Human Monoclonal Antibodies from Transgenic Mice

  • N. Lonberg
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 181)

Since the 1986 regulatory approval of muromonomab-CD3, a mouse monoclonal antibody (MAb) directed against the T cell CD3ε antigen, MAbs have become an increasingly important class of therapeutic compounds in a variety of disease areas ranging from cancer and autoimmune indications to infectious and cardiac diseases. However, the pathway to the present acceptance of therapeutic MAbs within the pharmaceutical industry has not been smooth. A major hurdle for antibody therapeutics has been the inherent immunogenicity of the most readily available MAbs, those derived from rodents. A variety of technologies have been successfully employed to engineer MAbs with reduced immunogenicity. Implementation of these antibody engineering technologies involves in vitro optimization of lead molecules to generate a clinical candidate. An alternative technology, involving the engineering of strains of mice to produce human instead of mouse antibodies, has been emerging and evolving for the past two decades. Now, with the 2006 US regulatory approval of panitumumab, a fully human antibody directed against the epidermal growth factor receptor, transgenic mice expressing human antibody repertoires join chimerization, CDR grafting, and phage display technologies, as a commercially validated antibody drug discovery platform. With dozens of additional transgenic mouse-derived human MAbs now in clinical development, this new drug discovery platform appears to be firmly established within the pharmaceutical industry.


Epidermal Growth Factor Receptor Transgenic Mouse Human Monoclonal Antibody Human Immunoglobulin Human MAbs 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Alt FW, Blackwell TK, Yancopoulos GD (1985) Immunoglobulin genes in transgenic mice. Trends Genet 1:231-236Google Scholar
  2. Attia P, Phan GQ, Maker AV et al. (2005) Autoimmunity correlates with tumor regre7sion in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23:6043-6053PubMedGoogle Scholar
  3. Babcock GJ, Broering TJ, Hernandez HJ et al. (2006) Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters. Infect Immun 74:6339-6347PubMedGoogle Scholar
  4. Baert F, Noman M, Vermeire S et al. (2003) Influence of immunogenicity on the long-term efficacy of imfliximab in Crohn’s disease. N Engl J Med 348:601-608PubMedGoogle Scholar
  5. Ball WJ, Kasturi R, Dey P et al. (1999) Isolation and characterization of human monoclonal antibodies to digoxin. J Immunol 163:2291-2298PubMedGoogle Scholar
  6. Beck KE, Blansfield JA, Tran KQ et al. (2006) Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol 24:2283-2289PubMedGoogle Scholar
  7. Bekker PJ, Holloway D, Rasmussen S et al. (2004) A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 19:1059-1066PubMedGoogle Scholar
  8. Bender NK, Heilig CE, Dr öll B et al. (2007) Immunogenicity, efficacy and adverse events of adalimumab in RA patients. Rheumatol Int 27:269-274PubMedGoogle Scholar
  9. Bieber MM, Bhat NM, Teng NN (1995) Anti-endotoxin human monoclonal antibody A6H4C5 (HA-1A) utilizes the VH4.21 gene. Clin Infect Dis 21(Suppl 2):S186-S189PubMedGoogle Scholar
  10. Blansfield JA, Beck KE, Tran K et al. (2005) Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 28:593-598PubMedGoogle Scholar
  11. Bleeker WK, Lammerts van Bueren JJ, van Ojik HH et al. (2004) Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy. J Immunol 173:4699-4707PubMedGoogle Scholar
  12. Body JJ, Facon T, Coleman RE et al. (2006) 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 12:1221-1228PubMedGoogle Scholar
  13. Boll B, Hansen H, Heuck F et al. (2005) The fully human anti-CD30 antibody 5F11 activates NF-{kappa}B and sensitizes lymphoma cells to bortezomib-induced apoptosis. Blood 106:1839-1842PubMedGoogle Scholar
  14. Borchmann P, Treml JF, Hansen H et al. (2003) The human anti-CD30 antibody 5F11 shows in vitro and in vivo activity against malignant lymphoma. Blood 102:3737-3742PubMedGoogle Scholar
  15. Borchmann P, Schnell R, Schulz H et al. (2004) Monoclonal antibody-based immunotherapy of Hodgkin’s lymphoma. Curr Opin Investig Drugs 5:1262-1267PubMedGoogle Scholar
  16. Borchmann P, Schnell R, Engert A (2005) Immunotherapy of Hodgkin’s lymphoma. Eur J Haematol 75(Suppl 66):159-165Google Scholar
  17. Brinster RL, Chen HY, Trumbauer M et al. (1981) Somatic expression of herpes thymidine kinase in mice following injection of a fusion gene into eggs. Cell 27:223-231PubMedGoogle Scholar
  18. Brinster RL, Ritchie KA, Hammer RE et al. (1983) Expression of a microinjected immunoglobulin gene in the spleen of transgenic mice. Nature 306:332-336PubMedGoogle Scholar
  19. Bruggemann M, Caskey HM, Teale C et al. (1989) A repertoire of monoclonal antibodies with human heavy chains from transgenic mice. Proc Natl Acad Sci USA 86:6709-6713PubMedGoogle Scholar
  20. Brun-Buisson C (1994) The HA-1A saga: the scientific and ethical dilemma of innovative and costly therapies. Intensive Care Med 20:314-316PubMedGoogle Scholar
  21. Bucchini D, Reynaud CA, Ripoche MA et al. (1987) Rearrangement of a chicken immunoglobulin gene occurs in the lymphoid lineage of transgenic mice. Nature 326:409-411PubMedGoogle Scholar
  22. Burgess T, Coxon A, Meyer S et al. (2006) Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors. Cancer Res 66:1721-1729PubMedGoogle Scholar
  23. Buttin G (1987) Exogenous Ig gene rearrangement in transgenic mice: a new strategy for human monoclonal antibody production? Trends Genet 3:205-206Google Scholar
  24. Calvo E, Rowinsky EK (2005) Clinical experience with monoclonal antibodies to epidermal growth factor receptor. Curr Oncol Rep 7:96-103PubMedGoogle Scholar
  25. Chang Q, Zhong Z, Lees A et al. (2002) Structure-function relationships for human antibodies to pneumococcal capsular polysaccharide from transgenic mice with human immunoglobulin Loci. Infect Immun 70:4977-4986PubMedGoogle Scholar
  26. Choi TK, Hollenbach PW, Pearson BE et al. (1993) Transgenic mice containing a human heavy chain immunoglobulin gene fragment cloned in a yeast artificial chromosome. Nat Genet 4:117-123PubMedGoogle Scholar
  27. Cohen BD, Baker DA, Soderstrom C et al. (2005) 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 11:2063-2073PubMedGoogle Scholar
  28. Cohen SB, Emery P, Greenwald MW et al. (2006) Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebocontrolled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 54:2793-806PubMedGoogle Scholar
  29. Cohenuram M, Saif MW (2007) Panitumumab the first fully human monoclonal antibody: from the bench to the clinic. Anticancer Drugs 18:7-15PubMedGoogle Scholar
  30. Coiffier B, Haioun C, Ketterer N et al. (1998) Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 92:1927-32PubMedGoogle Scholar
  31. Costantini F, Lacy E (1981) Introduction of a rabbit beta-globin gene into the mouse germ line. Nature 294:92-94PubMedGoogle Scholar
  32. Coughlin M, Lou G, Martinez O et al. (2006) Generation and characterization of human monoclonal neutralizing antibodies with distinct binding and sequence features against SARS coronavirus using XenoMouse((R)). Virology 361:93-102PubMedGoogle Scholar
  33. Cunningham D, Humblet Y, Siena S et al. (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345PubMedGoogle Scholar
  34. Davies NP, Rosewell IR, Richardson JC et al. (1993) Creation of mice expressing human antibody light chains by introduction of a yeast artificial chromosome containing the core region of the human immunoglobulin kappa locus. Nat Bio 11:911-914Google Scholar
  35. Davis MM (2004) The evolutionary and structural ‘logic’ of antigen receptor diversity. Semin Immunol 16:239-243PubMedGoogle Scholar
  36. Edgington SM (1992) What went wrong with Centoxin? Nat Bio 10:617-619Google Scholar
  37. Farr CD, Tabet MR, Ball WJ et al. (2002) Three-dimensional quantitative structure-activity relationship analysis of ligand binding to human sequence antidigoxin monoclonal antibodies using comparative molecular field analysis. J Med Chem 45:3257-3270PubMedGoogle Scholar
  38. Fishwild D, O’Donnell SL, Bengoechea T et al. (1996) High-avidity human IgG kappa monoclonal antibodies from a novel strain of minilocus transgenic mice. Nat Bio 14:845-851Google Scholar
  39. Fishwild D, Hudson DV, Deshpande U et al. (1999) Differential effects of administration of a human anti-CD4 monoclonal antibody, HM6G, in nonhuman primates. Clin Immunol 92:138-152PubMedGoogle Scholar
  40. Foon KA, Yang XD, Weiner LM et al. (2004) Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys 58:984-990PubMedGoogle Scholar
  41. Foote J, Eisen H (1995) Kinetic and affinity limits on antibodies produced during immune responses. Proc Natl Acad Sci USA 92:1254-1256PubMedGoogle Scholar
  42. Fuss IJ, Becker C, Yang Z et al. (2006) Both IL-12p70 and IL-23 are synthesizedduring active Crohn’s disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm Bowel Dis 12:9-15PubMedGoogle Scholar
  43. Garambois V, Glaussel F, Foulquier E et al. (2004) Fully human IgG and IgM antibodies directed against the carcinoembryonic antigen (CEA) Gold 4 epitope and designed for radioimmunotherapy (RIT) of colorectal cancers. BMC Cancer 4:75PubMedGoogle Scholar
  44. Gibson TB, Ranganathan A, Grothey A (2006) Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer. Clin Colorectal Cancer 6:29-31PubMedGoogle Scholar
  45. Goldstein G et al. (1985) A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. Ortho Multicenter Transplant Study Group. N Engl J Med 6:337-342Google Scholar
  46. Goodhardt M, Cavelier P, Akimenko MA et al. (1987) Rearrangement and expression of rabbit immunoglobulin kappa light chain gene in transgenic mice. Proc Natl Acad Sci USA 84:4229-4233PubMedGoogle Scholar
  47. Gordon JW, Ruddle FH (1981) Integration and stable germ line transmission of genes injected into mouse pronuclei. Science 214:1244-1246PubMedGoogle Scholar
  48. Green LL, Jakobovits A (1998) Regulation of B cell development by variable gene complexity in mice reconstituted with human immunoglobulin yeast artificial chromosomes. J Exp Med 188:483-495PubMedGoogle Scholar
  49. Green LL, Hardy MC, Maynard-Currie CE et al. (1994) Antigen-specific human monoclonal antibodies from mice engineered with human Ig heavy and light chain YACs. Nat Genet 7:13-21PubMedGoogle Scholar
  50. Greenough TC, Babcock GJ, Roberts A et al. (2005) Development and characterization of a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody that provides effective immunoprophylaxis in mice. J Infect Dis 191:507-514PubMedGoogle Scholar
  51. Harbers K, Jahner D, Jaenisch R (1981) Microinjection of cloned retroviral genomes into mouse zygotes: integration and expression in the animal. Nature 293:540-542PubMedGoogle Scholar
  52. Harding FA, Lonberg N (1995) Class switching in human immunoglobulin transgenic mice. Ann NY Acad Sci 764:536-546PubMedCrossRefGoogle Scholar
  53. He Y, Honnen WJ, Krachmarov CP et al. (2002) Efficient isolation of novel human monoclonal antibodies with neutralizing activity against HIV-1 from transgenic mice expressing human Ig loci. J Immunol 169:595-605PubMedGoogle Scholar
  54. Helmerhorst EJ, Maaskant JJ, Appelmelk MJ (1998) Anti-lipid A monoclonal antibody centoxin (HA-1A) binds to a wide variety of hydrophobic ligands. Infect Immun 66:870-873PubMedGoogle Scholar
  55. Heuck F, Ellermann J, Borchmann P et al. (2004) Combination of the human anti-CD30 antibody 5F11 with cytostatic drugs enhances its antitumor activity against Hodgkin and anaplastic large cell lymphoma cell lines. J Immunother 27:347-353PubMedGoogle Scholar
  56. Hodi FS, Mihm MC, Soiffer RJ et al. (2003) Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA 100:4712-4717PubMedGoogle Scholar
  57. Holmes EH (2001) PSMA specific antibodies and their diagnostic and therapeutic use. Expert Opin Investig Drugs 10:511-519PubMedGoogle Scholar
  58. Houghton AN, Brooks H, Cote RJ et al. (1983) Detection of cell surface and intracellular antigens by human monoclonal antibodies. Hybrid cell lines derived from lymphocytes of patients with malignant melanoma. J Exp Med 158:53-65PubMedGoogle Scholar
  59. Huang S, Mills L, Mian B et al. (2002) Fully humanized neutralizing antibodies to interleukin8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol 161:125-134PubMedGoogle Scholar
  60. Ignatovitch O, Tomlinson IM, Jones PT et al. (1997) The creation of diversity in the human immunoglobulin V(lambda) repertoire. J Mol Biol 268:69-77Google Scholar
  61. Imakiire T, Kuroki M, Shibaguchi H et al. (2004) Generation, immunologic characterization and antitumor effects of human monoclonal antibodies for carcinoembryonic antigen. Int J Cancer 108:564-570PubMedGoogle Scholar
  62. Ishida I, Tomizuka K, Yoshida H et al. (2002) Production of human monoclonal and polyclonal antibodies in TransChromo animals. Cloning Stem Cells 4:91-102PubMedGoogle Scholar
  63. Jaber SH, Cowen EW, Haworth LR et al. (2006) Skin Reactions in a Subset of Patients With Stage IV Melanoma Treated With Anti-Cytotoxic T-Lymphocyte Antigen 4 Monoclonal Antibody as a Single Agent. Arch Dermatol 142:166-172PubMedGoogle Scholar
  64. Jakobovits A, Moore AL, Green LL et al. (1993) Germ-line transmission and expression of a human-derived yeast artificial chromosome. Nature 362:255-258PubMedGoogle Scholar
  65. James K, Bell GT (1987) Human monoclonal antibody production. Current status and future prospects. J Immunol Methods 100:5-40PubMedGoogle Scholar
  66. Jones PT, Dear PH, Foote J et al. (1986) Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 321:522-525PubMedGoogle Scholar
  67. Kauffman CL, Araia N, Toichi E et al. (2004) A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis. J Invest Dermatol 123:1037-1044PubMedGoogle Scholar
  68. Kasper LH, Everitt D, Leist TP (2006) A phase I trial of an interleukin-12/23 monoclonal antibody in relapsing multiple sclerosis. Curr Med Res Opin 22:1671-1678PubMedGoogle Scholar
  69. Keler T, Halk E, Vitale L et al. (2003) Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques. J Immunol 171:6251-6259PubMedGoogle Scholar
  70. Klimm B, Schnell R, Diehl V et al. (2005) Current treatment and immunotherapy of Hodgkin’s lymphoma. Haematologica 90:1680-1692PubMedGoogle Scholar
  71. Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495-497PubMedGoogle Scholar
  72. Korman AJ, Peggs KS, Allison JP (2006) Checkpoint blockade in cancer immunotherapy. Adv Immunol 90:297-339PubMedGoogle Scholar
  73. Krueger GG, Langley RG, Leonardi C et al. (2007) A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 356:580-592PubMedGoogle Scholar
  74. Kuroiwa Y, Tomizuka K, Shinohara T et al. (2000) Manipulation of human minichromosomes to carry greater than megabase-sized chromosome inserts. Nat Biotechnol 18:1086-1090PubMedGoogle Scholar
  75. Kuroki M, Yamada H, Shibaguchi H et al. (2005) Preparation of human IgG and IgM monoclonal antibodies for MK-1/Ep-CAM by using human immunoglobulin gene-transferred mouse and gene cloning of their variable regions. Anticancer Res 25:3733-3739PubMedGoogle Scholar
  76. Kuus-Reichel K, Grauer LS, Karavodin LM et al. (1994) Will immunogenicity limit the use, efficacy, and future development of therapeutic monoclonal antibodies? Clin Diagn Lab Immunol 1:365-372PubMedGoogle Scholar
  77. Lammerts van Bueren JJ, Bleeker WK, Bogh HO et al. (2006) Effect of target dynamics on pharmacokinetics of a novel therapeutic antibody against the epidermal growth factor receptor: implications for the mechanisms of action. Cancer Res 66:7630-7638PubMedGoogle Scholar
  78. Larrick JW, Bourla JM (1986) Prospects for the therapeutic use of human monoclonal antibodies. J Biol Response Mod 5:379-393PubMedGoogle Scholar
  79. Leach DR, Krummel, MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734-1736PubMedGoogle Scholar
  80. Lenz H-J, Van Cutsem E, Khambata-Ford S et al. (2006) Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irenotecan, oxaloplatin, and fluoropyrimidines. J Clin Onc 24:4914-4921Google Scholar
  81. Lonberg N (2005) Human antibodies from transgenic animals. Nat Biotechnol 23:1117-1125PubMedGoogle Scholar
  82. Lonberg N, Huszar D (1995) Human antibodies from transgenic mice. Int Rev Immunol 13:65-93PubMedGoogle Scholar
  83. Lonberg N, Taylor LD, Harding FA et al. (1994) Antigen-specific human antibodies from mice comprising four distinct genetic modifications. Nature 368:856-859PubMedGoogle Scholar
  84. Ma D, Hopf CE, Malewicz, AD et al. (2006) Potent antitumor activity of an auristatin-conjugated, fully human monoclonal antibody to prostate-specific membrane antigen. Clin Cancer Res 12:2591-2596PubMedGoogle Scholar
  85. Maitta RW (2004) Protective and nonprotective human immunoglobulin M monoclonal antibodies to Cryptococcus neoformans glucuronoxylomannan manifest different specificities and gene use profiles. Infect Immun 72:4810-4818PubMedGoogle Scholar
  86. Maker AV, Phan GQ, Attia P et al. (2005) Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol 12:1005-1016PubMedGoogle Scholar
  87. Maker AV, Attia P, Rosenberg SA (2005b) Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol 175: 7746-7754Google Scholar
  88. Maker AV, Yang JC, Sherry RM et al. (2006) Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother 29:455-463PubMedGoogle Scholar
  89. Mannon PJ, Fuss IJ, Mayer L et al. (2004) Anti-interleukin-12 antibody for active Crohn’s disease. N Engl J Med 351:2069-2079PubMedGoogle Scholar
  90. Mansour SL, Thomas KR, Capecchi MR (1988) Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature 336:348-352PubMedGoogle Scholar
  91. Martin PL, Jiao Q, Cornacoff J, Hall W et al. (2005) Absence of adverse effects in cynomolgus macaques treated with CNTO 95, a fully human anti-alphav integrin monoclonal antibody, despite widespread tissue binding. Clin Cancer Res 11:6959-6965PubMedGoogle Scholar
  92. McCafferty J, Griffiths AD, Winter G et al. (1990) Phage antibodies: filamentous phage displaying antibody variable domains. Nature 348:552-554PubMedGoogle Scholar
  93. McCloskey RV, Straube RC, Sanders et al. (1994) Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group. Ann Intern Med 121:1-5PubMedGoogle Scholar
  94. McClung MR, Lewiecki EM, Cohen SB et al. (2006) Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 354:821-31PubMedGoogle Scholar
  95. Melnikova VO, Bar-Eli M (2006) Bioimmunotherapy for melanoma using fully human antibodies targeting MCAM/MUC18 and IL-8. Pigment Cell Res 19:395-405PubMedGoogle Scholar
  96. Mendez MJ, Green LL, Corvalan JRF et al. (1997) Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat Genet 15:146-156PubMedGoogle Scholar
  97. Mian BM, Dinney CPN, Bermejo CE et al. (2003) Fully human anti-interleukin 8 antibody inhibits tumor growth in orthotopic bladder cancer xenografts via down-regulation of matrix metalloproteases and nuclear factor-kappaB. Clin Cancer Res 9:3167-3175PubMedGoogle Scholar
  98. Mori E, Thomas M, Motoki K et al. (2004) Human normal hepatocytes are susceptible to apoptosis signal mediated by both TRAIL-R1 and TRAIL-R2. Cell Death Differ 11:203-207PubMedGoogle Scholar
  99. Morrison SL, Johnson MJ, Herzenberg LA et al. (1984) Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc Natl Acad Sci USA 81:6851-6855PubMedGoogle Scholar
  100. Mukherjee J, Chios K, Fishwild D et al. (2002) Human Stx2-specific monoclonal antibodies prevent systemic complications of Escherichia coli O157:H7 infection. Infect Immun 70:612-619PubMedGoogle Scholar
  101. Mukherjee J, Chios K, Fishwild D et al. (2002b) Production and characterization of protective human antibodies against Shiga toxin 1. Infect Immun 70:5896-5899Google Scholar
  102. Nagy A, Gerstenstein M, Vinterstein K et al. (2003) Manipulating the Mouse Embryo, A Laboratory Manual, 3rd edn. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NYGoogle Scholar
  103. Nicholson IC, Zou X, Popov AV et al. (1999) Antibody repertoires of four- and five-feature translocus mice carrying human immunoglobulin heavy chain and kappa and lambda light chain yeast artificial chromosomes. J Immunol 163:6898-6906PubMedGoogle Scholar
  104. Nozawa S, Aoki D, Tsukazaki K et al. (2004) HMMC-1: a humanized monoclonal antibody with therapeutic potential against Mullerian duct-related carcinomas. Clin Cancer Res 10: 7071-7078PubMedGoogle Scholar
  105. Olsson L, Andreasen RB, Ost A et al. (1984) Antibody producing human-human hybridomas. II. Derivation and characterization of an antibody specific for human leukemia cells. J Exp Med 159:537-550Google Scholar
  106. Ostendorf T, van Roeyen CRC, Peterson JD et al. (2003) A fully human monoclonal antibody (CR002) identifies PDGF-D as a novel mediator of mesangioproliferative glomerulonephritis. J Am Soc Nephrol 14:2237-2247PubMedGoogle Scholar
  107. Parren PW, Warmerdam PA, Boeije LC et al. (1992) On the interaction of IgG subclasses with the low affinity Fc gamma RIIa (CD32) on human monocytes, neutrophils, and platelets. Analysis of a functional polymorphism to human IgG2. J Clin Invest 90:1537-1546PubMedGoogle Scholar
  108. Parry R, Schneider D Hudson D et al. (2005) Identification of a novel prostate tumor target, mindin/RG-1, for antibody-based radiotherapy of prostate cancer. Cancer Res 65:8397-8405PubMedGoogle Scholar
  109. Pendley C, Schantz A, Wagner C (2003) Immunogenicity of therapeutic monoclonal antibodies. Curr Opin Mol Ther 5:172-179PubMedGoogle Scholar
  110. Phan GQ, Yang JC, Sherry RM et al. (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372-8377PubMedGoogle Scholar
  111. Popov AV, Zou X, Xian J et al. (1999) A human immunoglobulin lambda locus is similarly well expressed in mice and humans. J Exp Med 189:1611-1620PubMedGoogle Scholar
  112. Ramakrishna V, Treml JF, Vitale L et al. (2004) Mannose receptor targeting of tumor antigen pmel17 to human dendritic cells directs anti-melanoma T cell responses via multiple HLA molecules. J Immunol 172:2845-2852PubMedGoogle Scholar
  113. Rathanaswami P, Roalstad S, Roskos L et al. (2005) Demonstration of an in vivo generated subpicomolar affinity fully human monoclonal antibody to interleukin-8. Biochem Biophys Res Commun 334:1004-1013PubMedGoogle Scholar
  114. Reuben JM, Lee BN, Li C et al. (2006) Biologic and immunomodulatory events after CTLA4 blockade with ticilimumab in patients with advanced malignant elanoma. Cancer 106: 2437-2444PubMedGoogle Scholar
  115. Ribas A, Camacho LH, Lopez-Berestein G et al. (2005) Antitumor activity in melanoma and antiself responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675206. J Clin Oncol 23:8968-8977PubMedGoogle Scholar
  116. Ribas A, Glaspy JA, Lee Y et al. (2004) Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy. J Immunother 27:354-367PubMedGoogle Scholar
  117. Roost HP, Bachmann MF, Haag A et al. (1995) Early high-affinity neutralizing anti-viral IgG responses without further overall improvements of affinity. Proc Natl Acad Sci USA 92: 1257-1261PubMedGoogle Scholar
  118. Rowinski EK, Schwartz GH, Gollob JA et al. (2004) 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 22:3003-3015Google Scholar
  119. Sanderson K, Scotland R, Lee P et al. (2005) Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J Clin Oncol 23:741-750PubMedGoogle Scholar
  120. Schedl A, Larin Z, Montoliu L et al. (1993) A method for the generation of YAC transgenic mice by pronuclear microinjection. Nucleic Acids Res 21:4783-4787PubMedGoogle Scholar
  121. Schuler W, Bigaud M, Brinkmann V et al. (2004) Efficacy and safety of ABI793, a novel human anti-human CD154 monoclonal antibody, in cynomolgus monkey renal allotransplantation. Transplantation 77:717-726PubMedGoogle Scholar
  122. Schwartzberg PL, Goff SP, Robertson EJ (1989) Germ-line transmission of a c-abl mutation produced by targeted gene disruption in ES cells. Science 246:799-803PubMedGoogle Scholar
  123. Sheoran AS, Chapman-Bonofiglio S, Harvey BR et al. (2005) Human antibody against shiga toxin 2 administered to piglets after the onset of diarrhea due to Escherichia coli O157:H7 prevents fatal systemic complications. Infect Immun 73:4607-4613PubMedGoogle Scholar
  124. Simoons ML, de Boer MJ, van den Brand MJ et al. (1994) Randomized trial of a GPIIb/IIIa platelet receptor blocker in refractory unstable angina. European Cooperative Study Group. Circulation 89:596-603PubMedGoogle Scholar
  125. Skov L, Kragbelle K, Zachariae C et al. (2003) HuMax-CD4: a fully human monoclonal anti-CD4 antibody for the treatment of psoriasis vulgaris. Arch Dermatol 139:1433-1439PubMedGoogle Scholar
  126. Spalding BJ (1992) FDA setback flattens Centocor. Nat Bio 10:616Google Scholar
  127. Strauss WM, Dausman J, Beard C et al. (1993) Germ line transmission of a yeast artificial chromosome spanning the murine alpha 1(I) collagen locus. Science 259:1904-1907PubMedGoogle Scholar
  128. Suarez E, Y á ñez R, Barrios Y, Díaz-Espada F (2004) Human monoclonal antibodies produced in transgenic BABkappa,lambda mice recognising idiotypic immunoglobulins of human lymphoma cells. Mol Immunol 41:519-526PubMedGoogle Scholar
  129. Suzuki N, Aoki D, Tamada Y et al. (2004) HMOCC-1, a human monoclonal antibody that inhibits adhesion of ovarian cancer cells to human mesothelial cells. Gynecol Oncol 95:290-298PubMedGoogle Scholar
  130. Tai YT, Li X, Tong X et al. (2005) Human anti-CD40 antagonist antibody triggers significant antitumor activity against human multiple myeloma. Cancer Res 65:5898-5906PubMedGoogle Scholar
  131. Taylor LD, Carmack CE, Schramm SR et al. (1992) A transgenic mouse that expresses a diversity of human sequence heavy and light chain immunoglobulins. Nucleic Acids Res 20:6287-6295PubMedGoogle Scholar
  132. Taylor LD, Carmack CE, Huszar D et al. (1994) Human immunoglobulin transgenes undergo rearrangement, somatic mutation and class switching in mice that lack endogenous IgM. Int Immunol 6:579-591PubMedGoogle Scholar
  133. Teeling JL, French RR, Cragg MS et al. (2004) Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood 104: 1793-1800PubMedGoogle Scholar
  134. Teeling JL, Mackus WJ, Wiegman LJJM et al. (2006) The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol 177:362-371PubMedGoogle Scholar
  135. Thompson RH, Allison JP, Kwon ED (2006) Anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) immunotherapy for the treatment of prostate cancer. Urol Oncol 24:442-447PubMedGoogle Scholar
  136. Toichi E, Torres G, McCormick TS (2006) An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis. J Immunol 177:4917-4926PubMedGoogle Scholar
  137. Tomizuka K, Yoshida H, Uejima H et al. (1997) Functional expression and germline transmission of a human chromosome fragment in chimaeric mice. Nat Genet 16:133-143PubMedGoogle Scholar
  138. Tomizuka K, Shinohara T, Yoshida H et al. (2000) Double trans-chromosomic mice: maintenance of two individual human chromosome fragments containing Ig heavy and kappa loci and expression of fully human antibodies. Proc Natl Acad Sci USA 97:722-727PubMedGoogle Scholar
  139. Tomlinson IM, Walterb G, Jonesc PT et al. (1996) The imprint of somatic hypermutation on the repertoire of human germline V genes. J Mol Biol 256:813-817PubMedGoogle Scholar
  140. Trikha M, Zhou Z, Nemeth JA et al. (2004) CNTO 95, a fully human monoclonal antibody that inhibits alpha v integrins, has antitumor and antiangiogenic activity in vivo. Int J Cancer 110:326-335PubMedGoogle Scholar
  141. Tse KF, Jeffers M, Pollack VA et al. (2006) CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma. Clin Cancer Res 12:1373-1382PubMedGoogle Scholar
  142. Tzipori S, Sheoran A, Akiyoshi D et al. (2004) Antibody therapy in the management of shiga toxin-induced hemolytic uremic syndrome. Clin Microbiol Rev 17:926-941PubMedGoogle Scholar
  143. van Royen-Kerkhof A, Sanders EA, Walraven V et al. (2005) A novel human CD32 mAb blocks experimental immune haemolytic anaemia in FcgammaRIIA transgenic mice. Br J Haematol 130:130-137PubMedGoogle Scholar
  144. Villadsen LS, Schuurman J, Beurskens F et al. (2003) Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model. J Clin Invest 112:1571-1580PubMedGoogle Scholar
  145. Villadsen LS, Skov L, Dam TN et al. (2007) In situ depletion of CD4+ T cells in human skin by Zanolimumab. Arch Dermatol Res 298:449-455PubMedGoogle Scholar
  146. Vitale L, Blanset D, Lowy I et al. (2006) Prophylaxis and therapy of inhalational anthrax by a novel monoclonal antibody to protective antigen that mimics vaccine-induced immunity. Infect Immun 74:5840-5847PubMedGoogle Scholar
  147. Wagner EF, Stewart TA, Mintz B (1981a) The human beta-globin gene and a functional viral thymidine kinase gene in developing mice. Proc Natl Acad Sci USA 78:5016-5020Google Scholar
  148. Wagner TE, Hoppe PC, Jollick JD et al. (1981b) Microinjection of a rabbit beta-globin gene into zygotes and its subsequent expression in adult mice and their offspring. Proc Natl Acad Sci USA 78:6376-6380Google Scholar
  149. Wang Y, Hailey J, Williams D et al. (2005) Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody. Mol Cancer Ther 4:1214-1221PubMedGoogle Scholar
  150. Weinblatt ME, Keystone EC, Furst DE et al. (2003) Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 48:35-45PubMedGoogle Scholar
  151. Weng WK, Levy R (2003) Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 21:3940-3947PubMedGoogle Scholar
  152. Wu Y, Zhong Z, Huber J et al. (2006) Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer. Clin Cancer Res 12:6573-6584PubMedGoogle Scholar
  153. Xu JL, Davis, MM (2000) Diversity in the CDR3 region of V(H) is sufficient for most antibody specificities. Immunity 13:37-45PubMedGoogle Scholar
  154. Yamamura K-I, Kudo A, Ebihara T et al. (1986) Cell-type-specific and regulated expression of a rearranged human gamma1 heavy-chain immunoglobulin gene in transgenic mice. Proc Natl Acad Sci USA 83:2152-2156PubMedGoogle Scholar
  155. Yang X-D, Jia X-C, Corvalan JR et al. (1999) Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res 59:1236-1243PubMedGoogle Scholar
  156. Yang X-D, Corvalen JR, Wang P et al. (1999b) Fully human anti-interleukin-8 monoclonal antibodies: potential therapeutics for the treatment of inflammatory disease states. J Leukoc Biol 66:401-410Google Scholar
  157. Yang X-D, Jia X-C, Corvalan JR et al. (2001) Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol 38:17-23PubMedGoogle Scholar
  158. Zijlstra M, Li E, Sajjadi F et al. (1989) Germ-line transmission of a disrupted beta 2-microglobulin gene produced by homologous recombination in embryonic stem cells. Nature 342:435-438PubMedGoogle Scholar
  159. Zou YR, Muller W, Gu H et al. (1994) Cre-loxP-mediated gene replacement: a mouse strain producing humanized antibodies. Curr Biol 4:1099-1103PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • N. Lonberg
    • 1
  1. 1.MedarexMilpitasUSA

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