4-1BB and CD40 agonists are promising candidates for cancer immunotherapy but have had limited success due to systemic toxicity risk. We generated a 4-1BB×CD40 bsAb (BCG021) with a more reasonable affinity. BCG021 demonstrated conditional 4-1BB and CD40 agonistic activity and did not show a bell-shaped response as observed for benchmark bsAb. Moreover, BCG021 also exhibited superior in vitro and in vivo efficacy, with ideal physiochemical properties and a better PK profile than the benchmark.
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4-1BB is a costimulatory receptor expressed on activated T cells that enhances their proliferation, survival, and effector functions. It plays a key role in amplifying anti-tumor immune responses, making it a promising target for immunotherapy. However, therapeutic strategies targeting 4-1BB must balance efficacy with potential systemic toxicity.
CD40 is a co-stimulatory protein found on antigen-presenting cells such as dendritic cells, B cells, and macrophages. It is crucial for activating the adaptive immune response, including T cell priming and antibody production. Modulating CD40 signaling can boost anti-tumor immunity, but it requires careful control to minimize adverse inflammatory effects.
