Inhibition of Cancer Cell Adhesion, Migration and Proliferation by a Bispecific Antibody that Targets two Distinct Epitopes on αv Integrins. Issue 15 (23rd July 2021)

• Record Type: Journal Article
• Authors: Gallo, Eugenio; Kelil, Abdellali; Haughey, Michael; Cazares-Olivera, Mariana; Yates, Bradley P.; Zhang, Mingjun; Wang, Nai-Yu; Blazer, Levi; Carderelli, Lia; Adams, Jarrett J.; Kossiakoff, Anthony A.; Wells, James A.; Xie, Weilin; Sidhu, Sachdev S.
• Is Part Of: Journal of molecular biology. Volume 433:Issue 15(2021)
• Publication Date: 2021-07-23
• Subjects: integrins -- αvβ1 -- CellectSeq -- bispecific antibody -- cancer therapeutics; TGFβ Transforming growth factor beta -- ECM extracellular matrix -- LAP latency-associated peptide -- Abs antibodies -- SEC size exclusion chromatography -- CHO Chinese hamster ovary -- DMEM Dulbecco's Modified Eagle medium -- FBS fetal bovine seru -- ATCC American Type Culture Collection -- EDTA ethylenediaminetetraacetic acid -- HBSS Hank's Balanced Salt Solution; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2021.167090
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: Cell-based selections identified inhibitory Abs targeting αv integrins. Engineered a bispecific Ab targeting two inhibitory epitopes on αv integrins. The bispecific Ab selectively inhibited integrins αvβ1, αvβ3 and αvβ5. The bispecific Ab inhibited proliferation and migration of lung cancer cells. The bispecific Ab is a therapeutic candidate for cancer and fibrosis. Abstract: 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.