Abstract 5549: First-in-class TNFR2 agonist & antagonist antibodies as Treg-Teff modulator for cancer immunotherapy

Abstract

Abstract Tumor necrosis factor receptor 2 (TNFR2) is expressed on highly suppressive tumor-infiltrating T regulatory cells (Treg), activated T effector cells (Teff), as well as many tumor cells in the tumor microenvironment, which makes TNFR2 a novel and very promising target for cancer immunotherapy. We have identified and characterized a wide panel of first-in-class highly selective TNFR2 agonist and antagonist antibodies, from murine hybridoma and camelid phage display campaigns. Our Treg antagonist lead candidate IAT0981-1A8 is a humanized single domain antibody (VHH), which showed tight TNFR2 binding with low-digit nanomolar affinity. IAT0981-1A8 potently blocked ligand TNFa binding to TNFR2, and elicited strong Treg proliferation inhibition activities. Our Teff agonist lead candidate IAT0981-231 is a humanized monoclonal antibody with sub-nanomolar affinity to TNFR2, which potently stimulated CD8+ T cell activation, proliferation and cytokine secretion, without blocking endogenous TNFa activity. Both IAT0981-1A8 and IAT0981-231 did not cross-react with TNFR1, and exhibited extremely potent tumor growth inhibition activities as single agent in multiple tumor models in TNFR2 transgenic animals, better than tested benchmarks. Our epitope binning studies demonstrated that IAT0981-1A8 and IAT0981-231 bound to totally different epitopes on TNFR2. We also evaluated several bispecific antibodies composing of tumor associated antigens or other immune cell modulators in tumor microenvironment, with either IAT0981-1A8 or IAT0981-231. We have generated high quality commercial stable cell line for the Teff agonist lead candidate IAT0981-231, and completed several batches of 200L non-GMP and GMP production. Our preclinical cynomolgus monkey toxicity studies revealed extremely good safety profile for IAT0981-231, with no significant toxicity observed even with high 200mg/kg repeated dose. We are currently performing IND-enabling studies for the agonist lead candidate IAT0981-231, and aim to enter clinical studies in the first half of 2022, with first-in-class potential as monotherapy and I/O combination therapy for advanced cancers. Citation Format: Xiaoling Jiang, Chonging Wu, Liusong Yin. First-in-class TNFR2 agonist & antagonist antibodies as Treg-Teff modulator for cancer immunotherapy [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 5549.