Description:
A Genetically Humanized Mouse for Preclinical Testing of Specific Reagents Targeting Human CD81 and/or Occludin for study of B cell Lymphoma and Hepatitis C
Docket# 19-3577-1
The tetraspanin CD81, which is part of the B cell receptor complex, has emerged as an important immunotherapeutic target for treating B cell lymphoma. Researchers at Princeton University have constructed a knock-in mouse in which the second extracellular loop of CD81 was replaced with the respective human sequence. In this mouse model, humanized CD81 is expressed at physiological levels. Mice bearing the humanized allele do not exhibit any immunologic abnormalities. This mouse model has great utility for efficacy testing of compounds, including but not limited to biologics and small molecules, interacting specifically with the human extracellular loops of CD81.
Human CD81 is also a receptor for hepatitis C virus (HCV) which causes chronic infection in at least 71 million individuals world-wide. Despite the introduction of highly effective and directly acting antivirals, the number of chronic carriers has not decreased and new infections remain high. Thus, the development of a prophylactic vaccine remains a top priority. It was previously demonstrated that differences in the amino acid sequences between the human and mouse orthologues of two essential host factors, CD81 and the tight junction protein occludin (OCLN), are responsible for HCV’s limited ability to enter mouse hepatocytes.
To study HCV infection in vivo, scientist at Princeton University have created a knock-in mouse in which the second extracellular loop of OCLN was replaced with the human sequence, which is critical for HCV uptake. Similar to the human CD81 knock-in mouse, OCLN is expressed at physiological levels. Mice bearing the humanized OCLN allele form normal tight junctions. Importantly, in mice in which both human CD81 and OCLN alleles are combined, HCV can enter mouse hepatocyte with an efficiency similar to that in mice expressing CD81 and OCLN transgenically or adenovirally. These experiments highlight the utility of the model for studying HCV infection in vivo and for testing the efficacy of anti-HCV vaccines.
Applications:
• Humanized mouse model to test human CD81 immuno-therapeutics against B cell lymphomas and related diseases
• Humanized mouse model to test the efficacy of anti-HCV vaccines and efficacy of compounds interfering with uptake of HCV
• Model to test human monoclonal antibodies binding to the second extracellular loops of CD81 and/or OCLN
Advantages:
• Only mouse model that expresses partially human CD81 and/or OCLN under the control of endogenous murine promoters
• Established and well characterized model to study uptake and infection of HCV in vivo
Stage of Development
The researchers have experimentally verified that the knock-in mice can take up HCV with an efficiency similar to that in mice expressing CD81 and OCLN transgenically or adenovirally. Mice harboring the humanized alleles developed normally and did not exhibit any overt phenotype.
Publication
Ding Q, von Schaewen M, Hrebikova G, Heller B, Sandmann L, Plaas M, Ploss A. Mice Expressing Minimally Humanized CD81 and Occludin Genes Support Hepatitis C Virus Uptake In Vivo. J Virol. 2017 Jan 31;91(4).
Faculty Inventor
Alexander Ploss is an Associate Professor in the Department of Molecular Biology at Princeton University. He completed his Ph.D. in Immunology at Memorial Sloan-Kettering Cancer Center and Cornell University and postdoctoral training at the Rockefeller University in New York. Dr. Ploss held previously faculty positions at the Rockefeller University before joining the faculty of the Department of Molecular Biology at Princeton University where he is currently an Associate Professor. His research focuses on analyzing the host tropism of human hepatotropic pathogens and the construction of humanized animal models to study host responses at the organismal level. In support and recognition of his work he received several awards including the including the Astella’s Young Investigator Award from the Infectious Disease Society of America, the Liver Scholar Award from the American Liver Foundation, the Löffler-Frosch Prize from the German Society of Virology, Merck Irving Sigal Memorial Award from the American Society for Microbiology and the Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease Award. Professor Ploss is a member of the Genomic Instability and Tumor Progression Program at the Cancer Institute of NJ.
Intellectual Property Status
Patent protection is pending. Princeton is currently seeking commercial partners for the further development and commercialization of this opportunity.
Contacts
Laurie Tzodikov
Princeton University Office of Technology Licensing • (609) 258-7256• tzodikov@princeton.edu