Large biotech firms are scurrying to exploit bi-specific antibodies as well. Novartis recently paid GenMab $2 million to tap into the latter’s DuoBody™ technology for creating bi-specific mAbs. The full value of the deal could reach $175 million for GenMab, which has its own development pipeline as well.
Bi-specific antibodies combine the affinities and activities of two different mAb fragments and target two distinct antigens simultaneously, for example a tumor target and a cytotoxic immune system cell.
“Bi-specific antibodies pose unique challenges in development and manufacturing and can require added effort and time in bringing new therapeutics to commercialization,” says Kevin Bailey, Ph.D., vp for preclinical manufacturing at Regeneron Pharmaceuticals. Regeneron develops monoclonal antibodies to block individual therapeutic targets in oncology, cardiovascular diseases, infectious diseases, and others.
A somewhat related approach is to administer two mAbs at once with the idea of delivering an orthogonal one-two punch to the therapeutic target. Such treatments would be prohibitively expensive unless the innovator companies collaborated on a designated combination product, an unlikely occurrence. An innovative way around this idea is to produce two or more mAbs simultaneously in the same cells.
That is the idea behind Oligoclonics® from Merus, which creates mixtures of mAbs with different specificities through co-transfection of cells for multiple antibodies. This approach essentially creates a combination therapy in one manufacturing process. Merus received the first European patent for the technology in June.
Engineered antibodies seek to improve the safety or efficacy of conventional antibodies or fragments through modification of glycosylation. In particular glyco-engineered antibodies containing low or no core fucose residues on the Fc N-glycan show improved affinity for Fc gamma receptor IIIa, and thus improve antibody-dependent cellular cytotoxicity—a critical factor in antitumor activity.
BioWa is one firm at the forefront of eliminating fucose from antibodies. The company’s Potelligent® technology enhances mAb activity, increases Fc binding, lowers the effective dose of an antibody therapeutic, and requires no change in the manufacturing process. In June, BioWa signed an agreement with Lonza to investigate the potential for reducing fucose residues in mAbs produced through Lonza’s GS Gene Expression™ system.
Improving mAbs through genetic engineering, manufacturing innovations, formulation, or some combination of the three is, of course, the idea behind “biobetters.” Formulation and preformulation are established strategies for improving prospects of development-stage small molecule drugs, for example by improving solubility.
The same is true for proteins and antibodies, notes Indu S. Javeri, Ph.D., CEO of CuriRx. “Preformulation is essential for mAbs, as it allows us to identify and understand the molecule’s strengths and weaknesses. This information, in turn, helps manufacturers develop high-yield purification processes and resolve manufacturing-related issues.”
Some enhancement strategies involve non-mammalian expression systems, others improve on CHO cells. All pose both advantages and disadvantages in terms of economics, productivity, and regulatory risk.
Some larger CMOs offer proprietary cell lines and expression systems for mAbs and other therapeutic proteins. But, according to Hetrick, proprietary technology “seems to add little value to the service offerings of smaller to mid-sized CMOs.”
He cites the limited reactor volumes and number of campaigns possible at such organizations, which would not support the infrastructure of proprietary expression systems. Since smaller CMOs operate mostly in Phase II and earlier, proprietary technologies would “not in most cases translate into a significant decision criterion for selecting that CMO. Moreover, CMOs tend to employ whatever cell line a client specifies.”