A novel mouse strain optimized for chronic human antibody administration

Proc Natl Acad Sci U S A. 2022 Mar 8;119(10):e2123002119. doi: 10.1073/pnas.2123002119. Epub 2022 Mar 2.

Abstract

Therapeutic human IgG antibodies are routinely tested in mouse models of oncologic, infectious, and autoimmune diseases. However, assessing the efficacy and safety of long-term administration of these agents has been limited by endogenous anti-human IgG immune responses that act to clear human IgG from serum and relevant tissues, thereby reducing their efficacy and contributing to immune complex–mediated pathologies, confounding evaluation of potential toxicity. For this reason, human antibody treatment in mice is generally limited in duration and dosing, thus failing to recapitulate the potential clinical applications of these therapeutics. Here, we report the development of a mouse model that is tolerant of chronic human antibody administration. This model combines both a human IgG1 heavy chain knock-in and a full recapitulation of human Fc receptor (FcγR) expression, providing a unique platform for in vivo testing of human monoclonal antibodies with relevant receptors beyond the short term. Compared to controls, hIgG1 knock-in mice mount minimal anti-human IgG responses, allowing for the persistence of therapeutically active circulating human IgG even in the late stages of treatment in chronic models of immune thrombocytopenic purpura and metastatic melanoma.

Keywords: Fc receptors; humanized mouse; immunoglobulin; tolerance.

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antibodies, Monoclonal, Humanized / toxicity
  • Antibody Formation / genetics
  • Chronic Disease
  • Humans
  • Immune Tolerance
  • Immunoglobulin G / administration & dosage
  • Immunoglobulin G / genetics
  • Immunoglobulin G / immunology*
  • Immunoglobulin Heavy Chains / genetics
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Transgenic
  • Models, Animal
  • Purpura, Thrombocytopenic, Idiopathic / immunology
  • Purpura, Thrombocytopenic, Idiopathic / therapy

Substances

  • Antibodies, Monoclonal, Humanized
  • Immunoglobulin G
  • Immunoglobulin Heavy Chains