Integrin alpha(v)beta3 targeted therapy for Kaposi's sarcoma with an in vitro evolved antibody.
Here, we define integrin alpha(v)beta3 as a molecular target for antibody therapy for Kaposi's sarcoma (KS). We previously reported, using a new phage display strategy based on designed combinatorial V gene libraries, the humanization of mouse monoclonal antibody LM609 directed to human integrin alpha(v)beta3. In the present study, we describe the in vitro affinity maturation of humanized LM609 by using a phage display strategy for the sequential and parallel optimization of three complementarity determining regions of the antibody molecule. The evolved Fab had an affinity of 150 pM and was converted into IgG1 by use of a new mammalian expression vector. The resulting whole antibody, designated JC-7U IgG1, was found to selectively target human KS in a nude mouse model and inhibit tumor growth at a therapeutically relevant dose. Because of its high affinity and its high degree of humanization, JC-7U IgG1 is an excellent drug candidate for therapeutic applications that involve integrin alpha(v)beta3 as the molecular target. Of particular interest is therapy for KS, breast cancer, melanoma, and other cancers in which integrin alpha(v)beta3 is expressed on both angiogenic endothelial cells and tumor cells, which would allow a dual antiangiogenic and antitumor strike with a single drug.
Rader
Christoph
C
Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA. carlos@scripps.edu
Popkov
Mikhail
M
Neves
John A
JA
Barbas
Carlos F
CF
D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002455:Cell Division; D019020:Directed Molecular Evolution; D016503:Drug Delivery Systems; D015696:Gene Products, tat / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D019151:Peptide Library; D012514:Sarcoma, Kaposi / Q000473:pathology / Q000628:therapy*
D000906:Antibodies; D000970:Antineoplastic Agents; D015696:Gene Products, tat; D039302:Integrin alphaVbeta3; D019151:Peptide Library