Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human PD-1xLAG-3–Knockin Mice

Abstract

In the tumor microenvironment, multiple inhibitory checkpoint receptors can suppress T-cell function, thereby enabling tumor immune evasion. Blockade of one of these checkpoint receptors, PD-1, with therapeutic antibodies has produced positive clinical responses in various cancers; however, the efficacy of this approach can be further improved. Simultaneously targeting multiple inhibitory checkpoint receptors has emerged as a promising therapeutic strategy. Here, we report the development and characterization of REGN3767, a fully human IgG4 antibody targeting LAG-3, another inhibitory receptor on T cells. REGN3767 binds human and monkey LAG-3 with high affinity and specificity and blocks the interaction of LAG-3 with its ligand, MHC class II. In an engineered T-cell/antigenpresenting cell bioassay, REGN3767 alone, or in combina-tion with cemiplimab (REGN2810, human anti-PD-1 antibody), blocked inhibitory signaling to T cells mediated by hLAG-3/MHCII in the presence of PD-1/PD-L1. To test the in vivo activity of REGN3767 alone or in combination with cemiplimab, we generated human PD-1xLAG-3 knockin mice, in which the extracellular domains of mouse Pdcd1 and Lag3 were replaced with their human counterparts. In these humanized mice, treatment with cemiplimab and REGN3767 showed increased efficacy in a mouse tumor model and enhanced the secretion of proinflammatory cytokines by tumor-specific T cells. The favorable pharmacokinetics and toxicology of REGN3767 in nonhuman primates, together with enhancement of antitumor efficacy of anti-PD-1 antibody in preclinical tumor models, support its clinical development.

The Next-Generation Immune Checkpoint LAG-3 and Its Therapeutic Potential in Oncology: Third Time’s a Charm

“…Since its discovery, many preclinical studies confirmed that the blockade of LAG-3 could support anti-cancer immune responses, leading to a significant delay in tumor growth compared to control conditions [ 3 , 4 , 103 , 104 , 105 , 106 , 107 , 108 , 109 ]. Notwithstanding these preclinical data, more recent clinical research shows that the blockade of LAG-3 alone might not be an ideal treatment strategy.…”

PD-1/PD-L1 Based Combinational Cancer Therapy: Icing on the Cake

“…In these humanized mice, treatment with cemiplimab and REGN3767 showed increased efficacy in a mouse tumor model and enhanced the secretion of proinflammatory cytokines by tumor-specific T cells. The favorable pharmacokinetics and toxicology of REGN3767 in non-human primates, together with enhancement of antitumor efficacy of anti-PD-1 Ab in preclinical tumor models, supports its clinical development (Burova et al, 2019).…”

Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy

“…Combination treatment with mAbs against both negative receptors significantly reduced tumor growth in mouse models that were unresponsive to monotherapy mAb treatment, which indicates synergy between the PD-1 and LAG-3 inhibitory pathways ( 232 ). Other mouse studies revealed that anti-LAG-3 mAbs enhanced anti-PD-1 therapies and increased the secretion of activating cytokines released by tumor-infiltrating T cells ( 233 ).…”