Direct targeting of αvβ3 integrin on tumor cells with a monoclonal antibody, Abegrin™

Abstract

The humanized monoclonal antibody Abegrin TM , currently in phase II trials for treatment of solid tumors, specifically recognizes the integrin A v B 3 . Due to its high expression on mature osteoclasts, angiogenic endothelial cells, and tumor cells, integrin A v B 3 functions in several pathologic processes important to tumor growth and metastasis. Targeting of this integrin with Abegrin TM results in antitumor, antiangiogenic, and antiosteolytic activities. Here, we exploit the species specificity of Abegrin TM to evaluate the effects of direct targeting of tumor cells (independent of targeting of endothelia or osteoclasts). Flow cytometry analysis of human tumor cell lines shows high levels of A v B 3 on many solid tumors, including cancers of the prostate, skin, ovary, kidney, lung, and breast. We also show that tumor growth of A v B 3 -expressing tumor cells is inhibited by Abegrin TM in a dose-dependent manner. We present a novel finding that high-dose administration can actively impair the antitumor activity of Abegrin TM . We also provide evidence that antibody-dependent cellular cytotoxicity contributes to in vitro and in vivo antitumor activity. Finally, it was observed that peak biological activity of Abegrin TM arises at serum levels that are consistent with those achieved in clinical trials. These results support a concept that Abegrin TM can be used to achieve selective targeting of the many tumor cells that express A v B 3 integrin. In combination with the well-established concept that A v B 3 plays a key role in cancer-associated angiogenesis and osteolytic activities, this triad of activity could provide new opportunities for therapeutic targeting of cancer.

Integrin αvβ3-Targeted Radioimmunotherapy of Glioblastoma Multiforme

“…In our study, Abegrin treatment alone did not induce tumor regression, apoptosis, or vascular injury. One possible reason may be the ''dose-limited'' antitumor activity whereby high-dose Abegrin therapy does not induce the same tumor regression observed at low doses (27). Thus, the majority of cytotoxicity seen with 90 Y-Abegrin may be attributed to radiation-induced damage rather than a V h 3 signaling inhibition.…”

“…It has shown high glioma-specific uptake as well as ideal pharmacokinetics and dose optimization in glioblastoma multiforme murine models (12). It is hypothesized that the ''triad'' of Abegrin activity results in the reduction of tumor growth, angiogenesis, and distant metastasis (27). Thus, this antibody is well suited for targeting glioblastoma multiforme cells in vivo.…”

β1 and β3 integrins in breast, prostate and pancreatic cancer: A novel implication (Review)

“…In preclinical studies, the antagonists of β1 or β3 integrin effectively inhibited tumor growth by affecting tumor cells and tumor-associated host cells (33,40,(42)(43)(44)(45). These antagonists include monoclonal antibodies and arginylglycylaspartic acid (RGD) peptide mimetics, which mimic the structure of the RGD sequence in the ligands, and inhibit the binding of integrins with their ligands.…”

“…Regarding monoclonal antibodies, etaracizumab, a function-blocking monoclonal antibody of αvβ3 integrin, has demonstrated anti-angiogenic activity, direct inhibition of the tumor cell growth and a reduction in bone metastasis rates in preclinical studies (43,45). In clinical trials, etaracizumab also demonstrated antiangiogenic activity, low toxicity and disease stabilization in patients with certain types of cancer (48,49).…”

The Foxc2 Transcription Factor Regulates Angiogenesis via Induction of Integrin β3 Expression

“…However, given that Itgb3 and Itgb5 are highly expressed in vascular vessels in pathological angiogenesis, blockade of these integrins with specific antagonists inhibits angiogenesis in cancer as well as arthritis and ischemic retinopathy (2,5,6). Therefore, as a therapeutic approach to prevent pathological angiogenesis and tumor growth, Abegrin, a humanized monoclonal antibody that targets ␣v␤3 integrin, is being tested in the phase II clinical trial for antitumor therapy of melanoma patients (7).…”