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From XenoMouse technology to panitumumab, the first fully human antibody product from transgenic mice

Abstract

Therapeutic monoclonal antibodies have shown limited efficacy and safety owing to immunogenicity of mouse sequences in humans. Among the approaches developed to overcome these hurdles were transgenic mice genetically engineered with a 'humanized' humoral immune system. One such transgenic system, the XenoMouse, has succeeded in recapitulating the human antibody response in mice, by introducing nearly the entire human immunoglobulin loci into the germ line of mice with inactivated mouse antibody machinery. XenoMouse strains have been used to generate numerous high-affinity, fully human antibodies to targets in multiple disease indications, many of which are progressing in clinical development. However, validation of the technology has awaited the recent regulatory approval of panitumumab (Vectibix), a fully human antibody directed against epidermal growth factor receptor (EGFR), as treatment for people with advanced colorectal cancer. The successful development of panitumumab represents a milestone for mice engineered with a human humoral immune system and their future applications.

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Figure 1: Creation of XenoMouse strains.

Katie Ris-Vicari

Figure 2: The role of EGFR activation in tumorigenesis (a) and its related signal transduction pathways (b).

Katie Ris-Vicari

Figure 3: Pharmacokinetics of panitumumab.
Figure 4: Progression-free survival of panitumumab versus best supportive care at prespecified tumor assessment time points in the phase 3 trial.
Figure 5: Hazard ratios of progression-free survival in subject subsets in the phase 3 trial.
Figure 6: Overall survival by worst severity of skin toxicity in the phase 3 trial.

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References

  1. Kohler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975).

    Article  CAS  Google Scholar 

  2. Pendley, C., Schantz, A. & Wagner, C. Immunogenicity of therapeutic monoclonal antibodies. Curr. Opin. Mol. Ther. 5, 172–179 (2003).

    CAS  PubMed  Google Scholar 

  3. Winter, G. & Milstein, C. Man-made antibodies. Nature 349, 293–299 (1991).

    Article  CAS  Google Scholar 

  4. Morrison, S.L. & Oi, V.T. Chimeric immunoglobulin genes. in Immunoglobulin genes. (eds. Honjo, T.F, Alts, F.W. & Rabbits, T.H.) 260–274 (Academic Press, London; 1989).

    Google Scholar 

  5. Riechmann, L., Clark, M., Waldmann, H. & Winter, G. Reshaping human antibodies for therapy. Nature 332, 323–327 (1988).

    Article  CAS  Google Scholar 

  6. Burton, D.R. & Barbas, C.F. Human antibodies from combinatorial libraries, in Protein engineering of antibody molecules for prophylactic and therapeutic antibodies in man. (ed. M. Clark) 65–82 (Nottingham Academic Titles, Nottingham, UK; 1993).

    Google Scholar 

  7. Hoogenboom, H.R. Selecting and screening recombinant antibody libraries. Nat. Biotechnol. 23, 1105–1116 (2005).

    Article  CAS  Google Scholar 

  8. Lonberg, N. Human antibodies from transgenic animals. Nat. Biotechnol. 23, 1117–1125 (2005).

    Article  CAS  Google Scholar 

  9. Jakobovits, A. 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 90, 2551–2555 (1993).

    Article  CAS  Google Scholar 

  10. Green, L.L. & Jakobovits, A. Regulation of B cell development by variable gene complexity in mice reconstituted with human immunoglobulin yeast artificial chromosomes. J. Exp. Med. 188, 483–495 (1998).

    Article  CAS  Google Scholar 

  11. Green, L.L. et al. Antigen-specific human monoclonal antibodies from mice engineered with human Ig heavy and light chain YACs. Nat. Genet. 7, 13–21 (1994).

    Article  CAS  Google Scholar 

  12. Matsuda, F. & Honjo, T. Organization of the human immunoglobulin heavy-chain locus. Adv. Immunol. 62, 1–29 (1996).

    Article  CAS  Google Scholar 

  13. Cook, G.P. & Tomlinson, I.M. The human immunoglobulin VH repertoire. Immunol. Today 16, 237–242 (1995).

    Article  CAS  Google Scholar 

  14. Max, E. Immunoglobulins: molecular genetics, in Fundamental Immunology. (ed. W.E. Paul) 315–382 (Raven Press, New York; 1993).

    Google Scholar 

  15. Mendez, M.J. et al. Analysis of the structural integrity of YACs comprising human immunoglobulin genes in yeast and in embryonic stem cells. Genomics 26, 294–307 (1995).

    Article  CAS  Google Scholar 

  16. Mendez, M.J. et al. Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat. Genet. 15, 146–156 (1997).

    Article  CAS  Google Scholar 

  17. Weichhold, G.M., Ohnheiser, R. & Zachau, H.G. The human immunoglobulin kappa locus consists of two copies that are organized in opposite polarity. Genomics 16, 503–511 (1993).

    Article  CAS  Google Scholar 

  18. Jakobovits, A. et al. Germ-line transmission and expression of a human-derived yeast artificial chromosome. Nature 362, 255–258 (1993).

    Article  CAS  Google Scholar 

  19. Kellermann, S.A. & Green, L.L. Antibody discovery: the use of transgenic mice to generate human monoclonal antibodies for therapeutics. Curr. Opin. Biotechnol. 13, 593–597 (2002).

    Article  CAS  Google Scholar 

  20. Gallo, M.L., Ivanov, V.E., Jakobovits, A. & Davis, C.G. The human immunoglobulin loci introduced into mice: V (D) and J gene segment usage similar to that of adult humans. Eur. J. Immunol. 30, 534–540 (2000).

    Article  CAS  Google Scholar 

  21. Fishwild, D.M. et al. High-avidity human IgG kappa monoclonal antibodies from a novel strain of minilocus transgenic mice. Nat. Biotechnol. 14, 845–851 (1996).

    Article  CAS  Google Scholar 

  22. Lonberg, N. et al. Antigen-specific human antibodies from mice comprising four distinct genetic modifications. Nature 368, 856–859 (1994).

    Article  CAS  Google Scholar 

  23. Huang, S. et al. Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am. J. Pathol. 161, 125–134 (2002).

    Article  CAS  Google Scholar 

  24. McGary, E.C. et al. A fully human antimelanoma cellular adhesion molecule/MUC18 antibody inhibits spontaneous pulmonary metastasis of osteosarcoma cells in vivo. Clin. Cancer Res. 9, 6560–6566 (2003).

    CAS  PubMed  Google Scholar 

  25. Ostendorf, T. et al. A fully human monoclonal antibody (CR002) identifies PDGF-D as a novel mediator of mesangioproliferative glomerulonephritis. J. Am. Soc. Nephrol. 14, 2237–2247 (2003).

    Article  CAS  Google Scholar 

  26. Cohen, B.D. et al. Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871. Clin. Cancer Res. 11, 2063–2073 (2005).

    Article  CAS  Google Scholar 

  27. Wang, T. Ticilimumab. Drugs Fut. 32, 337 (2007).

    Article  CAS  Google Scholar 

  28. Gladue, R.P. & Bedian, V. Identification and characterization of a human CD40 agonist antibody with efficacy against human tumors SCID mice. Proc. Am. Assoc. Cancer Res. 47, Abstract no. 1355 (2006).

  29. Long, L. et al. Antagonist anti-CD40 monoclonal antibody, CHIR-12.12, inhibits growth of a rituximab-resistant NHL xenograft model and achieves synergistic activity when combined with ineffective rituximab. Blood 104, Abstract no. 3281 (2004).

  30. Burgess, T. et al. Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors. Cancer Res. 66, 1721–1729 (2006).

    Article  CAS  Google Scholar 

  31. Bekker, P.J. et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J. Bone Miner. Res. 19, 1059–1066 (2004).

    Article  CAS  Google Scholar 

  32. Jakobovits, A. et al. A fully human monoclonal antibody to prostate stem cell antigen (PSCA) for the treatment prostate pancreatic cancers. J. Clin. Oncol. 23 (16s), Abstract no. 4722 (2005).

  33. Mahler, D.A., Huang, S., Tabrizi, M. & Bell, G.M. Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study. Chest 126, 926–934 (2004).

    Article  CAS  Google Scholar 

  34. Mendelsohn, J. & Baselga, J. Epidermal growth factor receptor targeting in cancer. Semin. Oncol. 33, 369–385 (2006).

    Article  CAS  Google Scholar 

  35. Francoual, M. et al. EGFR in colorectal cancer: more than a simple receptor. Ann. Oncol. 17, 962–967 (2006).

    Article  CAS  Google Scholar 

  36. Defize, L.H. et al. Signal transduction by epidermal growth factor occurs through the subclass of high affinity receptors. J. Cell Biol. 109, 2495–2507 (1989).

    Article  CAS  Google Scholar 

  37. Bellot, F. et al. High-affinity epidermal growth factor binding is specifically reduced by a monoclonal antibody, and appears necessary for early responses. J. Cell Biol. 110, 491–502 (1990).

    Article  CAS  Google Scholar 

  38. Normanno, N. et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366, 2–16 (2006).

    Article  CAS  Google Scholar 

  39. Yarden, Y. & Sliwkowski, M.X. Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol. 2, 127–137 (2001).

    Article  CAS  Google Scholar 

  40. Debuire, B. et al. Sequencing the erbA gene of avian erythroblastosis virus reveals a new type of oncogene. Science 224, 1456–1459 (1984).

    Article  CAS  Google Scholar 

  41. Riedel, H., Massoglia, S., Schlessinger, J. & Ullrich, A. Ligand activation of overexpressed epidermal growth factor receptors transforms NIH 3T3 mouse fibroblasts. Proc. Natl. Acad. Sci. USA 85, 1477–1481 (1988).

    Article  CAS  Google Scholar 

  42. Sargent, E.R., Gomella, L.G., Belldegrun, A., Linehan, W.M. & Kasid, A. Epidermal growth factor receptor gene expression in normal human kidney and renal cell carcinoma. J. Urol. 142, 1364–1368 (1989).

    Article  CAS  Google Scholar 

  43. Ogiso, Y. et al. Expression of proto-oncogenes in normal and tumor tissues of human skin. J. Invest. Dermatol. 90, 841–844 (1988).

    Article  CAS  Google Scholar 

  44. Sakai, K. et al. Expression of epidermal growth factor receptors on normal human gastric epithelia and gastric carcinomas. J. Natl. Cancer Inst. 77, 1047–1052 (1986).

    CAS  PubMed  Google Scholar 

  45. van der Laan, B.F., Freeman, J.L. & Asa, S.L. Expression of growth factors and growth factor receptors in normal and tumorous human thyroid tissues. Thyroid 5, 67–73 (1995).

    Article  CAS  Google Scholar 

  46. Henzen-Logmans, S.C. et al. Occurrence of epidermal growth factor receptors in benign and malignant ovarian tumors and normal ovarian tissues: an immunohistochemical study. J. Cancer Res. Clin. Oncol. 118, 303–307 (1992).

    Article  CAS  Google Scholar 

  47. Terada, T., Ohta, T. & Nakanuma, Y. Expression of transforming growth factor-alpha and its receptor during human liver development and maturation. Virchows Arch. 424, 669–675 (1994).

    Article  CAS  Google Scholar 

  48. Ozanne, B., Richards, C.S., Hendler, F., Burns, D. & Gusterson, B. Over-expression of the EGF receptor is a hallmark of squamous cell carcinomas. J. Pathol. 149, 9–14 (1986).

    Article  CAS  Google Scholar 

  49. Mendelsohn, J. & Baselga, J. The EGF receptor family as targets for cancer therapy. Oncogene 19, 6550–6565 (2000).

    Article  CAS  Google Scholar 

  50. Mendelsohn, J. & Baselga, J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J. Clin. Oncol. 21, 2787–2799 (2003).

    Article  CAS  Google Scholar 

  51. Yang, X.D. et al. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res. 59, 1236–1243 (1999).

    CAS  PubMed  Google Scholar 

  52. Yang, X.D., Roskos, L.K., Davis, C.G. & Schwab, G. From XenoMouse® technology to panitumumab. in Cancer Drug Discovery and Development, the Oncogenomics Handbook (eds. W.J. LaRochelle & R.A. Shimkets) 647–657 (Humana Press Inc., Totowa, NJ, USA; 2005).

    Google Scholar 

  53. Foltz, I.N. et al. Panitumumab induces internalization of the epidermal growth factor receptor. Drugs 66, 2005–2014 (2006).

    Article  Google Scholar 

  54. Yang, X.D., Jia, X.C., Corvalan, J.R., Wang, P. & Davis, C.G. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit. Rev. Oncol. Hematol. 38, 17–23 (2001).

    Article  CAS  Google Scholar 

  55. Bush, T. et al. Antitumor efficacy of panitumumab alone or in combination with chemotherapy against human pancreatic carcinoma xenografts. Clin. Cancer Res. 11, Abstract no. B72 (2005).

  56. Weiner, L.M. et al. Updated results from a dose and schedule study of Panitumumab (ABX-EGF) monotherapy, in patients with advanced solid malignancies. J. Clin. Oncol. 23 (suppl 16), Abstract no. 3059 (2005).

    Article  Google Scholar 

  57. Rowinsky, E.K. 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. 22, 3003–3015 (2004).

    Article  CAS  Google Scholar 

  58. Hecht, J.R. et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer. 110, 980–987 (2007).

    Article  CAS  Google Scholar 

  59. Mitchell, E. P. et al. Panitumumab activity in metastatic colorectal cancer (mCRC) patients (pts) with low or negative tumor epidermal growth factor receptor (EGFr) levels: an updated analysis. J. Clin. Oncol. 25 (suppl 18), Abstract no. 4082 (2007).

  60. Berlin, J. et al. Panitumumab antitumor activity in patients (pts) with metastatic colorectal cancer (mCRC) expressing >10% epidermal growth factor receptor (EGFr). J. Clin. Oncol. 24 (suppl 18), Abstract no. 3548 (2006).

  61. Berlin, J. et al. Panitumumab with irinotecan, leucovorin, and 5-fluorouracil (IFL or FOLFIRI) for first-line treatment of metastatic colorectal cancer. Clin. Colorectal Cancer 6, 427–432 (2007).

    Article  CAS  Google Scholar 

  62. Saltz, L.B. et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J. Clin. Oncol. 22, 1201–1208 (2004).

    Article  CAS  Google Scholar 

  63. Cunningham, D. et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med. 351, 337–345 (2004).

    Article  CAS  Google Scholar 

  64. Chung, K.Y. et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J. Clin. Oncol. 23, 1803–1810 (2005).

    Article  CAS  Google Scholar 

  65. Van Cutsem, E. et al. An open-label, randomized, phase 3 clinical trial of panitumumab plus best supportive care versus best supportive care in patients with chemotherapy-refractory metastatic colorectal cancer. J. Clin. Oncol. 25, 1658–1664 (2007).

    Article  CAS  Google Scholar 

  66. Perez-Soler, R. & Saltz, L. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J. Clin. Oncol. 23, 5235–5246 (2005).

    Article  Google Scholar 

  67. McClung, M.R. et al. Denosumab in postmenopausal women with low bone mineral density. N. Engl. J. Med. 354, 821–831 (2006).

    Article  CAS  Google Scholar 

  68. Body, J.J. et al. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin. Cancer Res. 12, 1221–1228 (2006).

    Article  CAS  Google Scholar 

  69. Patton, A., Mullenix, M.C., Swanson, S.J. & Koren, E. An acid dissociation bridging ELISA for detection of antibodies directed against therapeutic proteins in the presence of antigen. J. Immunol. Methods 304, 189–195 (2005).

    Article  CAS  Google Scholar 

  70. Lofgren, J. et al. Comparison of ELISA and Biacore assay for detection of anti-panitumumab antibodies in clinical studies. J. Immunol. (Manuscript in press) (2007).

  71. Hecht, J.R., Chidiac, T. & Mitchell, E. An interim analysis of efficacy and safety from a randomized controlled trial of panitumumab with chemotherapy plus bevacizumab (bev) for metastatic colorectal cancer (mCRC). Presented at the 9th World Congress of Gastrointestinal Cancer, June 20–27, 2007, Barcelona, Spain., Abstract no. O-0033 (2007).

    Google Scholar 

  72. Herbst, R.S. et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J. Clin. Oncol. 23, 5578–5587 (2005).

    Article  CAS  Google Scholar 

  73. Burtness, B., Goldwasser, M.A., Flood, W., Mattar, B. & Forastiere, A.A. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J. Clin. Oncol. 23, 8646–8654 (2005).

    Article  Google Scholar 

  74. Baselga, J. et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J. Clin. Oncol. 23, 5568–5577 (2005).

    Article  CAS  Google Scholar 

  75. Lenz, H.J. et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J. Clin. Oncol. 24, 4914–4921 (2006).

    Article  CAS  Google Scholar 

  76. Helbling, D. & Borner, M. Successful challenge with the fully human EGFR antibody panitumumab following an infusion reaction with the chimeric EGFR antibody cetuximab. Ann. Oncol. 18, 963–964 (2007).

    Article  CAS  Google Scholar 

  77. Heun, J. & Holen, K. Treatment with panitumumab after a severe infusion reaction to cetuximab in a patient with metastatic colorectal cancer: a case report. Clin. Adv. Hematol. Oncol. 7, 529–531 (2007).

    Google Scholar 

  78. Shepherd, F.A. et al. Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med. 353, 123–132 (2005).

    Article  CAS  Google Scholar 

  79. Moroni, M. et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol. 6, 279–286 (2005).

    Article  CAS  Google Scholar 

  80. Lievre, A. et al. KRAS Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer. Cancer Res. 66, 3992–3995 (2006).

    Article  CAS  Google Scholar 

  81. Ford, S.K. et al. Preclinical discovery and clinical validation of predictive markers of response to cetuximab (Erbitux) in metastatic colorectal cancer. Proc. Amer. Assoc. Cancer Res. 47, 950-a. Abstract no. 4032 (2006).

    Google Scholar 

  82. Engelman, J.A. et al. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc. Natl. Acad. Sci. USA 102, 3788–3793 (2005).

    Article  CAS  Google Scholar 

  83. Matsuda, F. et al. The complete nucleotide sequence of the human immunoglobulin heavy chain variable region locus. J. Exp. Med. 188, 2151–2162 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

We wish to acknowledge the Abgenix research teams for their involvement with the generation and characterization of the XenoMouse strains and for the identification of panitumumab, the Amgen clinical study team for the panitumumab clinical development program, and Mee Rhan Kim of Amgen Inc. for assistance with the preparation of this manuscript. All animal studies were conducted under an internal IACUC protocol and satisfied all AAALAC specifications.

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Correspondence to Aya Jakobovits.

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A.J. was an employee of Abgenix and is currently an employee of Agensys. R.G.A. is an employee of Amgen and owns Amgen stock. L.R. was an employee of Abgenix and Amgen and is currently an employee of AstraZeneca. X.Y. was an employee of Abgenix and Amgen and is currently an employee of Intradigm. G.S. was a former employee of Abgenix and Amgen, is currently an employee of Exelixis and owns stock in both Amgen and Excelixis.

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Jakobovits, A., Amado, R., Yang, X. et al. From XenoMouse technology to panitumumab, the first fully human antibody product from transgenic mice. Nat Biotechnol 25, 1134–1143 (2007). https://doi.org/10.1038/nbt1337

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