期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 433, 期 15, 页码 -出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2021.167090
关键词
integrins; alpha v beta 1;; CellectSeq; bispecific antibody; cancer therapeutics
资金
- Charles H. Best foundation fellowship
- Canadian Institutes of Health Research [MOP-136944]
- Bristol-Myers Squibb
Phage display selections with live cells can generate high quality anti-integrin antibodies, which were used as biparatopic building blocks to construct a bispecific antibody that strongly inhibits integrin function, making it a potential therapeutic candidate for cancer and fibrosis.
Members of the alpha v family of integrins regulate activation of transforming growth factor beta (TGF beta) and are directly involved in pro-tumorigenic phenotypes. Thus, alpha v integrins may be therapeutic targets for fibrosis and cancer, yet the isolation of selective inhibitors is currently a challenge. We generated synthetic antibodies selective for alpha v integrins by phage display selections on cell lines that displayed integrin heterodimers. We identified antibodies that targeted two distinct epitopes on cell-surface alpha v integrins and partially inhibited cell adhesion mediated by interactions between integrins and the latency-associated peptide, part of the pro-form of TGF beta. Using the isolated antibody paratope sequences we engineered a bispecific antibody capable of binding to both epitopes simultaneously; this antibody potently and completely inhibited cell adhesion mediated by integrins alpha v beta 1, alpha v beta 3 and alpha v beta 5. In addition, the bispecific antibody inhibited proliferation and migration of lung carcinoma lines, where the highest and lowest potencies observed correlated with integrin-alpha v cell surface expression levels. Taken together, our results demonstrate that phage display selections with live cells can yield high quality anti-integrin antibodies, which we used as biparatopic building blocks to construct a bispecific antibody that strongly inhibited integrin function and may be a therapeutic candidate for cancer and fibrosis. (C) 2021 Elsevier Ltd. All rights reserved.
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