Costimulatory T-cell engagement by PRS-343, a CD137 (4-1BB)/HER2 bispecific, leads to tumor growth inhibition and TIL expansion in a humanized mouse model

• Published in: European journal of cancer (1990) 2016-12, Vol.69, p.S99-S99
• Main Authors: Hinner, M.J, Bel Aiba, R.S, Schlosser, C, Jaquin, T, Allersdorfer, A, Berger, S, Wiedenmann, A, Matschiner, G, Schüler, J, Moebius, U, Rothe, C, Olwill, S.A
• Format: Article
• Language: English
• Subjects: Activation; Anticancer properties; Backbone; Benchmarks; Biocompatibility; Cancer; CD137 antigen; CD8 antigen; Clinical trials; Clustering; ErbB-2 protein; Hematology, Oncology and Palliative Medicine; Immune system; Immunoglobulins; Immunotherapy; Infiltration; Inhibition; Lymphocytes; Lymphocytes T; Medical research; Metastases; Mice; Monoclonal antibodies; Peripheral blood mononuclear cells; Proteins; Targeted cancer therapy; Therapeutic applications; Toxicity; Trastuzumab; Tumor cells; Tumors; Xenografts; Xenotransplantation
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)32894-5

Background: CD137 (4-1BB) is a key costimulatory immunoreceptor and a highly promising therapeutic target in cancer. To overcome limitations of current mAb-based approaches which monospecifically target CD137, we generated PRS-343, a CD137/HER2 bispecific designed to promote CD137 clustering by bridging CD137-positive T cells with HER2-positive tumor cells, thereby providing a potent costimulatory signal to tumor antigen-specific T cells. Methods: We have previously described the generation of PRS-343 as a fusion of a CD137-specific Anticalin® protein to a variant of the HER2-targeting monoclonal antibody trastuzumab with an engineered lgG4 backbone. PRS-343 was found to efficiently activate T cells ex vivo in the presence of HER2-positive cells. Here, in vivo proof of concept data is presented utilizing a humanized mouse model in immunocompromised mice and the SK-OV-3 cell line as a HER2-positive xenograft. When tumors had reached a predefined size, mice received human PBMC and weekly injections of PRS-343 for three weeks. An lgG4 isotype antibody served as the negative control, while a CD137-targeting benchmark antibody and trastuzumab with an engineered lgG4 backbone ("tras-lgG4") served as controls for monospecific targeting of CD137 and HER2, respectively. Results: PRS-343 activity was investigated at four different weekly doses, ranging from 4 µg to 200 µg. We found that PRS-343 dose-dependently led to strong tumor growth inhibition compared to treatment with the isotype control, and that the tumor response was accompanied by a significantly higher tumor infiltration with human lymphocytes (hCD45·). Both these activities were absent in the anti-CD137 benchmark. The tras-lgG4 control was also devoid of lymphocyte infiltration into the tumor, but displayed a tumor growth inhibition comparable to PRS-343. The animal model also allowed investigating the potential safety of PRS-343: While the anti-CD137 benchmark accelerated the onset of graft-versus-host-disease and led to stronger expansion of CD8· T cells in the peripheral blood compared to the isotype control group, both of these effects were absent for PRS-343, indicating tumor-localized activation of CD137 only. Conclusion: We report potent costimulatory T-cell engagement of the immunoreceptor CD137 in a HER2-dependent manner, utilizing the CD137/HER2 bispecific PRS-343. PRS-343 displays dual activity in vivo based on monospecific HER2-targeting and bispecific, tumor-localized costimulation of CD137