Comprehensive Report on Acasunlimab (GEN1046/BNT311): An Investigational PD-L1 x 4-1BB Bispecific Antibody for Cancer Immunotherapy

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1. Executive Summary

Acasunlimab (GEN1046/BNT311) is an investigational, first-in-class, Fc-silenced human immunoglobulin G1 (IgG1) bispecific antibody meticulously engineered to dually target programmed death-ligand 1 (PD-L1) and the co-stimulatory receptor 4-1BB (CD137).[1] Developed utilizing Genmab's proprietary DuoBody® technology, Acasunlimab is designed to provide conditional 4-1BB co-stimulation that is dependent on its binding to PD-L1, typically within the tumor microenvironment (TME). This mechanism aims to enhance T-cell and Natural Killer (NK)-cell mediated anti-tumor activity while concurrently mitigating the potential for systemic toxicities that have been associated with conventional 4-1BB agonistic antibodies.[1]

Extensive preclinical investigations have substantiated Acasunlimab's proposed mechanism of action, demonstrating potent anti-tumor activity and superior immune activation when compared to monospecific antibody counterparts, including in models resistant to checkpoint inhibitors (CPIs).[2] The clinical development program, now primarily spearheaded by Genmab following BioNTech's strategic decision to opt-out of further co-development in August 2024 [13], has concentrated on evaluating Acasunlimab in patients with advanced solid tumors. A significant focus has been on metastatic non-small cell lung cancer (mNSCLC), particularly in patients whose disease has progressed following prior CPI therapy, an area of substantial unmet medical need.