title: Chemically programmed antibodies targeting multiple alpha(v) integrins and their effects on tumor-related functions in vitro.
abstract: Integrins αvβ3 and αvβ6 are highly expressed on tumor cells and/or by the tumor vasculature of many human cancers, and represent promising targets for anticancer therapy. Novel chemically programmed antibodies (cpAbs) targeting these integrins were prepared using the catalytic aldolase Antibody (Ab) programming strategy. The effects of the cpAbs on cellular functions related to tumor progression were examined in vitro using tumor cell lines and their cognate integrin ligands, fibronectin and osteopontin. The inhibitory functions of the conjugates and their specificity were examined based on interference with cell-cell and cell-ligand interactions related to tumor progression. Cell binding analyses of the anti-integrin cpAbs revealed high affinity for tumor cells that overexpressed αvβ3 and αvβ6 integrins, and weak interactions with αvβ1 and αvβ8 integrins, in vitro. Functional analyses demonstrated that the cpAbs strongly inhibited cell-cell interactions through osteopontin binding, and they had little or no immediate effects on cell viability and proliferation. On the basis of these characteristics, the cpAbs are likely to have a broad range of activities in vivo, as they can target and antagonize one or multiple αv integrins expressed on tumors and tumor vasculatures. Presumably, these conjugates may inhibit the establishment of metastastatic tumors in distant organs through interfering with cell adhesion more effectively than antibodies or compounds targeting one integrin only. These anti-integrin cpAbs may also provide useful reagents to study combined effect of multiple αv integrins on cellular functions in vitro, on pathologies, including tumor angiogenesis, fibrosis, and epithelial cancers, in vivo.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Rajib K
authors.initials: RK
authors.lastname: Goswami
authors.forename: Krishna M
authors.initials: KM
authors.lastname: Bajjuri
authors.forename: Jane S
authors.initials: JS
authors.lastname: Forsyth
authors.forename: Sanjib
authors.initials: S
authors.lastname: Das
authors.forename: Wolf
authors.initials: W
authors.lastname: Hassenpflug
authors.forename: Zheng-Zheng
authors.initials: ZZ
authors.lastname: Huang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lerner
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Felding-Habermann
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Sinha
mesh_terms: D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents; D002450:Cell Communication; D045744:Cell Line, Tumor; D005634:Fructose-Bisphosphate Aldolase; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D039564:Integrin alphaV / Q000276:immunology*; D039302:Integrin alphaVbeta3 / Q000276:immunology; D016023:Integrins / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology*
chemical_list: D000906:Antibodies; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D039564:Integrin alphaV; D039302:Integrin alphaVbeta3; D016023:Integrins; C073878:integrin alphavbeta6; D005634:Fructose-Bisphosphate Aldolase