Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity Compared with Traditional Anti–PD-1/PD-L1 Agents
Hikmat H. Assi, Chihunt Wong, Kimberly A. Tipton, Li Mei, Ken Wong, Jennifer Razo, Chanty Chan, Bruce Howng, Jason Sagert, Michael Krimm, Linnea Diep, Andrew Jang, Margaret T. Nguyen, Nicole Lapuyade, Victoria Singson, Ruth Villanueva, Madan Paidhungat, Shouchun Liu, Vangipuram Rangan, Olga Vasiljeva, James W. West, Jennifer H. Richardson, Bryan Irving, Dylan Daniel, Marcia Belvin, W. Michael Kavanaugh
Abstract
Immune-checkpoint blockade has revolutionized cancer treatment. However, most patients do not respond to single-agent therapy. Combining checkpoint inhibitors with other immune-stimulating agents increases both efficacy and toxicity due to systemic T-cell activation. Protease-activatable antibody prodrugs, known as Probody therapeutics (Pb-Tx), localize antibody activity by attenuating capacity to bind antigen until protease activation in the tumor microenvironment. Herein, we show that systemic administration of anti-programmed cell death ligand 1 (anti-PD-L1) and anti-programmed cell death protein 1 (anti-PD-1) Pb-Tx to tumor-bearing mice elicited antitumor activity similar to that of traditional PD-1/PD-L1-targeted antibodies. Pb-Tx exhibited reduced systemic activity and an improved nonclinical safety profile, with markedly reduced target occupancy on peripheral T cells and reduced incidence of early-onset autoimmune diabetes in nonobese diabetic mice. Our results confirm that localized PD-1/PD-L1 inhibition by Pb-Tx can elicit robust antitumor immunity and minimize systemic immune-mediated toxicity. These data provide further preclinical rationale to support the ongoing development of the anti-PD-L1 Pb-Tx CX-072, which is currently in clinical trials.