Preclinical evaluation of MORAb-003, a humanized monoclonal antibody antagonizing folate receptor-alpha.
The highly restricted distribution of human folate receptor-alpha (FRalpha) in normal tissues and its high expression in some tumors, along with its putative role in tumor cell transformation, make this antigen a suitable target for antigen-specific, monoclonal antibody-based immunotherapy for oncology indications. We have developed a therapeutic humanized monoclonal antibody with high affinity for FRalpha, named MORAb-003, which was derived from the optimization of the LK26 antibody using a whole cell genetic evolution platform. Here we show that MORAb-003 possesses novel, growth-inhibitory functions on cells overexpressing FRalpha. In addition, MORAb-003 elicited robust antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in vitro, and inhibited growth of human ovarian tumor xenografts in nude mice. Because of its multimodal activity in vitro and its safe toxicology profile in non-human primates, MORAb-003 development has recently been advanced to clinical trials involving ovarian cancer patients.
Ebel
Wolfgang
W
Morphotek Inc., 210 Welsh Pool Road, Exton, PA, USA.
Routhier
Eric L
EL
Foley
Brian
B
Jacob
Sara
S
McDonough
Jennifer M
JM
Patel
Rina K
RK
Turchin
Howard A
HA
Chao
Qimin
Q
Kline
J Bradford
JB
Old
Lloyd J
LJ
Phillips
Martin D
MD
Nicolaides
Nicholas C
NC
Sass
Philip M
PM
Grasso
Luigi
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D016466:CHO Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000276:immunology; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011323:Primates / Q000276:immunology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; C079669:LK26 antigen; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface