Patent No. 7,179,900)—Office Action dated Oct. 19, 2005.|
|267||U.S. Appl. No. 10/403,180 (U.S. Patent No. 7,179,900)—Office Action dated Sep. 6, 2006.|
|268||U.S. Appl. No. 10/461,863 (U.S. Patent No. 7,425,618)—Office Action / Notice of Allowability dated Nov. 19, 2007.|
|269||U.S. Appl. No. 10/461,863 (U.S. Patent No. 7,425,618)—Office Action dated Dec. 18, 2006.|
|270||U.S. Appl. No. 10/461,863 (U.S. Patent No. 7,425,618)—Office Action dated Jun. 11, 2007.|
|271||U.S. Appl. No. 10/461,904 (U.S. Patent No. 7,132,100)—Office Action / Notice of Allowability dated May 2, 2006.|
|272||U.S. Appl. No. 10/461,904 (U.S. Patent No. 7,132,100)—Office Action dated Dec. 14, 2004.|
|273||U.S. Appl. No. 10/461,904 (U.S. Patent No. 7,132,100)—Office Action dated Nov. 25, 2005.|
|274||U.S. Appl. No. 10/900,230 (U.S. Publ. No. 2005/0002926) - Interview Summary dated Mar. 27, 2009.|
|275||U.S. Appl. No. 10/900,230 (U.S. Publ. No. 2005/0002926) - Office Action / Notice of Allowability dated Jun. 17, 2009.|
|276||U.S. Appl. No. 10/900,230 (U.S. Publ. No. 2005/0002926)—Office Action dated Dec. 26, 2006.|
|277||U.S. Appl. No. 10/900,230 (U.S. Publ. No. 2005/0002926)—Office Action dated Feb. 21, 2008.|
|278||U.S. Appl. No. 10/900,230 (U.S. Publ. No. 2005/0002926)—Office Action dated Jan. 24, 2006.|
|279||U.S. Appl. No. 10/900,230 (U.S. Publ. No. 2005/0002926)—Office Action dated Jun. 27, 2007.|
|280||U.S. Appl. No. 10/900,230 (U.S. Publ. No. 2005/0002926)—Office Action dated Jun. 30, 2006.|
|281||U.S. Appl. No. 10/900,230 (U.S. Publ. No. 2005/0002926)—Office Action dated Sep. 18, 2008.|
|282||U.S. Appl. No. 10/962,285 (U.S. Patent No. 7,323,172)—Office Action / Notice of Allowability dated Sep. 6, 2007.|
|283||U.S. Appl. No. 10/962,285 (U.S. Patent No. 7,323,172)—Office Action dated Apr. 13, 2007.|
|284||U.S. Appl. No. 10/962,285 (U.S. Patent No. 7,323,172)—Office Action dated Oct. 26, 2006.|
|285||U.S. Appl. No. 11/263,230 (U.S. Publ. No. 2006/0115485) - Office Action dated Mar. 30, 2009.|
|286||U.S. Appl. No. 11/263,230 (U.S. Publ. No. 2006/0115485)—Office Action dated Jan. 9, 2008.|
|287||U.S. Appl. No. 11/263,230 (U.S. Publ. No. 2006/0115485)—Office Action dated Oct. 2, 2008.|
|288||U.S. Appl. No. 11/362,267 (U.S. Patent No. 7,294,336)—Office Action / Notice of Allowability dated Aug. 6, 2007.|
|289||U.S. Appl. No. 11/362,267 (U.S. Patent No. 7,294,336)—Office Action dated May 4, 2007.|
|290||U.S. Appl. No. 11/397,328 (U.S. Publ. No. 2006/0198840) - Office Action / Notice of Allowability dated Sep. 29, 2009.|
|291||U.S. Appl. No. 11/397,328 (U.S. Publ. No. 2006/0198840) - Office Action dated Feb. 13, 2009.|
|292||U.S. Appl. No. 11/397,328 (U.S. Publ. No. 2006/0198840)—Office Action / Notice of Allowability dated Aug. 7, 2008.|
|293||U.S. Appl. No. 11/397,328 (U.S. Publ. No. 2006/0198840)—Office Action dated Oct. 18, 2007.|
|294||U.S. Appl. No. 11/643,982 (U.S. Publ. No. 2007/0196916) - Office Action / Notice of Allowability dated Feb. 13, 2009.|
|295||U.S. Appl. No. 11/643,982 (U.S. Publ. No. 2007/0196916)—Office Action dated Sep. 2, 2008.|
|296||U.S. Appl. No. 11/649,455 ( U.S. Publ. No. 2007/0122403) - Office Action dated Feb. 26, 2009.|
|297||U.S. Appl. No. 11/906,543 (U.S. Publ. No. 2008/0286270) - Office Action dated Jun. 12, 2009.|
|298||U.S. Appl. No. 11/906,543 (U.S. Publ. No. 2008/0286270) - Office Action dated Oct. 19, 2009.|
|299||U.S. Appl. No. 12/075,197, filed Mar. 10, 2008, Oliver et al.|
|300||U.S. Appl. No. 12/476,183, filed Jun. 1, 2009, Young et al.|
|301||U.S. Appl. No. 12/559,375, filed Sep. 14, 2009, Young et al.|
|302||Van Der Merwe et al., 1993, "Affinity and kinetic analysis of the interaction of the cell adhesion molecules rat CD2 and CD48," EMBO J. 12(13):4945-4954.|
|303||Van Der Merwe et al., 1994, "Human cell-adhesion molecule CD2 binds CD58 (LFA-3) with a very low affinity and an extremely fast dissociation rate but does not bind CD48 or CD59," Biochemistry 33(33):10149-10160.|
|304||Van Wyke Coelingh et al., 1985. Antigenic variation in the hemagglutinin-neuraminidase protein of human parainfluenza type 3 virus, Virology 143(2):569-582.|
|305||Vancott et al., 1994, "Dissociation rate of antibody-gp120 binding interactions is predictive of V3-mediated neutralization of HIV-1," J. Immunol. 153(1):449-59.|
|306||Verma et al., 1997. Gene therapy - promises, problems and prospects, Nature 389:239-242.|
|307||Wald et al., 1988. In re ribavirin: a case of premature adjudication? J. Pediatr. 112(1):154-158.|
|308||Walsh et al., 1984. Protection from respiratory syncytial virus infection in cotton rats by passive transfer of monoclonal antibodies. Infect Immun. 43(2):756-8.|
|309||Walsh et al., 1987, "Immunization with Glycoprotein Subunits of Respiratory Syncytial Virus to Protect Cotton Rats Against Viral Infection", J Infect Dis. 155(6):1198-204.|
|310||Ware et al., 1985. Human, rat or mouse hybridomas secrete high levels of monoclonal antibodies following transplantation into mice with severe combined immunodeficiency disease (SCID). J Immunol Methods. 85(2):353-61.|
|311||Watkins et al., 1997. Determination of the relative affinities of antibody fragments expressed in Escherichia coli by enzyme-linked immunosorbent assay. Anal Biochem. 253(1):37-45.|
|312||Watkins et at., 1998. Discovery of human antibodies to cell surface antigens by capture lift screening of phage-expressed antibody libraries. Anal Biochem. 256(2):169-77.|
|313||Weltzin et al., 1989. Binding and transepithelial transport of immunoglobulins by intestinal M cells: demonstration using monoclonal IgA antibodies against enteric viral proteins. J. Cell Biol. 108(5):1673-85.|
|314||Weltzin et al., 1994, "Intranasal Monoclonal Immunoglobulin A against Respiratory Syncytial Virus Protects against Upper and Lower Respiratory Tract Infections in Mice." Anitmicro Agents & Chemo. 38(12):2785-2791.|
|315||Weltzin et al., 1996, "Intranasal Monoclonal IgA Antibody to Respiratory Syncytial Virus Protects Rhesus Monkeys against Upper and Lower Tract Infection." J. of Infect Dis. 174:256-241.|
|316||Weltzin et al., 1999, Intranasal antibody prophylaxis for protection against viral disease. Clin Microbiol Rev. 12(3):383-93.|
|317||Whitlow et al, Protein Engineering 8, 749-761 (1995).|
|318||Wilson et al., 1984. The structure of an antigenic determinant in a protein. Cell. 37(3):767-78.|
|319||Wright et al., 1982. Administration of a highly attenuated, live respiratory syncytial virus vaccine to adults and children, Infect. Immun. 37(1):397-400.|
|320||Wu et al, 2002, "Tailoring Kinetics of Antibodies Using Focused Combinatorial Libraries" chapter 13 from Methods in Molecular Biology vol. 207, Eds. Welschop and Krauss, Humana Press Inc., Totowa, NJ, pp. 213-233.|
|321||Wu et al., "Development of Motavizumab, an Ultra-potent Antibody for the Prevention of Respiratory Syncytial Virus Infection in the Upper and Lower Respiratory Tract," J. Mol. Biol. 368:652-665 (2007).|
|322||Wu et al., "Ultra-potent Antibodies Against Respiratory Syncytial Virus: Effects of Binding Kinetics and Binding Valence on Viral Neutralization," J. Mol. Biol. 350:126-144 (2005).|
|323||Wu et al., 1998, "Stepwise in vitro affinity maturation of Vitaxin, an avb-specific humanized mAb," PNAS 95:6037-6042.|
|324||Wu et al., 1999, "Humanization of murine monoclonal antibody by simultaneous optimization of framework and CDR residues," J. Mol. Biol. 294(1): 151-62.|
|325||Wu et al., 2008, Immunoprophylaxis of RSV Infection: Advancing from RSV-IGIV to Palivizumab and Motavizumab, Curr Topics Microbiol Immunol; 317:103-123.|
|326||Wu et al., 2008. Immunoprophylaxis of RSV Infection: Advancing from RSV-IGIV to Palivizumab and Motavizumab in Human Antibody Therapeutics for Viral Disease. Current Topics in Microbiology and Immunology 317. Springer-Verlag Berlin Heidelberg, p. 103-123.|
|327||Wu, et al., "Stepwise In vitro Affinity Maturation of Vitaxin, an alpha,betaa-specific Humanized mAb," The National Academy of Sciences, vol. 95, pp. 6037-6042 (May 1998).|
|328||Wu, et al., "Stepwise In vitro Affinity Maturation of Vitaxin, an α,βa-specific Humanized mAb," The National Academy of Sciences, vol. 95, pp. 6037-6042 (May 1998).|
|329||Yang et al., J. Mol. Biol. 254, 392-403 (1995).|
|Patente citante||Fecha de presentación||Fecha de publicación||Solicitante||Título|
|US8007793||16 Jun 2010||30 Ago 2011||Medimmune, Llc||Stabilized liquid anti-RSV antibody formulations|
|US8012476||21 Ene 2010||6 Sep 2011||Medimmune, Llc||Molecules with extended half-lives, compositions and uses thereof|
|US8153133 *||17 Feb 2010||10 Abr 2012||Medimmune, Llc||High potency recombinant antibodies and method for producing them|
|US8206951||15 Jul 2011||26 Jun 2012||Medimmune, Llc||Stabilized liquid anti-RSV antibody formulations|
|US8323962||27 Jul 2011||4 Dic 2012||Medimmune, Llc||Molecules with extended half-lives, compositions and uses thereof|
|US8460663||11 Jun 2013||Medimmune, Llc||Stabilized liquid anti-RSV antibody formulations|
|US8475792||24 Oct 2012||2 Jul 2013||Medimmune, Llc||Molecules with extended half-lives, compositions and uses thereof|
|US8562996||30 May 2008||22 Oct 2013||Medimmune Limited||RSV-specific binding molecules and means for producing them|
|US8568726||5 Oct 2010||29 Oct 2013||Medimmune Limited||RSV specific binding molecule|
|US8775090||10 Dic 2009||8 Jul 2014||Medimmune, Llc||Crystals and structure of a human IgG Fc variant with enhanced FcRn binding|
|US8795661||20 May 2013||5 Ago 2014||Medimmune, Llc||Molecules with extended half-lives, compositions and uses thereof|
|US8986686||30 Abr 2013||24 Mar 2015||Medimmune, Llc||Stabilized liquid anti-RSV antibody formulations|
|US20100189718 *||21 Ene 2010||29 Jul 2010||Medimmune, Llc||Molecules with extended half-lives, compositions and uses thereof|
|US20100239574 *||23 Sep 2010||Medimmune, Llc||High potency recombinant antibodies and method for producing them|
|US20100239593 *||30 May 2008||23 Sep 2010||Medimmune Limited||Rsv-specific binding molecules and means for producing them|
|US20100266614 *||21 Oct 2010||Medimmune, Llc||Ultra high affinity neutralizing antibodies|
|US20110158985 *||30 Jun 2011||Medimmune, Llc||Methods of preventing and treating rsv infections and related conditions|
|Clasificación de EE.UU.||424/147.1, 424/130.1, 424/141.1|
|Clasificación internacional||A61P11/00, A61P31/12, A61K39/395, C07K16/46, C07K16/10, C12P21/08, A61K39/42|
|Clasificación cooperativa||C07K16/1027, C07K2319/00, C07K2317/24, C07K2317/92, A61K2039/505, C07K2317/565, C07K2317/76, C07K16/00|
|Clasificación europea||C07K16/00, C07K16/10F|
|26 Abr 2010||AS||Assignment|
Owner name: MEDIMMUNE, LLC,MARYLAND
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:APPLIED MOLECULAR EVOLUTION;REEL/FRAME:024290/0704
Effective date: 20100414
|27 Abr 2010||AS||Assignment|
Owner name: MEDIMMUNE, LLC,MARYLAND
Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNOR S NAME SHOULD READ: APPLIED MOLECULAR EVOLUTION, INC.PREVIOUSLY RECORDED ON REEL 024290 FRAME 0704. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT OF ASSIGNOR S INTEREST;ASSIGNOR:APPLIED MOLECULAR EVOLUTION, INC.;REEL/FRAME:024297/0696
Effective date: 20100414
|4 May 2010||AS||Assignment|
Owner name: MEDIMMUNE, INC.,MARYLAND
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:YOUNG, JAMES F.;KOENIG, SCOTT;JOHNSON, LESLIE S.;SIGNINGDATES FROM 20020919 TO 20020924;REEL/FRAME:024332/0278
Owner name: APPLIED MOLECULAR EVOLUTION,CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HUSE, WILLIAM D.;WATKINS, JEFFRY D.;WU, HERREN;SIGNING DATES FROM 20020919 TO 20020920;REEL/FRAME:024332/0428
Owner name: MEDIMMUNE, LLC,MARYLAND
Free format text: CHANGE OF NAME;ASSIGNOR:MEDIMMUNE, INC.;REEL/FRAME:024332/0601
Effective date: 20080326
|6 May 2010||AS||Assignment|
Owner name: APPLIED MOLECULAR EVOLUTION, INCORPORATED,CALIFORN
Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE NAME. PLEASE ADD ", INCORPORATED" AFTER ASSIGNEE NAME "APPLIED MOLECULAR EVOLUTION" PREVIOUSLY RECORDED ON REEL 024332 FRAME 0428. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT;ASSIGNORS:WATKINS, JEFFRY D.;HUSE, WILLIAM D.;WU, HERREN;SIGNING DATES FROM 20020919 TO 20020920;REEL/FRAME:024347/0958
|31 Ene 2014||REMI||Maintenance fee reminder mailed|
|22 Jun 2014||LAPS||Lapse for failure to pay maintenance fees|
|12 Ago 2014||FP||Expired due to failure to pay maintenance fee|
Effective date: 20140622