From XenoMouse® Technology to Panitumumab (ABX-EGF)

  • Xiaodong Yang
  • Lorin Roskos
  • C. Geoffrey Davis
  • Gisela Schwab
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Recent success of antibody therapeutics in oncology has revived a keen interest in the development of monoclonal antibodies (mAbs) for the treatment of cancer. To date, eight mAbs have been approved in the United States for the treatment of hematological malignancies or solid tumors. The increased success has been largely attributed to advances in antibody technology such as chimerization and humanization of mAbs and the development of fully human antibodies allowing for reduction in immunogenicity and creation of antibodies of desired affinity and isotype. XenoMouse® technology is a technology that allows for the generation of fully human mAbs in transgenic mice. Using this technology, the anti-epidermal growth factor receptor (EGFR) antibody, panitumumab, has been created.

Panitumumab (ABX-EGF) is a fully human IgG2 anti-EGFR mAb. Panitumumab binds EGFR with high affinity, inhibits ligand-dependent receptor activation, and effectively inhibits the growth of multiple human tumor xenografts in mouse models. To date, in phase 1 and phase 2 clinical studies, panitumumab has been generally well tolerated, exhibited no immunogenicity, and demonstrated low interpatient and intrapatient pharmacokinetic variability. Objective responses have been observed in patients with metastatic colorectal cancer and advanced renal cell carcinoma.

Key Words

Panitumumab ABX-EGF EGFR mAb cancer XenoMouse targeted therapy IgG2 

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References

  1. 1.
    Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256:495–497.PubMedCrossRefGoogle Scholar
  2. 2.
    Dillman RO. Human antimouse and antiglobulin responses to monoclonal antibodies. Antibody Immunocon Radiopharm 1990; 3:1–15.Google Scholar
  3. 3.
    Isaacs JD. The antiglobulin response to therapeutic antibodies. Semin Immunol 1990; 2:449–456.PubMedGoogle Scholar
  4. 4.
    Morrison S, Oi VT. Chimeric immunoglobulin genes. In: Hongo T, Alt FW, Rabbitts TH (eds.). Immunoglobulin genes. London: Academic, 1989:260–274.Google Scholar
  5. 5.
    Grillo-Lopez AJ, White CA, Varns C, Shen D, Wei A, McClure A, et al. Overview of the clinical development of rituximab: first monoclonal antibody approved for the treatment of lymphoma. Semin Oncol 1999; 26(5 Suppl 14):66–73.PubMedGoogle Scholar
  6. 6.
    Baselga J. The EGFR as a target for anticancer therapy-focus on cetuximab. Eur J Cancer 2001; 37(Suppl 4):S16–S22.PubMedCrossRefGoogle Scholar
  7. 7.
    Herbst RS, Shin DM. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. Cancer 2002; 94:1593–1611.PubMedCrossRefGoogle Scholar
  8. 8.
    Riechmann L, Clark M, Waldmann H, Winter G. Reshaping human antibodies for therapy. Nature 1988; 332:323–327.PubMedCrossRefGoogle Scholar
  9. 9.
    Baselga J. Clinical trials of Herceptin (trastuzumab). Eur J Cancer 2001; 37(Suppl 1):S18–S24.PubMedCrossRefGoogle Scholar
  10. 10.
    Miller KD, Rugo HS, Cobleigh MA, Marcom PK, Chap LI, et al. Phase III trial of capecitabine (Xeloda®) plus bevacizumab (Avastin®) versus capecitabine alone in women with metastatic breast cancer (MBC) previously treated with an anthracycline and a taxane. In: 26th Annual San Antonio Breast Cancer Symposium 2002; 12: 11.Google Scholar
  11. 11.
    Robert F, Ezekiel MP, Spencer SA, et al. Phase I study of anti-epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol 2001; 19:3234–3243.PubMedGoogle Scholar
  12. 12.
    Scott AM, Wiseman G, Welt S, Adjei A, Lee FT, et al. A phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res 2003; 9: 1639–1647.PubMedGoogle Scholar
  13. 13.
    Weinblatt ME, Maddison PJ, Bulpitt KJ, Hazleman BL, Urowitz MB, Sturrock RD, et al. Campath-1H, a humanized monoclonal antibody, in refractory rheumatoid arthritis. An intravenous dose-escalation study. Arthritis Rheum 1995; 38:1589–1594.PubMedCrossRefGoogle Scholar
  14. 14.
    Welt S, Ritter G, Williams C Jr, Cohen LS, John M, Jungbluth A, et al. Phase I study of anticolon cancer humanized antibody A33. Clin Cancer Res 2003; 9:1338–1346.PubMedGoogle Scholar
  15. 15.
    Kretzschmar T, von Ruden T. Antibody discovery: phage display. Curr Opin Biotechnol 2002; 3: 598–602.CrossRefGoogle Scholar
  16. 16.
    Green L. Antibody engineering via genetic engineering of the mouse: XenoMouse strains are vehicles for the facile generation of therapeutic human monoclonal antibodies. J Immunol Methods 1999; 231:11–23.PubMedCrossRefGoogle Scholar
  17. 17.
    Yarden Y, Sliwkowski M. Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2001; 2: 127–137.PubMedCrossRefGoogle Scholar
  18. 18.
    Lewis TS, Shapiro PS, Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res 1998; 74:49–139.PubMedCrossRefGoogle Scholar
  19. 19.
    Chan TO, Rittenhouse SE, Tisichlis PN. AKT/PKB and D3 phosphinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem 1999; 68:965–1014.PubMedCrossRefGoogle Scholar
  20. 20.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase-Akt pathway in human cancer. Nat Rev Cancer 2002; 2:489–501.PubMedCrossRefGoogle Scholar
  21. 21.
    Modjtahedi H, Dean C. The receptor for EGF and its ligands: expression, prognostic value and target for therapy in cancer. Intl J Oncol 1994; 4:277–296.Google Scholar
  22. 22.
    Gullick WJ. Prevalence of aberrant expression of the epidermal growth factor receptor in human cancers. Br Med Bull 1991; 47:87–98.PubMedGoogle Scholar
  23. 23.
    Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19:183–232.PubMedCrossRefGoogle Scholar
  24. 24.
    Neal DE, Marsh C, Bennett MK, et al. Epidermal-growth-factor receptors in human bladder cancer: comparison of invasive and superficial tumours. Lancet 1985; 1:366–368.PubMedCrossRefGoogle Scholar
  25. 25.
    Di Marco E, Pierce JH, Fleming TP, et al. Autocrine interaction between TGF alpha and the EGF-receptor: quantitative requirements for induction of the malignant phenotype. Oncogene 1989; 4:831–838.PubMedGoogle Scholar
  26. 26.
    Yang XD, Jia XC, Corvalan JR, Wang P, Davis C, Jakobovits A. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res 1999; 59:1236–1243.PubMedGoogle Scholar
  27. 27.
    Azemar M, Scmidt M, Arlt F, et al. Recombinant antibody toxins specific for ErbB2 and EGF receptor inhibit the in vivo growth of human head and neck cancer cells and cause rapid regression in vivo. Int J Cancer 2000; 86: 269–275.PubMedCrossRefGoogle Scholar
  28. 28.
    Ciardiello F, Caputo R, Bianco R, et al. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (‘Iressa’), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 2001; 7:1459–1465.PubMedGoogle Scholar
  29. 29.
    Hightower M. Erlotinib (OSI-774, Tarceva), a selective epidermal growth factor receptor tyrosine kinase inhibitor, in combination with chemotherapy for advanced non-small-cell lung cancer. Clin Lung Cancer 2003; 4(6): 336–338.PubMedGoogle Scholar
  30. 30.
    AstraZeneca UK Ltd. Iressa™ (gefitinib tablets) product package insert. AstraZeneca, Wilmington, DE, 2003.Google Scholar
  31. 31.
    Imclone Systems and Bristol-Myers Squibb. Erbitux™ (Cetuximab) product package insert. Imclone Systems Inc., Branchburg, NJ, and Bristol-Myers Squibb Company, Princeton, NJ, 2004.Google Scholar
  32. 32.
    Foon KA, Yang XD, Weiner LM, et al. Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys 2004; 58:984–990.PubMedCrossRefGoogle Scholar
  33. 33.
    Jakobovits A, Vergara GJ, Kennedy JL, et al. Analysis of homozygous mutant chimeric mice: deletion of the immunoglobulin heavy-chain joining region blocks B-cell development and antibody production. Proc Natl Acad Sci USA 1993; 90:2551–2555.PubMedCrossRefGoogle Scholar
  34. 34.
    Green LL, Jakobovits A. Regulation of B cell development by variable gene complexity in mice reconstituted with human immunoglobulin yeast artificial chromosomes. J Exp Med 1998; 188:483–495.PubMedCrossRefGoogle Scholar
  35. 35.
    Jakobovits A, Moore AL, Green LL, et al. Germ-line transmission and expression of a human-derived yeast artificial chromosome. Nature 1993; 362:255–258.PubMedCrossRefGoogle Scholar
  36. 36.
    Mendez MJ, Green LL, Corvalan JR, et al. Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat Genet 1997; 15:146–156.PubMedCrossRefGoogle Scholar
  37. 37.
    Gallo ML, Ivanov VE, Jakobovits A, Davis CG. The human immunoglobulin loci introduced into mice: V(D)and J gene segment usage similar to that of adult humans. Eur J Immunol 2000; 30:534–540.PubMedCrossRefGoogle Scholar
  38. 38.
    Kellermann SA, Green L. Antibody discovery: the use of transgenic mice to generate human monoclonal antibodies for therapeutics. Curr Opin Biotechnol 2002; 13:593–597.PubMedCrossRefGoogle Scholar
  39. 39.
    Davis CG, Gallo ML, Corvalan JRF. Transgenic mice as a source of fully human antibodies for the treatment of cancer. Cancer Metastasis Rev 1999; 18:421–425.PubMedCrossRefGoogle Scholar
  40. 40.
    Yang XD, Wang P, Fredlin P, Jia XC, Oppenheim JJ, Davis CG. Preclinical evaluation of ABX-EGF as a potent anti-tumor agent. Proc Annu Meet Am Assoc Cancer Res 2002; 43:1004 (abstract).Google Scholar
  41. 41.
    Yang XD, Jia XC, Corvalan JR, Wang P, Davis CG. Therapeutic potential of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer treatment. Proc Am Soc Clin Oncol 2000; 19:41a.Google Scholar
  42. 42.
    Yang XD, Wang P, Fredlin P, Davis CG. ABX-EGF, a fully human anti-EGF receptor monoclonal antibody: inhibition of prostate cancer in vitro and in vivo. Proc Annu Meet Am Assoc Cancer Res 2002; 21:116b (abstract).Google Scholar
  43. 43.
    Wang P, Fredlin P, Davis CG. Yang XD. Human anti-EGF receptor monoclonal antibody ABX-EGF: a potential therapeutic for the treatment of prostate cancer. Proc Annu Meet Am Assoc Cancer Res 2002; 43:913 (abstract).Google Scholar
  44. 44.
    McDorman K, Freemen DJ, Bush T, Cerretti D, Fanslow W, Starnes C, et al. ABX-EGF tumor penetration and EGFR saturation correlate with pharmacokinetic, pharmacodynamic, and antitumor activity in an A431 xenograft model system. Proc Annu Meet Am Assoc Cancer Res. 2004; 45(Suppl):109 (abstract).Google Scholar
  45. 45.
    Lynch DH, Yang XD. Therapeutic potential of ABX-EGF: a fully human anti-epidermal growth factor receptor monoclonal antibody for cancer treatment. Semin Oncol 2002; 29(1 Suppl 4):47–50.PubMedCrossRefGoogle Scholar
  46. 46.
    Salcedo R, Martins-Green M, Gertz B, Oppenheim JJ, Murphy WJ. Combined administration of antibodies to human interleukin 8 and epidermal growth factor receptor results in increased antimetastatic effects on human breast carcinoma xenografts. Clin Cancer Res 2002; 8:2655–2665.PubMedGoogle Scholar
  47. 47.
    Yang XD, Jia XC, Corvalan JR, Wang P, Davis CG. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol 2001; 38:17–23.PubMedCrossRefGoogle Scholar
  48. 48.
    Figlin RA, Belldegrun AS, Crawford J, et al. ABX-EGF, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with advanced cancer: phase 1 clinical results. Proc Am Soc Clin Oncol 2002; 21:10a.Google Scholar
  49. 49.
    Rowinsky E, Schwartz G, Dutcher J, et al. ABX-EGF, a fully human anti-epidermal growth factor receptor (EGFr) monoclonal antibody: phase 2 clinical trial in renal cell cancer (RCC). In: 14th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Frankfurt, 2002:1.Google Scholar
  50. 50.
    Rowinsky F, Schwartz G, Gollob J, Thompson J, Vogelzang N, Figlin R, et al. Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer. J Clin Oncol 2004; 22:3003–3015.PubMedCrossRefGoogle Scholar
  51. 51.
    Roskos L, Lohner M, Osbern K, Pasumarti R, Lu H, Funelas C, et al. Optimal dosing of ABX-EGF in cancer patients. Int J Cancer 2002; 13(Suppl):444.Google Scholar
  52. 52.
    Meropol NJ, Berlin J, Hecht JR, et al. Multicenter study of ABX-EGF monotherapy in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 2003; 22:256.Google Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2005

Authors and Affiliations

  • Xiaodong Yang
    • 1
  • Lorin Roskos
    • 1
  • C. Geoffrey Davis
    • 1
  • Gisela Schwab
    • 1
  1. 1.Abgenix Inc.Fremont

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