In light of recent experience with adverse reactions associated with the immunostimulatory properties of anti-CD28, GCGH projects proposing antibody-based vaccine delivery systems or immunotherapeutics for specific infectious diseases will benefit from the availability of improved predictive methods for pre-clinical safety evaluation of their approach before proceeding to human trials.
Among the factors that may play a role in the toxicity of antibody-based products are the affinities of the individual activating and inhibitory Fc receptors for a specific IgG ligand and the expression level of the receptor pairs on antigen presenting and immune effector cells.
The physiological response is the net of the opposing activation and inhibitory signaling pathways that each receptor triggers. The affinity of different antibody isotypes and subclasses for their respective activating and inhibitory FcRs varies significantly, thus explaining the differential activity of antibody isotypes in vivo.
There is, at present, no animal system that fully recapitulates the diversity and allelic complexity of the human FcR system. We propose to develop mice that are fully humanized with respect to their Fcγ receptors as a critical path development tool for the evaluation of humanized antibodies and Fc-based products. FcR humanized mice will provide a sensitive model to test the in vivo properties of human IgG’s since these mice will express FcR in a tissue restricted fashion for studies of safety and immune efficacy.
This work supports the following GCGH grants: