Epitope and Fc-Mediated Cross-linking, but Not High Affinity, Are Critical for Antitumor Activity of CD137 Agonist Antibody with Reduced Liver Toxicity

Abstract

CD137 (TNFRSF9, 4-1BB) agonist antibodies (mAb) have demonstrated potent antitumor 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 nonexistent (utomilumab). To exploit the antitumor potential of CD137 signaling, we identified a new class of CD137 agonist mAbs with strong antitumor potency without significant transaminitis in vivo compared with CD137 agonists previously reported. These mAbs are crossreactive to mouse and cynomolgus monkey and showed crosslinking-dependent T-cell costimulation activity in vitro. Antitu-mor efficacy was maintained in Fc gamma receptor (FcgR) IIIdeficient mice but diminished in FcgRIIB-deficient mice, suggesting the critical role for FcgRIIB 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 FcgR interaction, but not necessarily high affinity, are important for antitumor efficacy and reduced liver toxicity of CD137 mAb. Our study suggests the possibility of CD137 agonist therapy with improved safety profile in humans.

How to select IgG subclasses in developing anti-tumor therapeutic antibodies

“…Accumulated clinical data was not promising for either antibody [53]. Efforts have been made to mitigate the liver toxicity and improve the efficacy of 4-1BB antibodies [52,54] by engineering the Fc portion of the antibody to eliminate binding to the activating FcγRs, including FcγRI, FcγRIIA, and FcγRIIIA, while retaining binding to the inhibitory Fc receptor FcγRIIB [52]. Alternatively, antibodies targeting different epitopes away from the ligand-binding sites may have better efficacy as well as safety profiles if they are IgG4, which have better binding affinity to FcγRIIB than IgG2, which only binds to FcγRIIA [54].…”

An engineered 4-1BBL fusion protein with “activity on demand”

“…Efforts are underway to develop 4-1BB agonists with more favorable toxicity profiles that retain potent costimulatory capacities (80)(81)(82). In addition to the optimization of anti-4-1BB immunoglobulins (80,81), various formats of targeted 4-1BB agonists are being investigated.…”

4-1BB is a target for immunotherapy in patients with undifferentiated pleomorphic sarcoma

“…Studies have focused on the development of bispecific agonists promoting agonist localisation to the tumour microenvironment 56,58 , or have sought to understand the relative roles of Fab region binding versus FcR clustering. New preclinical studies of 4-1BB agonists have shown that strong anti-tumor efficacy can be generated whilst avoiding both 4-1BBL ligand-blocking and liver toxicity due to crosslinking 57,59 . One study has indicted that 4-1BB antibodies that are weak agonists from Fab binding alone, but require inhibitory Fcreceptor FcgRIIB-mediated crosslinking, retain anti-tumour activity in the absence of liver toxicity 57 .…”