Abstract
Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, however, only a fraction of patients benefit. Combining CD137 agonists with these inhibitors increases anti-tumor activity preclinically, but attempts to translate these observations to the clinic have been hampered by systemic toxicity. Here we describe a human CD137xPD-L1 bispecific antibody, MCLA-145, identified through functional screening of agonist- and immune checkpoint inhibitor arm combinations. MCLA-145 potently activates T cells at sub-nanomolar concentrations, even under suppressive conditions, and enhances T cell priming, differentiation and memory recall responses. In vivo, MCLA-145 anti-tumor activity is superior to immune checkpoint inhibitor comparators and linked to recruitment and intra-tumor expansion of CD8 + T cells. No graft-versus-host-disease is observed in contrast to other antibodies inhibiting the PD-1 and PD-L1 pathway. Non-human primates treated with 100 mg/kg/week of MCLA-145 show no adverse effects. The conditional activation of CD137 signaling by MCLA-145, triggered by neighboring cells expressing >5000 copies of PD-L1, may provide both safety and potency advantages.
Highlights
Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, only a fraction of patients benefit
The bispecific antibody (bAb) were expressed as immunoglobulin G1 (IgG1) molecules with Fc CH3 modifications to force heavy chain heterodimerization[30] and CH2 modifications to abrogate binding to Fc receptors[31]
Our data demonstrate that dual engagement of CD137 and PD-1 or PD-L1 by bAbs either on the same T cell or possibly on adjacent T cells was not able to effectively induce CD137 receptor downstream signaling
Summary
Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, only a fraction of patients benefit. PD-L1 expression can be increased in the tumor microenvironment by IFNγ, a cytokine released by activated T cells[9] Such PD-1/PD-L1 interactions deliver a negative signal to T cells dampening anti-tumor responses. This immune suppression can be blocked by ICIs such as antagonistic antibodies against PD-1 or PD-L18. ICI treatment has demonstrated remarkably durable responses in a subset of cancer patients that are correlated with activated CD8+ T cell infiltration and proliferation[10,11] Combinations of ICIs (e.g., anti-PD-1 and antiCTLA-4) have been shown to further enhance efficacy, at the cost of toxicity, as the majority of patients experience grade 3 or 4 treatment-related adverse events[12]. Strategies that add to the benefit of ICI therapies without further increasing toxicity are needed
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