title: An efficient chemical approach to bispecific antibodies and antibodies of high valency.
abstract: Irreversible chemical programming of monoclonal aldolase antibody (mAb) 38C2 has been accomplished with beta-lactam equipped mono- and bifunctional targeting modules, including a cyclic-RGD peptide linked to either the peptide (D-Lys(6))-LHRH or another cyclic RGD unit and a small-molecule integrin inhibitor SCS-873 conjugated to (D-Lys(6))LHRH. We also prepared monofunctional targeting modules containing either cyclic RGD or (D-Lys(6))-LHRH peptides. Binding of the chemically programmed antibodies to integrin receptors alpha(v)beta(3) and alpha(v)beta(5) and to the luteinizing hormone releasing hormone receptor were evaluated. The bifunctional and bivalent c-RGD/LHRH and SCS-783/LHRH, the monofunctional and tetravalent c-RGD/c-RGD, and the monofunctional bivalent c-RGD chemically programmed antibodies bound specifically to the isolated integrin receptor proteins as well as to integrins expressed on human melanoma M-21 cells. c-RGD/LHRH, SCS-783/LHRH, and LHRH chemically programmed antibodies bound specifically to the LHRH receptors expressed on human ovarian cancer cells. This approach provides an efficient, versatile, and economically viable route to high-valency therapeutic antibodies that target defined combinations of specific receptors. Additionally, this approach should be applicable to chemically programmed vaccines.
authors.affiliation: The Skaggs Institute for Chemical Biology, Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Julia I
authors.initials: JI
authors.lastname: Gavrilyuk
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wuellner
authors.forename: Syed
authors.initials: S
authors.lastname: Salahuddin
authors.forename: Rajib K
authors.initials: RK
authors.lastname: Goswami
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Sinha
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Barbas
mesh_terms: D018033:Antibodies, Bispecific / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry; D045744:Cell Line, Tumor; D005634:Fructose-Bisphosphate Aldolase / Q000737:chemistry / Q000276:immunology; D007987:Gonadotropin-Releasing Hormone / Q000737:chemistry; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry; D011966:Receptors, LHRH / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000378:metabolism; D001618:beta-Lactamases / Q000096:biosynthesis / Q000276:immunology
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D011966:Receptors, LHRH; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D007987:Gonadotropin-Releasing Hormone; C047981:arginyl-glycyl-aspartic acid; D001618:beta-Lactamases; D005634:Fructose-Bisphosphate Aldolase