RenMice™ HiTS platform enables identification of novel therapeutic antibodies

Abstract

Abstract Despite an increase in approved cancer-targeting antibody drugs over the last decade, the process of identifying novel therapeutic antibodies is routinely hampered by limitations in the discovery process. Such barriers include immune tolerance of highly homologous genes, antibody sequence humanization, clone selection and models for drug efficacy/safety evaluation. To overcome these challenges and increase the diversity of antibody paratopes and sequences that recognize functional epitopes, we developed the RenMice™ HiTS (Hyperimmune Target Specific) Platform, which consists of chromosome engineered mice with fully human immunoglobulin variable domains replacing the mouse loci, each with a specific target gene knocked out. Immunization of target-specific RenMice™ generates a sizeable diversity of antibodies, including those that recognize conserved regions between the antigen and the endogenous proteins of the immunized species. The platform is ideal for challenging targets, such as proteins with high homology across species, or multi-pass transmembrane proteins, such as GPCRs/ion channels, and can be used to generate antibodies that cross-react with human, monkey, dog, and mouse targets using a hybrid immunization strategy with both human and mouse/dog antigen. Generation of these species cross-reactive antibodies can be used for high-throughput in vivo efficacy screening in wild-type mice, and the preliminary response and toxicity can be assessed in dogs. Altogether, the RenMice™ HiTS platform facilitates the generation of antibodies that recognize novel epitopes and challenging targets while simultaneously allowing for a streamlined and successful preclinical phase based on in vivo efficacy and safety.