CD137 or 4-1BB, as one representative TNF receptor family co-stimulatory receptor, is expressed on a few specific cell types, including activated T cells and NK cells. CD137 L–CD137 interaction can trigger an activation signal in all these cell types. Co-stimulation of T cell responses with monoclonal antibody agonists (mAb-AG) targeting CD137 showed robust anti-tumor activity in preclinical models, but their clinical development was hampered by low efficacy or severe liver toxicity. During our earlier study, we showed that isotype and intrinsic agonistic strength co-determine the efficacy and toxicity of anti- CD137 mAb-AG. While intrinsically strong agonistic anti- CD137 can activate CD137 in the absence of FcγRs, weak agonistic antibodies rely on FcγRs to activate CD137. All FcγRs can crosslink anti- CD137 antibodies to strengthen co-stimulation, but activating FcγR-induced antibody-dependent cell-mediated cytotoxicity compromises anti-tumor immunity by deleting CD137 + cells. This suggests balancing agonistic activity with the strength of FcγR interaction as a strategy to engineer CD137 mAb-AG with optimal therapeutic performance. We have developed LVGN6051, a humanized CD137 mAb-AG that shows high anti-tumor efficacy in the absence of liver toxicity in a mouse model of cancer immunotherapy.
We are conducting Phase I trials of LVGN6051 alone or in combination with anti-PD-1 antibody in the USA (NCT04130542), in adult patients with advanced malignancies. No MTD was reached at 7 mg/kg monotherapy and 4 mg/kg q3w monotherapy was determined as RP2D. Preliminary antitumor activity in late stage cancer patients was observed. Combination with pembrolizumab induced rapid antitumor responses in advanced cancer patients with immune-cold tumor or relapsed from prior immunotherapies. We've got the approval of IND in China in 2020, and the bridging testing is on-going.
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