Abstract 2729: Discovery and characterization of LILRB2XPD-L1 bispecific antibody SPX-303

Abstract The advent of immunotherapy has led to deep and sometimes durable remissions in certain cancers. However, the variable response rates and development of resistance mechanisms pose significant challenges to the current therapies. The immunosuppressive nature in the tumor microenvironment (TME) can drive many of these observations. Reversing this immunosuppression is a promising avenue for enhancing and broadening the applicability of IO therapies. Macrophages are critically modulated by LILRB2, a pivotal receptor in their maturation and polarization to the M2 immunosupressive phenotype. We report the discovery and development of a novel anti-LILRB2/PD-L1 bispecific antibody, SPX-303, designed using an anti-LILRB2 IgG4 derived from a mouse hybridoma screen and linked with an anti-PD-L1 epitope. SPX-303 demonstrates sub-nanomolar binding affinity to both LILRB2 and PD-L1 targets, effectively blocking the interaction between LILRB2 and its ligand, as well as inhibiting PD-1 binding to PD-L1. In in vitro functional assays, SPX-303 exhibits effects comparable to the parental monomeric anti-LILRB2 (SPX-104) in redirecting macrophage polarization from M2 to M1 stage, as observed in both cultured PBMC and human monocyte-derived macrophage (HMDM) models. Furthermore, SPX-303 demonstrates a synergistic effect in inducing T cell activation in the autologous mixed lymphocyte reaction assay (auto-MLR), surpassing the effects of the anti-LILRB2 epitope (SPX-104) and the anti-PDL1 fragment (single-domain anti-PDL1) alone or in combination. In vivo experiments reveal that SPX-303 significantly inhibits tumor growth. Collectively, these results support SPX-303 as a novel therapeutic antibody that effectively enhances anti-cancer immunity in the treatment of advanced solid tumors. The pre-clinical data as well as the clinical plan of SPX-303 will be presented. Citation Format: Anthony Haight, Qian Chen, Brandon William, Dinh-Duc Nguyen, Robert Cai, Jichun Ma, Michael White, Jindong Jin, Jadon Shen, Martin Siekierzycki, Victoria Hall, Hua Jin, Roland Meier, Justin Moser. Discovery and characterization of LILRB2XPD-L1 bispecific antibody SPX-303 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 2729.