Abstract
CD137 (4-1BB) is a member of the TNFR superfamily that represents a promising target for cancer immunotherapy. Recent insights into the function of TNFR agonist antibodies implicate epitope, affinity, and IgG subclass as critical features, and these observations help explain the limited activity and toxicity seen with clinically tested CD137 agonists. Here, we describe the preclinical characterization of CTX-471, a fully human IgG4 agonist of CD137 that engages a unique epitope that is shared by human, cynomolgus monkey, and mouse and is associated with a differentiated pharmacology and toxicology profile. In vitro, CTX-471 increased IFN-γ production by human T cells in an Fcγ receptor-dependent (FcγR-dependent) manner, displaying an intermediate level of activity between 2 clinical-stage anti-CD137 antibodies. In mice, CTX-471 exhibited curative monotherapy activity in various syngeneic tumor models and showed a unique ability to cure mice of very large (~500 mm3) tumors compared with validated antibodies against checkpoints and TNFR superfamily members. Extremely high doses of CTX-471 were well tolerated, with no signs of hepatic toxicity. Collectively, these data demonstrate that CTX-471 is a unique CD137 agonist that displays an excellent safety profile and an unprecedented level of monotherapy efficacy against very large tumors.
Highlights
While checkpoint inhibitors targeting PD-1 or CTLA-4 have been transformative therapies in immuno-oncology, they continue to have limited efficacy in the majority of patients in most indications
CD137L binds to a preformed complex of CD137 and urelumab, while utomilumab blocks ligand binding [16]
In domain mapping experiments using truncated versions of CD137, CTX-471 binds to the membrane proximal cysteine rich domains 3-4 (CRD3-4), similar to utomilumab and in contrast to urelumab, which binds to CRD1-2 (Figure 1B)
Summary
While checkpoint inhibitors targeting PD-1 or CTLA-4 have been transformative therapies in immuno-oncology, they continue to have limited efficacy in the majority of patients in most indications. Agonistic antibodies against costimulatory immune receptors, including members of the TNF receptor superfamily (TNFRSF), have potential to complement checkpoint blockers by directly activating immune cells [1]. Activation of CD137 delivers potent costimulatory signals to CD8+ cytotoxic T cells, promoting cell proliferation, facilitating differentiation into memory cells, and delivering important survival signals. The incorporation of the intracellular signaling domain of CD137 has improved the clinical activity of the second generation of CAR T cell therapies, indicating an important role of CD137 signaling in effective antitumor immunity [3, 4]. CD137 stimulation enhances NK cell proliferation and IFN-γ production, and it increases the ability of NK cells to perform antibody-dependent cell-mediated cytotoxicity (ADCC) against tumor cells, demonstrating potential of CD137 agonists to invoke and bridge innate and adaptive immunity [2]
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