Abstract 3920: BND-35, a novel anti-ILT3 antibody for remodulation of the tumor microenvironment

Abstract

Abstract Background: ILT3 (LILRB4) is expressed in various suppressive myeloid cells including tumor associated macrophages (TAM), myeloid derived suppressor cells (MDSCs) and tolerogenic dendritic cells (DCtol). The binding of ILT3 to its ligands induces an immunosuppressive phenotype in myeloid cells, mediates the inhibition of T cells activity and generates an immunosuppressive tumor microenvironment (TME) which supports tumor growth. The inhibition of ILT3 can restore the anti-tumor activity of myeloid cells and T cells, and thus remodulate the TME from immunosuppressive to pro-inflammatory. Here we describe preclinical characterization of BND-35, a humanized IgG4, ILT3 antagonist antibody developed for the treatment of solid tumors. Methods: BND-35 binding to ILT3 was evaluated by flow cytometry, ELISA and surface plasmon resonance. We investigated the ability of BND-35 to block ILT3 interactions with APOE and fibronectin, to enhance the pro inflammatory activity of various myeloid cells and reverse ILT3-mediated immune suppression of T cells by different suppressive myeloid cells using ELISA and in vitro and ex vivo cell-based assays. The anti-tumor activity of BND-35 was also evaluated in vivo in hILT3 transgenic mouse tumor models as well as in tumoroid systems generated from cancer patients. Results: BND-35 binds ILT3, but not other ILT-family receptors, with low nanomolar affinity and blocks its interaction with APOE and fibronectin in a concentration-dependent manner. ILT3 blockade with BND-35 restored the pro-inflammatory activity of FcR-stimulated DCs and THP1 cells inhibited by fibronectin. BND-35 was also shown to restore an M1 phenotype in cancer patients’ derived monocytes differentiated in the presence of autologous tumor cells. In addition, BND-35 restored T cell activity (both, CD4 and CD8 T cells) inhibited by either DCtol, MDSCs or M2 cells as a single agent and in combination with anti PD-1. BND-35 enhanced immune activity in a unique system of patient-derived tumoroids as evidenced by the secretion of pro-inflammatory cytokines. In vivo, blocking ILT3 activity with BND-35 resulted in decreased tumor growth and induced a pro-inflammatory phenotype in tumor resident T cells and myeloid cells populations as a single agent and in combination with anti PD-1. Conclusions: BND-35 is an anti-ILT3 antagonist antibody that was shown to induce potent pro inflammatory activity of myeloid cells and enhance T cells activity inhibited by ILT3 expressing myeloid suppressive cells in multiple in vitro, ex vivo and in vivo models. By doing so, BND-35 can lead to TME remodelling from immunosuppressive to proinflammatory. Safety, tolerability, and anti-tumor activity of BND-35 will be explored in a first-in-human clinical trial in cancer patients with solid tumors. Citation Format: Tsuri Peretz, Yoav Pizem, Liat Iancovici, Ella Peled, Motti Hakim, Sharon Hashmueli, Ilana Mandel, Yair Sapir, Tehila Ben Moshe. BND-35, a novel anti-ILT3 antibody for remodulation of the tumor microenvironment [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 3920.