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Investigational New Drugs

, Volume 31, Issue 6, pp 1436–1443 | Cite as

OM-RCA-01, a novel humanized monoclonal antibody targeting fibroblast growth factor receptor 1, in renal cell carcinoma model

  • Ilya Tsimafeyeu
  • Elina Zaveleva
  • Evgenia Stepanova
  • Walter Low
PRECLINICAL STUDIES

Summary

Fibroblast growth factor (FGF) receptor 1 (FGFR1) is a potential therapeutic target for treatment of metastatic renal cell carcinoma (RCC). We investigated the preclinical activity of OM-RCA-01, a novel therapeutic humanized anti-FGFR1 antibody in RCC. OM-RCA-01 has been shown to inhibit in vitro kinase activity of FGFR1 and has high affinity (Kd of 1.59 nM). In human renal carcinoma Caki-1 FGFR1-expressing cells, OM-RCA-01 potently inhibited FGF-mediated signaling and proliferation. In vivo, the tumors in untreated mice or mice treated with non-specific IgG continued their aggressive growth to reach the size of 2,000 cm3, at which point the mice were killed. In contrast, treatment with OM-RCA-01 not only significant arrested further growth of the tumors (P < 0.01) but also demonstrated differences in tumor volume compared with vehicle already on Day 13. A similar anti-tumor activity of OM-RCA-01 was observed when the antibody was given in low (1 mg/kg) or high (10 mg/kg) doses (P = 0.917). In Matrigel assay, OM-RCA-01 significantly inhibited FGF-induced endothelial cell migration, capillary-like tubular structure and mature vessels formation. Administration of 10 mg/kg antibody for up to 35 days resulted in minimal body weight loss and no observations of gross toxicity were made. Collectively, the data obtained with OM-RCA-01 are consistent with potent inhibition of FGFR1-signaling, angiogenesis, and tumor growth. OM-RCA-01 is being developed clinically as an intravenous therapy for the treatment of clear cell RCC.

Keywords

Fibroblast growth factors Fibroblast growth factor receptors FGFR1 antibody OM-RCA-01 Renal cell carcinoma Anti-tumor activity 

Notes

Acknowledgments

We would like to thank Maxwell Biotech, RVC and Skolkovo Funds for grant support.

Disclosures

IT, ES, and WL received research funding from OncoMax Ltd. EZ is a former employee of OncoMax Ltd.

References

  1. 1.
    Tsimafeyeu I, Aksel E (2010) Renal cell carcinoma in the Russian federation in 2008. Malign Tumours 1:1–4Google Scholar
  2. 2.
    Posadas EM, Figlin RA (2012) Systemic therapy in renal cell carcinoma: advancing paradigms. Oncology (Williston Park) 26(3):290–301Google Scholar
  3. 3.
    Tsimafeyeu I, Demidov L, Stepanova E et al (2011) Overexpression of fibroblast growth factor receptors FGFR1 and FGFR2 in renal cell carcinoma. Scand J Urol Nephrol 45:190–195CrossRefPubMedGoogle Scholar
  4. 4.
    Rini BI, Atkins MB (2009) Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol 10(10):992–1000CrossRefPubMedGoogle Scholar
  5. 5.
    Pal SK, Kortylewski M, Yu H, Figlin RA (2010) Breaking through a Plateau in renal cell carcinoma therapeutics: development and incorporation of biomarkers. Mol Cancer Ther 9(12):1–11CrossRefGoogle Scholar
  6. 6.
    Tsimafeyeu I, Demidov L, Ta H, Stepanova E, Wynn N (2010) Fibroblast growth factor pathway in renal cell carcinoma. J Clin Oncol (Meeting Abstr) 28(15Suppl):4621Google Scholar
  7. 7.
    Brochet X, Lefranc MP, Giudicelli V (2008) IMGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis. Nucleic Acids Res 36:W503–W508PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Thompson JD, Higgins DG, Gibson TJ, Clustal W (1994) Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties, and weight matrix choice. Nucleic Acids Res 22:4673–4680PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Giudicelli V, Chaume D, Lefranc MP (2005) IMGT/GENE-DB : a comprehensive database for human and mouse immunoglobulin and T cell receptor genes. Nucleic Acids Res 33:D256–D261PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Lefranc MP, Pommié C, Ruiz M et al (2003) IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains. Dev Comp Immunol 27(1):55–77CrossRefPubMedGoogle Scholar
  11. 11.
    Adams GP, Weiner LM (2005) Monoclonal antibody therapy of cancer. Nat Biotechnol 23:1147–1157CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Ilya Tsimafeyeu
    • 1
  • Elina Zaveleva
    • 2
  • Evgenia Stepanova
    • 3
  • Walter Low
    • 4
  1. 1.Kidney Cancer Research BureauMoscowRussian Federation
  2. 2.OncoMax LtdMoscowRussian Federation
  3. 3.Laboratory of Tumor AngiogenesisN.N. Blokhin Russian Cancer Research CenterMoscowRussian Federation
  4. 4.PX’TherapeuticsGrenobleFrance

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