Chemically programmed monoclonal antibodies for cancer therapy: adaptor immunotherapy based on a covalent antibody catalyst.
Proposing that a blend of the chemical diversity of small synthetic molecules with the immunological characteristics of the antibody molecule will lead to therapeutic agents with superior properties, we here present a device that equips small synthetic molecules with both effector function and long serum half-life of a generic antibody molecule. As a prototype, we developed a targeting device that is based on the formation of a covalent bond of defined stoichiometry between a 1,3-diketone derivative of an integrin alpha(v)beta(3) and alpha(v)beta(5) targeting Arg-Gly-Asp peptidomimetic and the reactive lysine of aldolase antibody 38C2. The resulting complex was shown to (i) spontaneously assemble in vitro and in vivo, (ii) selectively retarget antibody 38C2 to the surface of cells expressing integrins alpha(v)beta(3) and alpha(v)beta(5), (iii) dramatically increase the circulatory half-life of the Arg-Gly-Asp peptidomimetic, and (iv) effectively reduce tumor growth in animal models of human Kaposi's sarcoma and colon cancer. This immunotherapeutic has the potential to target a variety of human cancers, acting on both the vasculature that supports tumor growth as well as the tumor cells themselves. Further, by use of a generic antibody molecule that forms a covalent bond with a 1,3-diketone functionality, essentially any compound can be turned into an immunotherapeutic agent thereby not only increasing the diversity space that can be accessed but also multiplying the therapeutic effect.
Rader
Christoph
C
Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Sinha
Subhash C
SC
Popkov
Mikhail
M
Lerner
Richard A
RA
Barbas
Carlos F
CF
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002384:Catalysis; D006801:Humans; D007167:Immunotherapy; D009369:Neoplasms / Q000628:therapy*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal