Farletuzumab, an anti-folate receptor α antibody, does not block binding of folate or anti-folates to receptor nor does it alter the potency of anti-folates in vitro.
OBJECTIVE
Folate is a cofactor in the synthesis of purines and pyrimidines; folate analogs are potent cytotoxic drugs. Folate receptor alpha (FRα), a protein-mediating cellular accumulation of folate (and anti-folates), has limited expression in normal tissues and is overexpressed by numerous carcinomas. Limited distribution and high affinity for folic acid have resulted in the development of antibodies or the use of folic acid coupled to toxins or radionuclides as therapeutic and imaging agents. Farletuzumab is an anti-FRα antibody in clinical trials for ovarian and non-small cell lung cancers. Our goal was to evaluate the effect of farletuzumab on binding and uptake of folates and anti-folates and the potency of anti-folates in vitro.


METHODS
Direct binding and uptake of radiolabeled folates and anti-folates and the assessments of drug concentration of drug that inhibited cell growth 50 % (IC(50)) in vitro in the presence or absence of antibody.


RESULTS
Farletuzumab did not block membrane binding of radiolabeled folic acid, 5-methyltetrahydrofolate, pemetrexed, and other anti-folates; folic acid blocked >95 %. Farletuzumab had a minimal effect on the cytoplasmic accumulation of 5-methyltetrahydrofolate or pemetrexed; folic acid had a considerable but variable effect on the different cell lines. As a single agent, farletuzumab did not affect cell viability or the IC(50) of pemetrexed and other anti-folates in vitro.


CONCLUSIONS
Farletuzumab does not block FRα binding of folates and anti-folates, minimally retards folate delivery via FRα-mediated transport, and minimally retards the growth of cells in vitro. Concomitant use of farletuzumab and pemetrexed is not contraindicated.
Cancer Institute of New Jersey, Robert Wood Johnson Medical School, 195 Little Albany Street, New Brunswick, NJ 80901, USA. kamenbart@gmail.com
B A
BA
Kamen
A K
AK
Smith
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D058975:Folate Receptor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005492:Folic Acid / Q000378:metabolism* / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D000068437:Pemetrexed; D013763:Tetrahydrofolates / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium
D061067:Antibodies, Monoclonal, Humanized; D058975:Folate Receptor 1; D005971:Glutamates; D013763:Tetrahydrofolates; D000068437:Pemetrexed; D014316:Tritium; C527484:farletuzumab; D006147:Guanine; D005492:Folic Acid; C005984:5-methyltetrahydrofolate