Generation of fully human anti-GPC3 antibodies with high-affinity recognition of GPC3 positive tumors.

ABSTRACT

The acceleration of therapeutic antibody development has been motivated by the benefit to and their demand for human health. In particular, humanized transgenic antibody discovery platforms, combined with immunization, hybridoma fusion and/or single cell DNA sequencing are the most reliable and rapid methods for mining the human monoclonal antibodies. Human GPC3 protein is an oncofetal antigen, and it is highly expressed in most hepatocellular carcinomas and some types of squamous cell carcinomas. Currently, no fully human anti-GPC3 therapeutic antibodies have been reported and evaluated in extensive tumor tissues. Here, we utilized a new humanized transgenic mouse antibody discovery platform (CAMouse) that contains large V(D)J -regions and human gamma-constant regions of human immunoglobulin in authentic configurations to generate fully human anti-GPC3 antibodies. Our experiments resulted in four anti-GPC3 antibodies with high-specific binding and cytotoxicity to GPC3 positive cancer cells, and the antibody affinities are in the nanomolar range. Immunohistochemistry analysis demonstrated that these antibodies can recognize GPC3 protein on many types of solid tumors. In summary, the human anti-human GPC3 monoclonal antibodies described here are leading candidates for further preclinical studies of cancer therapy, further, the CAMouse platform is a robust tool for human therapeutic antibody discovery.