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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

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Abstract

Purpose

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 % (IC50) 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 IC50 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.

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References

  1. Fox JT, Stover PJ (2008) Folate-mediated one-carbon metabolism. In: Litwack G (ed) Vitamins and hormones: folic acid and folates (vol 79). Elsevier, Philadelphia, pp 1–29

  2. Kamen BA, Cole P, Bertino JR (2006) Chemotherapeutic agents: folic acid antagonists. In: Holland JF, Frei E, Bast RC, Kufe DW, Morton DL, Weichselbaum RR (eds) Cancer medicine. Williams and Wilkins, Philadelphia, pp 648–660

    Google Scholar 

  3. Westerhof GR, Schornagel JH, Kathmann I et al (1995) Carrier- and receptor mediated transport of folate antagonists targeting folate-dependent enzymes: correlates of molecular-structure and biological activity. Mol Pharmacol 48:459–471

    PubMed  CAS  Google Scholar 

  4. Elnakat H, Ratnam M (2004) Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv Drug Deliv Rev 56:1067–1084

    Article  PubMed  CAS  Google Scholar 

  5. Leamon CP, Reddy JA (2004) Folate-targeted chemotherapy. Adv Drug Deliv Rev 56:1127–1141

    Article  PubMed  CAS  Google Scholar 

  6. Konner JA, Bell-McGuinn KM, Sabbatini P, Hensley ML, Tew WP, Pandit-Taskar N, Vander Els N, Phillips MD, Schweizer C, Weil SC, Larson SM, Old LJ (2010) Farletuzumab, a humanized monoclonal antibody against folate receptor alpha, in epithelial ovarian cancer: a phase I study. Clin Cancer Res 16:5288–5295

    Article  PubMed  CAS  Google Scholar 

  7. Spannuth WA, Sood AK, Coleman RL (2010) Farletuzumab in epithelial ovarian carcinoma. Expert Opin Biol Ther 10:431–437

    Article  PubMed  CAS  Google Scholar 

  8. Miller DS, Blessing JA, Krasner CN, Mannel RS, Hanjani P, Pearl ML, Waggoner SE, Boardman CH (2009) Phase II evaluation of pemetrexed in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the Gynecologic Oncology Group. J Clin Oncol 27:2686–2691

    Article  PubMed  CAS  Google Scholar 

  9. Tomao F, Panici PB, Frati L, Tomao S, Federica et al (2009) Emerging role of pemetrexed in ovarian cancer. Expert Rev Anticancer Ther 9:1727–1735

    Article  PubMed  Google Scholar 

  10. Ebel W, Routhier EL, Foley B, Jacob S, McDonough JM, Patel RK, Turchin HA, Chao Q, Kline JB, Old LJ, Phillips MD, Nicolaides NC, Sass PM, Grasso L (2007) Preclinical evaluation of MORAb-003, a humanized monoclonal antibody antagonizing folate receptor-alpha. Cancer Immun 7:1–8

    Google Scholar 

  11. Chattopadhyay S, Wang Y, Zhao R, Goldman ID (2004) Lack of impact of the loss of constitutive folate receptor alpha expression, achieved by RNA Interference, on the activity of the new generation antifolate pemetrexed in HeLa cells. Clin Cancer Res 10:7986–7993

    Article  PubMed  CAS  Google Scholar 

  12. Nutt JE, Razak AR, O’Toole K, Black F, Quinn AE, Calvert AH, Plummer ER, Lunec J (2010) The role of folate receptor alpha (FRalpha) in the response of malignant pleural mesothelioma to pemetrexed-containing chemotherapy. Br J Cancer 102:553–560

    Article  PubMed  CAS  Google Scholar 

  13. Kamen BA, Smith AK (2004) A review of folate receptor alpha cycling and 5-methyltetra-hydrofolate accumulation with an emphasis on cell models in vitro. Adv Drug Deliv Rev 56:1085–1097

    Article  PubMed  CAS  Google Scholar 

  14. Kamen BA, Capdevilla A (1986) Receptor-mediated folate accumulation is regulated by the cellular folate content. Proc Natl Acad Sci USA 83:5983–5987

    Article  PubMed  CAS  Google Scholar 

  15. Kamen BA, Wang MT, Streckfuss AJ, Peryea X, Anderson RGW (1988) Delivery of folates to the cytoplasm of MA104 cells is mediated by a surface membrane receptor that recycles. J Biol Chem 263:13602–13609

    PubMed  CAS  Google Scholar 

  16. Kamen BA, Wang M-T, Johnson C, Anderson RGW (1989) Regulation of the cytoplasmic accumulation of 5-Methyltetrahydrofolate in MA104 cells is independent of folate receptor regulation. J Clin Invest 84:1379–1386

    Article  PubMed  CAS  Google Scholar 

  17. Nichols B (2009) Endocytosis of lipid-anchored proteins: excluding GEECs from the crowd. J Cell Biol 186:457–459

    Article  PubMed  CAS  Google Scholar 

  18. Zhao R, Qiu A, Tsai E, Jansen M, Akabas MH, Goldman ID (2008) The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier. Mol Pharmacol 74:854–862

    Article  PubMed  CAS  Google Scholar 

  19. Zhao R, Matherly LH, Goldman ID (2009) Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues. Expert Rev Mol Med 11:e4. doi:10.1017/S1462399409000969

    Article  PubMed  Google Scholar 

  20. Birn H, Spiegelstein O, Christensen EI, Finnell RH (2005) Renal tubular reabsorption of folate mediated by folate binding protein 1. J Am Soc Nephrol 16:608–615

    Article  PubMed  CAS  Google Scholar 

  21. Lewis CM, Smith AK, Nguyen C, Kamen BA (1998) PMA alters folate receptor distribution in the plasma membrane and increases the rate of 5-methyltetrahydrofolate delivery in mature MA104 cells. Biochim Biophys Acta 1401:157–169

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors acknowledge medical writing assistance by Robyn Boyle, RPh under the direction of the authors as well as financial assistance provided by Morphotek.

Conflict of interest

Barton Kamen is now a consultant for Morphotek, Inc. Angela Smith reports no conflicts of interest. The authors have full control of all primary data.

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Authors and Affiliations

  1. Cancer Institute of New Jersey, Robert Wood Johnson Medical School, 195 Little Albany Street, New Brunswick, NJ, 80901, USA

    B. A. Kamen & A. K. Smith

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  1. B. A. Kamen
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  2. A. K. Smith
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Correspondence to B. A. Kamen.

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Kamen, B.A., Smith, A.K. 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. Cancer Chemother Pharmacol 70, 113–120 (2012). https://doi.org/10.1007/s00280-012-1890-2

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  • DOI: https://doi.org/10.1007/s00280-012-1890-2

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