Humanized Cell Membrane Molecules

Model for Biologics Evaluation

The exponential development of monoclonal antibody and biologics has paved the way for innovative therapies. In vivo evaluation of monoclonal antibodies requires new types of animal models. Because of their high specificity, monoclonal antibodies cannot be properly evaluated on mouse proteins. Evaluation can only occur in a humanized animal model where the antibody will bind to the human antigen. Most of the time, it is required that after humanization the transduction pathway stays functional, which means that the human antigen be able to functionally substitute for the mouse homolog. Availability of a humanized model has become a compulsory step for the evaluation of monoclonal antibodies and biologics. Relying on its experience in humanized models (more than 250 models successfully created), genOway is recognized for its excellence in the development of humanized models for biologics testing.

 

Case study: Humanization of CTLA-4 (Cytotoxic T-lymphocyte antigen) for in vivo testing of monoclonal antibodies specificity and efficacy.

CTLA-4, a high affinity receptor for CD80 and CD86, can inhibit T-cell activation. Blocking of CTLA-4 has been shown to promote anti-tumor immunity.

Adapted from Lute et al. Blood 2005. Human CTLA-4 knock-in mice unravel the quantitative link between tumor immunity and autoimmunity induced by anti–CTLA-4 antibodies.

T-cell activation inhibition by CTLA-4 in humanized mice

 

Human CTLA-4 Gene is Expressed 

Human CTLA-4 gene is expressed in humanized animals, substituting the inactivated murine CTLA-4 gene.

Expression studies were performed by FACS on unstimulated CD4 splenocytes.

 

lymphoid development in CTLA-4 humanized mice

Human CTLA-4 Gene is Functional

Human CTLA-4 genes functionally substitute murine CTLA-4 genes.

Normal development of lymphoid organs in humanized CTLA-4 mice.

 

Antibody selection in humanized CTLA-4 miceHumanized CTLA-4 Model is a Highly Valuable Screening Tool

Reliable discrimination of therapeutic activity between anti-CTLA-4 antobodies with identical affinity and isotope in humanized CTLA-4 mice.

A complete rejection of tumors was observed in 2 out of 9 mice as well as a delayed tumor growth (data not shown) in the antibody 3-treated group.