Abstract 3352: Tumor dependent co-stimulation of CD137/4-1BB in PSMA positive tumors: Preclinical characterization of CB307, a half-life extended PSMAxCD137 bispecific Humabody therapeutic
Authors: James William Legg
Journal: Cancer Research (2020)

Abstract Introduction: Agonistic monoclonal antibodies targeting CD137/4-1BB have shown much preclinical promise but their clinical development has been slow due to treatment associated toxicities, in particular transaminitis and liver toxicity. We have developed CB307, a half-life extended bispecific Humabody VH co-targeting CD137 and the tumor associated antigen prostate specific membrane antigen (PSMA). PSMA is highly expressed on tumor cells in a number of cancer indications including metastatic castrate resistant prostate cancer (mCRPC) and non-small cell lung cancer, additionally PSMA expression is increased on the neovasculature of these tumors and in other solid tumors including renal cell carcinoma. Methods and Results: CD137 is a co-stimulatory receptor expressed on the surface of activated CD4+ and CD8+ T cells and NK cells. Using the Crescendo Mouse™, a transgenic platform which develops fully human VH domains in a background devoid of light chains, we have generated a half-life extended bispecific therapeutic (CB307) which has been specifically designed to enable agonism of CD137 positive cells in the tumor microenvironment of PSMA positive tumors and not in tissues where PSMA is absent. We hypothesize that the PSMA-dependent activation of CD137 signalling will enable durable anti-tumor immune responses with a more favorable therapeutic index compared to first generation monospecific CD137 antibodies. CB307 demonstrates PSMA-dependent T-cell activation in vitro as demonstrated by stimulation of T cell cytokine release, proliferation, cytotoxicity and increased expression of the pro-survival signalling molecule Bcl-XL. Cytokine production is further enhanced by combination with an anti-PD-1 antagonist antibody. In vivo, a surrogate bispecific increases CD8 T cell numbers in a prostate cancer tumor cell line model and mediates significant tumor growth delay. The serum half-life of CB307 has been extended by the inclusion of a third VH domain with specificity for human serum albumin. This has resulted in a serum half-life in cynomolgus monkey of 1.5 days (following a single i.v. dose of 3 mg/kg). In a four week, non-GLP, repeat dose toxicity study where CB307 was administered to cynomolgus monkeys at either 50 mg/kg or 160 mg/kg CB307 was well tolerated with no clinical signs, no effect on body weight or food consumption and no injection site observations. Importantly, no significant increases in ALT or AST were noted in the animals and no findings were observed on histopathology. Conclusions: There is a high unmet medical need for well tolerated and efficacious immunotherapy approaches in PSMA positive tumors such as mCRPC. We have shown that CB307, a half-life extended PSMAxCD137 bispecific delivers potent PSMA-targeted T cell activation. Non-clinical development activities for CB307 are ongoing in preparation for first in human studies. Citation Format: James William Legg. Tumor dependent co-stimulation of CD137/4-1BB in PSMA positive tumors: Preclinical characterization of CB307, a half-life extended PSMAxCD137 bispecific Humabody therapeutic [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3352.