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.
Fig: Screening of CD137 x PD-1/PD-L1 bAb combinations identifies MCLA-145: a Left panel activity of CD137xPD-L1 and CD137xPD-1 bispecifics in a CD137 NFκB-luc reporter assay (fold induction of luciferase signal) Right panel experiment repeated with the addition of an Fc binding antibody; b Left panel levels of IL-2 released by activated T cells after 3 days of incubation with eight candidate CD137xPD-L1 bAb combinations in a dose titration in the presence of CHO-PD-L1 cells, Right panel, experiment repeated in the presence wildtype CHO cells; c levels of IL-2, IFNγ and TNFα released by activated T cells after 3 days of incubation with the three best performing CD137xPD-L1 bAbs and control antibodies in a dose titration in the presence of CHO-PD-L1 cells (bAb001 = MCLA-145).
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.
Geuijen, C., Tacken, P., Wang, LC. et al. A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade. Nat Commun 12, 4445 (2021). https://doi.org/10.1038/s41467-021-24767-5