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

Mol Cancer Ther. 2019 Nov;18(11):2051-2062. doi: 10.1158/1535-7163.MCT-18-1376. Epub 2019 Aug 8.


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/antigen-presenting cell bioassay, REGN3767 alone, or in combination 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antigens, CD / chemistry*
  • Antigens, CD / genetics*
  • Antigens, CD / metabolism
  • Antineoplastic Agents, Immunological / administration & dosage*
  • Antineoplastic Agents, Immunological / chemistry
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Female
  • Gene Knock-In Techniques
  • Haplorhini
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Lymphocyte Activation Gene 3 Protein
  • Mice
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Programmed Cell Death 1 Receptor / genetics*
  • Protein Binding / drug effects
  • Signal Transduction / drug effects
  • Tumor Microenvironment / drug effects
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal, Humanized
  • Antigens, CD
  • Antineoplastic Agents, Immunological
  • Histocompatibility Antigens Class II
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • cemiplimab
  • Lymphocyte Activation Gene 3 Protein