Seung-Uon Shin, Ph.D.
Research Associate Professor of Medicine
Description of Research
Dr. Shin has developed novel reagents designed to target micrometastatic disease, causing cancer regression by inhibiting proliferation with anti-angiogenic factors or stimulating a systemic immune response with cytokines. His approach seeks to combine anti-angiogenic factors or cytokines with the targeting specificity of an anti-tumor antibody by producing antibody fusion proteins. To produce a more effective form of trastuzumab and improve the efficacy of anti-angiogenic protein endostatin, Dr. Shin constructed several anti-HER2 IgG3-endostatin fusion proteins by fusing murine or human endostatin to anti-HER2 IgG3 antibody. Linking endostatin to an antibody may significantly enhance anti-tumor activity of trastuzumab. Targeting of endostatin using antibody fusion proteins could improve anti-tumor activity of either anti-HER2 antibody and/or endostatin, and provides a versatile approach that could be applied to other tumor targets with alternative antibody specificities.
NKG2D ligands link the innate and adapative immue response by activating the receptors expressed on effector cells of both the innate (NK) and adaptive immune systems (CD8+ T cells). Recently, Dr. Shin constructed antibody-NKG2D ligand fusion proteins directed against HER2 antigen in order to deliver NKG2D ligand to the surface of HER2+ breast tumor cells. The targeting ability of NKG2D ligand fusion to HER2+ tumors may improve efficacy by stimulating NK cells at the site of the growing tumor, leading to a local innate response and potentially priming an adaptive anti-tumor response mediated by CD8+ T-cells with anti-tumor specificity. Mice implanted on one flank with HER2 tumor cells and contralaterally with control HER2- tumor cells exhibited rapid regression of HER2+ tumors but delayed regression of contralateral HER2- tumors. Mice rejecting HER2+ tumors after antibody-NKG2D ligand treatment showed markedly decreased tumor growth when rechallenged with HER2+ or HER2- tumor cells, whereas both HER2+ or HER2- tumor cells grew in control mice, indicating the development of an adaptive memory response.
- Discovered the anti-HER2 IgG3-human endostatin and anti-HER2 IgG3-human endostatin-mutant fusion proteins inhibited tumor growth. Treatment with the mutant fusion protein completely eradicated SK-BR-3 xenografts. The mutation of the human endostatin domain of the fusion protein increased the efficacy of anti-HER2 IgG3-human endostatin fusion proteins.
- Demonstrated that administration of an antibody-NKG2D ligand fusion protein could enhance innate and adaptive immune anti-tumor responses, also evoking additional non-targeted antigens to enhance the potential clinical utility of this approach.
Selected Cancer-Related Publications
- Cho HM, Rosenblatt JD, Tolba K, Shin SJ, Shin DS, Calfa C, Zhang Y, Shin SU. Delivery of NKG2D Ligand Using an Anti-HER2 Antibody-NKG2D Ligand Fusion Protein Results in an Enhanced Innate and Adaptive Antitumor Response. Cancer Res 70:10121-30, 2010. Read more »
Collaborating in the Multidisciplinary Research Program(s):