Epitope and Fc-mediated Crosslinking, but not High Affinity, Are Critical for Antitumor Activity of CD137 Agonist Antibody with Reduced Liver Toxicity

CD137 (TNFRSF9, 4-1BB) agonist antibodies (mAb) have demonstrated potent anti-tumor activity with memory response while causing hepatotoxicity in mouse models. In clinical trials, the degrees of liver toxicity of anti-CD137 vary from grade 4 transaminitis (urelumab) to non-existent (utomilumab). To exploit the anti-tumor potential of CD137 signaling, we identified a new class of CD137 agonist mAbs with strong anti-tumor potency without significant transaminitis in vivo compared to CD137 agonists previously reported. These mAbs are cross-reactive to mouse and cynomolgus monkey and showed crosslinking-dependent T cell costimulation activity in vitro. Anti-tumor efficacy was maintained in Fc gamma receptor (FcγR) III-deficient mice but diminished in FcγRIIB-deficient mice, suggesting the critical role for FcγRIIB to provide cross-linking in vivo. Interestingly, a single dose of an affinity reduced variant was sufficient to control tumor growth, but a higher affinity variant did not improve efficacy. These observations suggest that binding epitope and FcγR interaction, but not necessarily high affinity, are important for anti-tumor efficacy and reduced liver toxicity of CD137 mAb. Our study suggests the possibility of CD137 agonist therapy with improved safety profile in humans.