Inhibition of Cancer Cell Adhesion, Migration and Proliferation by a Bispecific Antibody that Targets two Distinct Epitopes on αv Integrins.

Autor: Gallo E; University of Toronto, Department of Molecular Genetics, Donnelly Centre, 160 College Street, Toronto, ON M5S 3E1, Canada., Kelil A; University of Toronto, Department of Molecular Genetics, Donnelly Centre, 160 College Street, Toronto, ON M5S 3E1, Canada., Haughey M; Bristol Myers Squibb Co., Discovery Biotherapeutics, 4242 Campus Point Court Suite 700, San Diego, CA 92121, USA., Cazares-Olivera M; University of Toronto, Department of Molecular Genetics, Donnelly Centre, 160 College Street, Toronto, ON M5S 3E1, Canada., Yates BP; University of Toronto, Department of Molecular Genetics, Donnelly Centre, 160 College Street, Toronto, ON M5S 3E1, Canada., Zhang M; Bristol Myers Squibb Co., Discovery Biotherapeutics, 4242 Campus Point Court Suite 700, San Diego, CA 92121, USA., Wang NY; Bristol Myers Squibb Co., Discovery Biotherapeutics, 4242 Campus Point Court Suite 700, San Diego, CA 92121, USA., Blazer L; University of Toronto, Department of Molecular Genetics, Donnelly Centre, 160 College Street, Toronto, ON M5S 3E1, Canada., Carderelli L; University of Toronto, Department of Molecular Genetics, Donnelly Centre, 160 College Street, Toronto, ON M5S 3E1, Canada., Adams JJ; University of Toronto, Department of Molecular Genetics, Donnelly Centre, 160 College Street, Toronto, ON M5S 3E1, Canada., Kossiakoff AA; The University of Chicago, Department of Biochemistry and Molecular Biology, 929 East 57th Street, Chicago, IL 60637, USA., Wells JA; University of California San Francisco, Department of Pharmaceutical Chemistry, 505 Parnassus Ave, San Francisco, CA 94143, USA., Xie W; Bristol Myers Squibb Co., Discovery Biotherapeutics, 4242 Campus Point Court Suite 700, San Diego, CA 92121, USA., Sidhu SS; University of Toronto, Department of Molecular Genetics, Donnelly Centre, 160 College Street, Toronto, ON M5S 3E1, Canada. Electronic address: sachdev.sidhu@utoronto.ca.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2021 Jul 23; Vol. 433 (15), pp. 167090. Date of Electronic Publication: 2021 Jun 04.
DOI: 10.1016/j.jmb.2021.167090
Abstrakt: Members of the αv family of integrins regulate activation of transforming growth factor beta (TGFβ) and are directly involved in pro-tumorigenic phenotypes. Thus, αv 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 αv integrins by phage display selections on cell lines that displayed integrin heterodimers. We identified antibodies that targeted two distinct epitopes on cell-surface αv integrins and partially inhibited cell adhesion mediated by interactions between integrins and the latency-associated peptide, part of the pro-form of TGFβ. 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 αvβ1, αvβ3 and αvβ5. In addition, the bispecific antibody inhibited proliferation and migration of lung carcinoma lines, where the highest and lowest potencies observed correlated with integrin-αv 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.
Competing Interests: Conflict of Interest Statement The authors declare no conflicts of interest.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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