Abstract 5313: CB307: A dual targeting costimulatory Humabody® VH therapeutic for treating PSMA-positive tumors

Abstract INTRODUCTION: CD137 is a T and NK cell costimulatory receptor involved in consolidating immunological responses. The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumour toxicities. A CD137 agonist targeted to the prostate-specific membrane antigen (PSMA), frequently and highly expressed on castration-resistant metastatic prostate cancer (mCRPC) tumour cells, could bring effective immunotherapy to this immunologically challenging to address disease. EXPERIMENTAL PROCEDURES: We designed and manufactured CB307, a novel half-life extended bispecific costimulatory Humabody® VH therapeutic to elicit CD137 agonism exclusively in a PSMA-high tumour microenvironment (TME). The functional activity of CB307 was assessed in cell-based assays and in syngeneic mouse anti-tumour pharmacology studies. Non-clinical toxicology and toxicokinetic properties of CB307 were assessed in a good laboratory practice (GLP) compliant study in cynomolgus macaques. RESULTS: CB307 provides effective CD137 agonism in a PSMA-dependent manner, with anti-tumour activity both in vitro and in vivo, and additional activity when combined with checkpoint inhibitors. A validated novel PSMA/CD137 immunohistochemistry (IHC) assay demonstrated a higher prevalence of CD137-postive cells in the PSMA-expressing human mCRPC TME with respect to primary lesions. CB307 did not show substantial toxicity in non-human primates and exhibited a plasma half-life supporting weekly clinical administration. CONCLUSIONS: CB307 is a first-in-class immunotherapeutic that triggers potent PSMA-dependent T cell activation thereby alleviating toxicological concerns against unrestricted CD137 agonism. Citation Format: Sophie Archer, Phillip M. Brailey, Minjung Song, Phillip D. Bartlett, Ines Figueiredo, Bora Gurel, Christina Guo, Verena Brucklacher-Waldert, H. Lorraine Thompson, Jude Akinwale, Samantha E. Boyle, Christine Rossant, Neil R. Birkett, Julia Pizzey, Mark Maginn, James Legg, Richard Williams, Colette M. Johnston, Philip Bland-Ward, Johann S. de Bono, Andrew J. Pierce. CB307: A dual targeting costimulatory Humabody® VH therapeutic for treating PSMA-positive tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5313.