Chemical adaptor immunotherapy: design, synthesis, and evaluation of novel integrin-targeting devices.
A series of beta-diketone derivatives of RGD peptidomimetics that selectively bind to alphavbeta3 and alphavbeta5 integrins were synthesized and covalently docked to the reactive lysine residues of monoclonal aldolase antibody 38C2. The resulting targeting devices strongly and selectively bound to human cancer cells expressing integrins alphavbeta3 and alphavbeta5 as analyzed by flow cytometry. In vitro and in vivo studies revealed that these novel integrin-targeting devices efficiently inhibit tumor growth. Thus, the combination of beta-diketone derivatives of RGD peptidomimetics that target cell surface integrins alphavbeta3 and alphavbeta5 with monoclonal aldolase antibodies through formation of a covalent bond of defined stoichiometry holds promise as a new approach to cancer therapy.
Li
Lian-Sheng
LS
The Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Rader
Christoph
C
Matsushita
Masayuki
M
Das
Sanjib
S
Barbas
Carlos F
CF
Lerner
Richard A
RA
Sinha
Subhash C
SC
D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000494:pharmacology; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D015195:Drug Design; D005260:Female; D005634:Fructose-Bisphosphate Aldolase / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D039302:Integrin alphaVbeta3 / Q000737:chemistry / Q000378:metabolism*; D016023:Integrins / Q000737:chemistry / Q000378:metabolism*; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008239:Lysine / Q000737:chemistry; D008545:Melanoma; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry*; D011485:Protein Binding; D019030:Receptors, Vitronectin / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000911:Antibodies, Monoclonal; D039302:Integrin alphaVbeta3; D016023:Integrins; D007659:Ketones; D009842:Oligopeptides; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; C047981:arginyl-glycyl-aspartic acid; D005634:Fructose-Bisphosphate Aldolase; D008239:Lysine