Antagonist antibodies to vascular endothelial growth factor receptor 2 (VEGFR-2) as anti-angiogenic agents.
Interaction of numerous signaling pathways in endothelial and mesangial cells results in exquisite control of the process of physiological angiogenesis, with a central role played by vascular endothelial growth factor receptor 2 (VEGFR-2) and its cognate ligands. However, deregulated angiogenesis participates in numerous pathological processes. Excessive activation of VEGFR-2 has been found to mediate tissue-damaging vascular changes as well as the induction of blood vessel expansion to support the growth of solid tumors. Consequently, therapeutic intervention aimed at inhibiting the VEGFR-2 pathway has become a mainstay of treatment in cancer and retinal diseases. In this review, we introduce the concepts of physiological and pathological angiogenesis, the crucial role played by the VEGFR-2 pathway in these processes, and the various inhibitors of its activity that have entered the clinical practice. We primarily focus on the development of ramucirumab, the antagonist monoclonal antibody (mAb) that inhibits VEGFR-2 and has recently been approved for use in patients with gastric, colorectal, and lung cancers. We examine in-depth the pre-clinical studies using DC101, the mAb to mouse VEGFR-2, which provided a conceptual foundation for the role of VEGFR-2 in physiological and pathological angiogenesis. Finally, we discuss further clinical development of ramucirumab and the future of targeting the VEGF pathway for the treatment of cancer.
Eli Lilly and Company, Indianapolis, IN, USA.
Beverly L
BL
Falcon
Eli Lilly and Company, Indianapolis, IN, USA.
Sudhakar
S
Chintharlapalli
Biothera, Eagan, MN, USA.
Mark T
MT
Uhlik
Eli Lilly and Company, New York, NY, USA. Electronic address: bronek.pytowski@lilly.com.
Bronislaw
B
Pytowski
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004359:Drug Therapy, Combination; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000503:physiopathology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D000096662:Ramucirumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D040301:Vascular Endothelial Growth Factor Receptor-2; D000096662:Ramucirumab; C511761:DC101 monoclonal antibody
Angiogenesis; DC101; Endothelial cell; Ramucirumab; Tumor vasculature; VEGFR-2