Abstract 3915: BMS-986442 (AGEN1777), a novel TIGIT/CD96 bispecific antibody, demonstrates superior monotherapy and combination activity versus conventional anti-TIGIT antibodies in preclinical models

Abstract TIGIT immune checkpoint blockade can enhance anti-tumor immunity, however conventional anti-TIGIT antibodies have shown suboptimal activity in the clinic. Here, we present the first preclinical disclosure of BMS-986442 (AGEN1777), a novel and fully human Fc-enhanced bispecific antibody against TIGIT and CD96 co-receptor, that demonstrates superior pharmacological activity compared to conventional TIGIT monospecific antibodies (mAbs). Gene expression of TIGIT, CD96, and the co-stimulatory counter-receptor CD226 in tumor samples from patients with cancer was identified using bulk and single cell RNA-sequencing. To target this interaction, Fc-engineered knob-in-hole bispecific antibodies against TIGIT and CD96 were developed and affinity optimized to achieve potent and complete blockade of TIGIT and CD96 ligand interactions. BMS-986442 and corresponding monospecific anti-TIGIT and anti-CD96 monoclonal antibodies were evaluated with or without anti-PD-1 in a variety of human T and NK cell stimulation assays. Mouse surrogate TIGIT/CD96 bispecific antibodies were developed and evaluated as monotherapy or together with anti-PD-1 in colorectal CT26 and breast orthotopic 4T1 tumor bearing mice. In CT26 and 4T1 tumor-bearing mouse models, the Fc-enhanced TIGIT/CD96 bispecific antibody demonstrated superior tumor control compared to either anti-TIGIT, anti-CD96, or the combination of anti-TIGIT and anti-CD96 mAbs. Tumor control was dependent on co-engaging activating Fcγ receptors, as an Fc-silent bispecific antibody lacked anti-tumor activity. In the tumor microenvironment, efficacy was associated with increased frequency of CD226+ effector and TCF-1+ GrzB- memory precursor CD8 T cells, increased frequency and activation of cytotoxic NK cells, and increased activation of professional APCs, including B cells, MHC Class II monocytes, and dendritic cells as determined by expression of CD40, CD83, and CD86. In primary human in vitro assays, BMS-986442 potently enhanced T cell responsiveness and activation compared with conventional anti-TIGIT mAbs alone and in combination with anti-PD-1 (nivolumab). Lastly, BMS-986442 promoted superior NK cell activation in tumor co-culture assays. In conclusion, BMS-986442 demonstrated a differentiated FcγR-dependent mechanism-of-action to enhance innate and adaptive immune responses compared with anti-TIGIT or anti-CD96 mAbs. BMS-986442 is currently advancing in phase I clinical studies in patients with advanced solid cancers (NCT05543629). Citation Format: Rebecca Ward, Nicola Ramsay, Spencer Campbell, Hema Patel, Mark Bushell, Benjamin M. Morin, Beth Wensley, David A. Savitsky, Pilar Garcia-Broncano, Bishnu Joshi, Emmanuel Briend, Olga Ignatovich, Zahra Jawad, Nils-Petter Rudqvist, Nicholas Wilson, Dhan Chand. BMS-986442 (AGEN1777), a novel TIGIT/CD96 bispecific antibody, demonstrates superior monotherapy and combination activity versus conventional anti-TIGIT antibodies in preclinical models [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(6_Suppl):Abstract nr 3915.