Antibody-Based Targeting of Angiogenesis

Abstract

The selective targeting of neovasculature opens new avenues for the diagnosis and therapy of angiogenesis-related diseases such as cancer, blinding ocular disorders, and rheumatoid arthritis. Here we review recent advances in the identification of markers of angiogenesis as well as in the isolation and use of antibodies (and their derivatives) for the in vivo targeting of both tumoral and nontumoral neovasculature.

The Targeted Immunocytokine L19-IL2 Efficiently Inhibits the Growth of Orthotopic Pancreatic Cancer

“…Third, as neoangiogenesis is a prerequisite of tumor growth and metastasis, the selective targeting approach of L19-Interleukin-2 (IL-2) to newly forming tumor blood vessels should result in a therapeutical benefit. Currently, one of the most selective oncofetal antigens associated with neoangiogenesis and tumor growth is the extradomain B (ED-B) of fibronectin (6,8). The fibronectin splice variant ED-B, a small domain of 91 amino acids, which is homologous from mouse to man, is usually absent in both plasma and tissue-fibronectin, except for some blood vessels of the regenerating endometrium and the ovaries (6,8).…”

“…Currently, one of the most selective oncofetal antigens associated with neoangiogenesis and tumor growth is the extradomain B (ED-B) of fibronectin (6,8). The fibronectin splice variant ED-B, a small domain of 91 amino acids, which is homologous from mouse to man, is usually absent in both plasma and tissue-fibronectin, except for some blood vessels of the regenerating endometrium and the ovaries (6,8). However, it may become inserted in the fibronectin molecule during active tissue remodeling associated with neoangiogenesis, thereby accumulating around the neovasculature and in the stroma of malignant tumors and other tissues undergoing angiogenesis (6,8).…”

“…The fibronectin splice variant ED-B, a small domain of 91 amino acids, which is homologous from mouse to man, is usually absent in both plasma and tissue-fibronectin, except for some blood vessels of the regenerating endometrium and the ovaries (6,8). However, it may become inserted in the fibronectin molecule during active tissue remodeling associated with neoangiogenesis, thereby accumulating around the neovasculature and in the stroma of malignant tumors and other tissues undergoing angiogenesis (6,8). Recently, a human single-chain Fv (scFv) antibody fragment L19 has been generated, which displays picomolar binding affinity for ED-B, and has been verified to selectively target tumor neovasculature in both experimental tumor models (9) and patients with cancer (10), thus paving the way for a novel therapeutic approach targeting tumor neovasculature.…”

Selective occlusion of tumor blood vessels by targeted delivery of an antibody‐photosensitizer conjugate

“…18 In the past, we have shown that the photosensitizer bis(triethanolamine)Sn(IV) chlorin e 6 (SnChe 6 ), coupled to the scFv(L19) monoclonal antibody fragment, mediated the selective occlusion of new blood vessels induced in the rabbit cornea, after irradiation with red light. 19 The human antibody fragment scFv(L19), 20 specific to the EDB domain of fibronectin, a marker of angiogenesis, [21][22][23][24] has been shown to localize to the tumor neovasculature after intravenous administration, both in animal models of cancer [25][26][27][28] and in patients with solid tumors. 29 Fusion proteins, based on scFv(L19), are capable of selective localization in tumors and display a potent anticancer activity in rodents.…”

Tumor‐targeting properties of antibody–vascular endothelial growth factor fusion proteins

“…7,8 Vascular targeting approaches are interesting for a number of reasons: (i) markers on the tumor neovasculature are readily accessible to i.v.-administered antibody derivatives; (ii) markers of neovasculature are typically produced by endothelial cells and/or fibroblasts, and such cells are genetically more stable than tumor cells; (iii) there is growing evidence that selective damage of the tumor neovasculature may lead to massive death of tumor cells, which rely on blood vessels for nutrients and oxygen to satisfy their metabolic needs 9 (it is estimated that more than 100 tumor cells rely on 1 endothelial cell for survival); (iv) therapeutic strategies directed against the tumor neovasculature appear to reduce the tumor's ability to develop metastases and may overcome multidrug resistance. 10 Angiogenesis, i.e., the formation of new blood vessels from pre-existing ones, is accompanied by the neosynthesis of antigens on tumor endothelial cells and of novel ECM components.…”