Abstract 2877: CB307: A novel selective CD137 agonist for enhancement of immune cell responses to PSMA+ tumors

Abstract

Abstract Introduction: CD137 (HGNC:TNFRSF9, 4-1BB) is a TNF receptor superfamily costimulatory receptor expressed by T cells and NK cells. Upon engagement, CD137 enhances immune cell survival, proliferation, cytokine production, and memory formation. As such, CD137 agonists have demonstrated promising pre-clinical anti-tumor effects, however their clinical utility has been limited due to dose-limiting hepatic toxicity. PSMA is highly upregulated on tumor cells and tumor neovasculature in prostate cancer and other solid tumors, including lung (NSCLC), kidney (clear cell RCC), bladder and colorectal cancers. CB307 is a half-life extended Humabody® that selectively agonizes CD137 only in the presence of prostate specific membrane antigen (PSMA, HGNC:FOLH1). CB307 is trispecific with VH components selected for optimal binding to PSMA, CD137 and human serum albumin (HSA). We present here the non-clinical pharmacology and toxicology of CB307. Methods: CD137 agonism and immune cell activation were evaluated in vitro using coculture assays with PSMA-expressing tumor cells as assessed by NFκB-driven luciferase and cytokine secretion. CB307 was evaluated as a single agent and in combination with enzalutamide, PD1 or PDL1 inhibitors. In vivo experiments used a syngeneic mouse system transgenic for the human CD137 immune cell target, and human PSMA expressed on mouse tumor cells. Nonclinical toxicology and pharmacokinetics of CB307 were assessed in cynomolgus macaques. Results: In reporter assays and PBMC cocultures, CB307 activated CD137 only in the presence of PSMA-expressing cells leading to enhanced immune cell activation. Enzalutamide pre-treatment of 22Rv1 (PSMA-low) cells induced a 1.5-fold increase in surface PSMA expression leading to enhanced CB307 activity. CB307 or PD1/PDL1 inhibition alone induced IL-2 secretion in PBMC/PSMA-expressing tumor cell cocultures; this effect was synergistically enhanced when CB307 was combined with either PD1 or PDL1 inhibition. In an in vivo pharmacology study in immuno-competent mice, CB307 demonstrated statistically significant inhibition of tumor growth. CB307 was well-tolerated in a GLP-toxicology study in cynomolgus macaques, with an observed half-life supporting weekly clinical administration. Summary: CB307 is a novel CD137 agonist that selectively enhances immune cell activity in the presence of PSMA-positive cells. Our data demonstrates CB307 immunological pharmacology both in vitro and in vivo which has supported the initiation of the phase I ‘POTENTIA’ clinical trial (NCT04839991). Citation Format: Andrew J. Pierce, Phillip M. Brailey, Clare Song, Sophie Archer, Phillip D. Bartlett, Philip Bland-Ward. CB307: A novel selective CD137 agonist for enhancement of immune cell responses to PSMA+ tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2877.