Small molecule drug activity in melanoma models may be dramatically enhanced with an antibody effector.
Monoclonal antibody (mAb) 38C2 belongs to a group of catalytic antibodies that were generated by reactive immunization and contains a reactive lysine. 38C2 catalyzes aldol and retro-aldol reactions, using an enamine mechanism, and mechanistically mimics natural aldolase enzymes. In addition, mAb 38C2 can be redirected to target integrins alpha(v)beta(3) and alpha(v)beta(5) through the formation of a covalent bond between a beta-diketone derivative of an arginine-glycine-aspartic acid (RGD) peptidomimetic and the reactive lysine residue in the antibody combining site to provide the chemically programmed mAb cp38C2. In this study, we investigated the potential of enhancing the activity of receptor-binding small molecule drug (SCS-873) through antibody conjugation. Using a M21 human melanoma xenograft model in nude mice, cp38C2 inhibited the growth of the tumor by 81%. The chemically programmed antibody was shown to be highly active at a low concentration while SCS-873 alone was ineffective even at dosages 1,000-fold higher than those used for the chemically programmed antibody. In vitro programming of the catalytic antibody was shown to be as effective as in vivo programming. In an experimental metastasis assay, treatment with mAb cp38C2 significantly prolonged overall survival of tumor-bearing severe combined immuno-deficient (SCID) mice when compared to treatment with unprogrammed mAb 38C2, SCS-873 alone or the integrin-specific monoclonal antibody LM609. In vitro, cp38C2 inhibited human and mouse endothelial and human melanoma cell adhesion, migration and invasion. Additionally, cp38C2 inhibited human and mouse endothelial cell proliferation and was active in complement-dependent cytotoxicity assays. These studies establish the potential of chemically programmed monoclonal antibodies as a novel and effective class of immunotherapeutics that combine the merits of traditional small molecule drug design with immunotherapy.
Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Mikhail
M
Popkov
Christoph
C
Rader
Beatriz
B
Gonzalez
Subhash C
SC
Sinha
Carlos F
CF
Barbas
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D005434:Flow Cytometry; D005634:Fructose-Bisphosphate Aldolase / Q000494:pharmacology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D016023:Integrins / Q000187:drug effects* / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007140:Immunoglobulin Fab Fragments; D016023:Integrins; C109536:antibody aldolase; D005634:Fructose-Bisphosphate Aldolase