An efficient chemical approach to bispecific antibodies and antibodies of high valency.

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.