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 β-lactam equipped mono- and bifunctional targeting modules, including a cyclic-RGD peptide linked to either the peptide (D-Lys6)-LHRH or another cyclic RGD unit and a small-molecule integrin inhibitor SCS-873 conjugated to (D-Lys6)LHRH. We also prepared monofunctional targeting modules containing either cyclic RGD or (D-Lys6)-LHRH peptides. Binding of the chemically programmed antibodies to integrin receptors α(v)β(3) and α(v)β(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 M21 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.

The Design and Characterization of Oligospecific Antibodies for Simultaneous Targeting of Multiple Disease Mediators

“…However, an efficient chemical approach for generating IgG-like bispecific antibodies had just been reported. 49 A monoclonal aldolase antibody was used as the backbone. Bifunctional targeting modules were then coupled to the antibody via amide bond formation with the lysine residue (catalytic site) located near the heavy-chain complementarity-determining region (CDR)-3.…”

Cyclic-RGD Peptides Increase the Adenoviral Transduction of Human Mesenchymal Stem Cells

“…Cyclic-RGD peptides have been covalently immobilized or genetically engineered into polymers [27], proteins [28], and therapeutic viruses to increase their internalization into cells [29]. However, these approaches could denature the biomolecules and have required reaction and purification schemes.…”

Chemical generation of bispecific antibodies

“…Here, we report a technology based on the aldolase catalytic antibodies (11)(12)(13)(14)(15) that facilitates rapid generation and optimization of unique bispecific agents termed bispecific CovX-Bodies. A bispecific CovX-Body contains two different pharmacophores, covalently bound to the nucleophilic heavy chain lysine at position 93 (according to Kabat numbering, ref.…”