Eph receptors as cancer targets for antibody-based therapy.

Abstract Receptor tyrosine kinases (RTKs) are integral membrane sensors that govern cell differentiation, proliferation and mobility, and enable rapid communication between cells and their environment. Of the 20 RTK subfamilies currently known, Eph receptors are the largest group. Together with their corresponding ephrin ligands, Eph receptors regulate a diverse array of physiologic processes including axonal guidance, bone remodeling, and immune cell development and trafficking. Deregulation of Eph signaling pathways is linked to cancer and other proliferative diseases and, because RTKs play critical roles in cancer development, the specific targeting of these molecules in malignancies provides a promising treatment approach. Monoclonal antibodies targeting RTKs represent a potentially attractive modality for pharmaceutical development due to their relatively high target specificity and low off-target binding rates. Therefore, new technologies to generate antibodies able to target RTKs in their native in vivo context are likely to facilitate pre-clinical and clinical development of antibody-based therapies. Our group has recently reported a platform discovery methodology termed Selection of Phage-displayed Accessible Recombinant Targeted Antibodies (SPARTA). SPARTA is a novel and robust stepwise method, which combines the attributes of in vitro screenings of a naive human recombinant antibody library against known tumor targets with those features of in vivo selections based on tumor-homing capabilities of a pre-enriched antibody pool. This unique approach overcomes several rate-limiting challenges to generate human monoclonal antibodies amenable to rapid translation into medical applications.