Abstract
The Eph subfamily of receptor tyrosine kinases mediate cell-cell communication controlling cell and tissue patterning during development. While generally less active in adult tissues, they often re-emerge in cancers, particularly on undifferentiated or progenitor cells in tumors and the tumor microenvironment, associated with tumor initiation, angiogenesis and metastasis. Eph receptors are thus attractive therapeutic targets, and monoclonal antibodies have been commonly developed and tested for anti-cancer activity in preclinical models, and in some cases in the clinic. This review summarizes 20 years of research on various antibody-based approaches to target Eph receptors in tumors and the tumor microenvironment, including their mode of action, tumor specificity, and efficacy in pre-clinical and clinical testing.
Highlights
IntroductionEph receptors (first isolated from an Erythropoietin-Producing Hepatocellular carcinoma) are receptor tyrosine kinases (RTKs) that mediate cell-cell interactions with their cell-bound ephrin ligands, controlling adhesion and migration, and influencing proliferation and cell fate
Eph receptors are receptor tyrosine kinases (RTKs) that mediate cell-cell interactions with their cell-bound ephrin ligands, controlling adhesion and migration, and influencing proliferation and cell fate
Ephs make up the largest family of RTKs, with 14 members classified into two subtypes, A and B, distinguished by sequence similarity, and their preferential binding to A- and B-type ephrins, respectively
Summary
Eph receptors (first isolated from an Erythropoietin-Producing Hepatocellular carcinoma) are receptor tyrosine kinases (RTKs) that mediate cell-cell interactions with their cell-bound ephrin ligands, controlling adhesion and migration, and influencing proliferation and cell fate. Two antibodies against the fibronectin domains in EphB4, mAb47 and mAb131, were found to inhibit tumor growth in a range of EphB4-expressing xenograft models, including prostate, colon, head and neck, and ovarian cancer [54] These appeared to function differently: mAb131 recognized only human EphB4 on the tumor cells, and caused receptor endocytosis and degradation; whereas mAb47, recognizing mouse EphB4, severely blocked blood vessel perfusion in tumors, and was active against tumors in which the tumor cells did not express EphB4, consistent with targeting the TME. MAb131 was shown to be effective in acute myeloid leukemia (AML) [70] Another mAb (C2), targeting the cysteine-rich domain of EphB4, inhibited the tube-forming behavior of MDA-MB-231 breast tumor cells in vitro (indicative of vasculogenic behavior), and tumor growth of xenografts; xenografts of PC3 prostate cells were unaffected, thought to be due to their low cell surface receptor expression [55]
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