Skip to main content
PMC home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2008;181:69–97. doi: 10.1007/978-3-540-73259-4_4

Human Monoclonal Antibodies from Transgenic Mice

N Lonberg 3
Editors: Yuti Chernajovsky1, Ahuva Nissim2
PMCID: PMC7120671  PMID: 18071942

Abstract

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.

Keywords: Epidermal Growth Factor Receptor, Transgenic Mouse, Human Monoclonal Antibody, Human Immunoglobulin, Human MAbs

Contributor Information

Yuti Chernajovsky, Email: y.chernajovsky@qmul.ac.uk.

Ahuva Nissim, Email: a.nissim@qmul.ac.uk.

N. Lonberg, Email: nlonberg@medarex.com

References

  1. Alt FW, Blackwell TK, Yancopoulos GD. Immunoglobulin genes in transgenic mice. Trends Genet. 1985;1:231–236. [Google Scholar]
  2. Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regre7sion in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23:6043–6053. doi: 10.1200/JCO.2005.06.205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Babcock GJ, Broering TJ, Hernandez HJ, et al. Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters. Infect Immun. 2006;74:6339–6347. doi: 10.1128/IAI.00982-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of imfliximab in Crohn’s disease. N Engl J Med. 2003;348:601–608. doi: 10.1056/NEJMoa020888. [DOI] [PubMed] [Google Scholar]
  5. Ball WJ, Kasturi R, Dey P, et al. Isolation and characterization of human monoclonal antibodies to digoxin. J Immunol. 1999;163:2291–2298. [PubMed] [Google Scholar]
  6. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24:2283–2289. doi: 10.1200/JCO.2005.04.5716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bekker PJ, Holloway D, Rasmussen S, 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. 2004;19:1059–1066. doi: 10.1359/JBMR.040305. [DOI] [PubMed] [Google Scholar]
  8. Bender NK, Heilig CE, Dr öll B, et al. Immunogenicity, efficacy and adverse events of adalimumab in RA patients. Rheumatol Int. 2007;27:269–274. doi: 10.1007/s00296-006-0183-7. [DOI] [PubMed] [Google Scholar]
  9. Bieber MM, Bhat NM, Teng NN. Anti-endotoxin human monoclonal antibody A6H4C5 (HA-1A) utilizes the VH4.21 gene. Clin Infect Dis. 1995;21((Suppl 2)):S186–S189. doi: 10.1093/clinids/21.supplement_2.s186. [DOI] [PubMed] [Google Scholar]
  10. Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28:593–598. doi: 10.1097/01.cji.0000178913.41256.06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Bleeker WK, Lammerts van Bueren JJ, van Ojik HH, et al. Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy. J Immunol. 2004;173:4699–4707. doi: 10.4049/jimmunol.173.7.4699. [DOI] [PubMed] [Google Scholar]
  12. Body JJ, Facon T, Coleman RE, 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. 2006;12:1221–1228. doi: 10.1158/1078-0432.CCR-05-1933. [DOI] [PubMed] [Google Scholar]
  13. Boll B, Hansen H, Heuck F, et al. The fully human anti-CD30 antibody 5F11 activates NF-{kappa}B and sensitizes lymphoma cells to bortezomib-induced apoptosis. Blood. 2005;106:1839–1842. doi: 10.1182/blood-2005-01-0427. [DOI] [PubMed] [Google Scholar]
  14. Borchmann P, Treml JF, Hansen H, et al. The human anti-CD30 antibody 5F11 shows in vitro and in vivo activity against malignant lymphoma. Blood. 2003;102:3737–3742. doi: 10.1182/blood-2003-02-0515. [DOI] [PubMed] [Google Scholar]
  15. Borchmann P, Schnell R, Schulz H, et al. Monoclonal antibody-based immunotherapy of Hodgkin’s lymphoma. Curr Opin Investig Drugs. 2004;5:1262–1267. [PubMed] [Google Scholar]
  16. Borchmann P, Schnell R, Engert A. Immunotherapy of Hodgkin’s lymphoma. Eur J Haematol. 2005;75((Suppl 66)):159–165. doi: 10.1111/j.1600-0609.2005.00471.x. [DOI] [PubMed] [Google Scholar]
  17. Brinster RL, Chen HY, Trumbauer M, et al. Somatic expression of herpes thymidine kinase in mice following injection of a fusion gene into eggs. Cell. 1981;27:223–231. doi: 10.1016/0092-8674(81)90376-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Brinster RL, Ritchie KA, Hammer RE, et al. Expression of a microinjected immunoglobulin gene in the spleen of transgenic mice. Nature. 1983;306:332–336. doi: 10.1038/306332a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Bruggemann M, Caskey HM, Teale C, et al. A repertoire of monoclonal antibodies with human heavy chains from transgenic mice. Proc Natl Acad Sci USA. 1989;86:6709–6713. doi: 10.1073/pnas.86.17.6709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Brun-Buisson C. The HA-1A saga: the scientific and ethical dilemma of innovative and costly therapies. Intensive Care Med. 1994;20:314–316. doi: 10.1007/BF01720901. [DOI] [PubMed] [Google Scholar]
  21. Bucchini D, Reynaud CA, Ripoche MA, et al. Rearrangement of a chicken immunoglobulin gene occurs in the lymphoid lineage of transgenic mice. Nature. 1987;326:409–411. doi: 10.1038/326409a0. [DOI] [PubMed] [Google Scholar]
  22. Burgess T, Coxon A, Meyer S, et al. Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors. Cancer Res. 2006;66:1721–1729. doi: 10.1158/0008-5472.CAN-05-3329. [DOI] [PubMed] [Google Scholar]
  23. Buttin G. Exogenous Ig gene rearrangement in transgenic mice: a new strategy for human monoclonal antibody production? Trends Genet. 1987;3:205–206. [Google Scholar]
  24. Calvo E, Rowinsky EK. Clinical experience with monoclonal antibodies to epidermal growth factor receptor. Curr Oncol Rep. 2005;7:96–103. doi: 10.1007/s11912-005-0034-9. [DOI] [PubMed] [Google Scholar]
  25. Chang Q, Zhong Z, Lees A, et al. Structure-function relationships for human antibodies to pneumococcal capsular polysaccharide from transgenic mice with human immunoglobulin Loci. Infect Immun. 2002;70:4977–4986. doi: 10.1128/IAI.70.9.4977-4986.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Choi TK, Hollenbach PW, Pearson BE, et al. Transgenic mice containing a human heavy chain immunoglobulin gene fragment cloned in a yeast artificial chromosome. Nat Genet. 1993;4:117–123. doi: 10.1038/ng0693-117. [DOI] [PubMed] [Google Scholar]
  27. Cohen BD, Baker DA, Soderstrom C, 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. 2005;11:2063–2073. doi: 10.1158/1078-0432.CCR-04-1070. [DOI] [PubMed] [Google Scholar]
  28. Cohen SB, Emery P, Greenwald MW, et al. 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. 2006;54:2793–806. doi: 10.1002/art.22025. [DOI] [PubMed] [Google Scholar]
  29. Cohenuram M, Saif MW. Panitumumab the first fully human monoclonal antibody: from the bench to the clinic. Anticancer Drugs. 2007;18:7–15. doi: 10.1097/CAD.0b013e32800feecb. [DOI] [PubMed] [Google Scholar]
  30. Coiffier B, Haioun C, Ketterer N, et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood. 1998;92:1927–32. [PubMed] [Google Scholar]
  31. Costantini F, Lacy E. Introduction of a rabbit beta-globin gene into the mouse germ line. Nature. 1981;294:92–94. doi: 10.1038/294092a0. [DOI] [PubMed] [Google Scholar]
  32. Coughlin M, Lou G, Martinez O, et al. Generation and characterization of human monoclonal neutralizing antibodies with distinct binding and sequence features against SARS coronavirus using XenoMouse((R)) Virology. 2006;361:93–102. doi: 10.1016/j.virol.2006.09.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–345. doi: 10.1056/NEJMoa033025. [DOI] [PubMed] [Google Scholar]
  34. Davies NP, Rosewell IR, Richardson JC, et al. 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. 1993;11:911–914. doi: 10.1038/nbt0893-911. [DOI] [PubMed] [Google Scholar]
  35. Davis MM. The evolutionary and structural ‘logic’ of antigen receptor diversity. Semin Immunol. 2004;16:239–243. doi: 10.1016/j.smim.2004.08.003. [DOI] [PubMed] [Google Scholar]
  36. Edgington SM. What went wrong with Centoxin? Nat Bio. 1992;10:617–619. [Google Scholar]
  37. Farr CD, Tabet MR, Ball WJ, et al. Three-dimensional quantitative structure-activity relationship analysis of ligand binding to human sequence antidigoxin monoclonal antibodies using comparative molecular field analysis. J Med Chem. 2002;45:3257–3270. doi: 10.1021/jm0102811. [DOI] [PubMed] [Google Scholar]
  38. Fishwild D, O’Donnell SL, Bengoechea T, et al. High-avidity human IgG kappa monoclonal antibodies from a novel strain of minilocus transgenic mice. Nat Bio. 1996;14:845–851. doi: 10.1038/nbt0796-845. [DOI] [PubMed] [Google Scholar]
  39. Fishwild D, Hudson DV, Deshpande U, et al. Differential effects of administration of a human anti-CD4 monoclonal antibody, HM6G, in nonhuman primates. Clin Immunol. 1999;92:138–152. doi: 10.1006/clim.1999.4734. [DOI] [PubMed] [Google Scholar]
  40. 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. doi: 10.1016/j.ijrobp.2003.09.098. [DOI] [PubMed] [Google Scholar]
  41. Foote J, Eisen H. Kinetic and affinity limits on antibodies produced during immune responses. Proc Natl Acad Sci USA. 1995;92:1254–1256. doi: 10.1073/pnas.92.5.1254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Fuss IJ, Becker C, Yang Z, et al. 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. 2006;12:9–15. doi: 10.1097/01.mib.0000194183.92671.b6. [DOI] [PubMed] [Google Scholar]
  43. Garambois V, Glaussel F, Foulquier E, et al. 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. 2004;4:75. doi: 10.1186/1471-2407-4-75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Gibson TB, Ranganathan A, Grothey A. Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer. Clin Colorectal Cancer. 2006;6:29–31. doi: 10.3816/CCC.2006.n.01. [DOI] [PubMed] [Google Scholar]
  45. Goldstein G, et al. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. Ortho Multicenter Transplant Study Group. N Engl J Med. 1985;6:337–342. doi: 10.1056/NEJM198508083130601. [DOI] [PubMed] [Google Scholar]
  46. Goodhardt M, Cavelier P, Akimenko MA, et al. Rearrangement and expression of rabbit immunoglobulin kappa light chain gene in transgenic mice. Proc Natl Acad Sci USA. 1987;84:4229–4233. doi: 10.1073/pnas.84.12.4229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Gordon JW, Ruddle FH. Integration and stable germ line transmission of genes injected into mouse pronuclei. Science. 1981;214:1244–1246. doi: 10.1126/science.6272397. [DOI] [PubMed] [Google Scholar]
  48. 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. doi: 10.1084/jem.188.3.483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Green LL, Hardy MC, Maynard-Currie CE, et al. Antigen-specific human monoclonal antibodies from mice engineered with human Ig heavy and light chain YACs. Nat Genet. 1994;7:13–21. doi: 10.1038/ng0594-13. [DOI] [PubMed] [Google Scholar]
  50. Greenough TC, Babcock GJ, Roberts A, et al. Development and characterization of a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody that provides effective immunoprophylaxis in mice. J Infect Dis. 2005;191:507–514. doi: 10.1086/427242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Harbers K, Jahner D, Jaenisch R. Microinjection of cloned retroviral genomes into mouse zygotes: integration and expression in the animal. Nature. 1981;293:540–542. doi: 10.1038/293540a0. [DOI] [PubMed] [Google Scholar]
  52. Harding FA, Lonberg N. Class switching in human immunoglobulin transgenic mice. Ann NY Acad Sci. 1995;764:536–546. doi: 10.1111/j.1749-6632.1995.tb55879.x. [DOI] [PubMed] [Google Scholar]
  53. He Y, Honnen WJ, Krachmarov CP, et al. Efficient isolation of novel human monoclonal antibodies with neutralizing activity against HIV-1 from transgenic mice expressing human Ig loci. J Immunol. 2002;169:595–605. doi: 10.4049/jimmunol.169.1.595. [DOI] [PubMed] [Google Scholar]
  54. Helmerhorst EJ, Maaskant JJ, Appelmelk MJ. Anti-lipid A monoclonal antibody centoxin (HA-1A) binds to a wide variety of hydrophobic ligands. Infect Immun. 1998;66:870–873. doi: 10.1128/iai.66.2.870-873.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Heuck F, Ellermann J, Borchmann P, et al. 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. 2004;27:347–353. doi: 10.1097/00002371-200409000-00003. [DOI] [PubMed] [Google Scholar]
  56. Hodi FS, Mihm MC, Soiffer RJ, et al. 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. 2003;100:4712–4717. doi: 10.1073/pnas.0830997100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Holmes EH. PSMA specific antibodies and their diagnostic and therapeutic use. Expert Opin Investig Drugs. 2001;10:511–519. doi: 10.1517/13543784.10.3.511. [DOI] [PubMed] [Google Scholar]
  58. Houghton AN, Brooks H, Cote RJ, et al. 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. 1983;158:53–65. doi: 10.1084/jem.158.1.53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Huang S, Mills L, Mian B, et al. Fully humanized neutralizing antibodies to interleukin8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol. 2002;161:125–134. doi: 10.1016/S0002-9440(10)64164-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Ignatovitch O, Tomlinson IM, Jones PT, et al. The creation of diversity in the human immunoglobulin V(lambda) repertoire. J Mol Biol. 1997;268:69–77. doi: 10.1006/jmbi.1997.0956. [DOI] [PubMed] [Google Scholar]
  61. Imakiire T, Kuroki M, Shibaguchi H, et al. Generation, immunologic characterization and antitumor effects of human monoclonal antibodies for carcinoembryonic antigen. Int J Cancer. 2004;108:564–570. doi: 10.1002/ijc.11608. [DOI] [PubMed] [Google Scholar]
  62. Ishida I, Tomizuka K, Yoshida H, et al. Production of human monoclonal and polyclonal antibodies in TransChromo animals. Cloning Stem Cells. 2002;4:91–102. doi: 10.1089/153623002753632084. [DOI] [PubMed] [Google Scholar]
  63. Jaber SH, Cowen EW, Haworth LR, et al. 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. 2006;142:166–172. doi: 10.1001/archderm.142.2.166. [DOI] [PubMed] [Google Scholar]
  64. 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. doi: 10.1038/362255a0. [DOI] [PubMed] [Google Scholar]
  65. James K, Bell GT. Human monoclonal antibody production. Current status and future prospects. J Immunol Methods. 1987;100:5–40. doi: 10.1016/0022-1759(87)90170-0. [DOI] [PubMed] [Google Scholar]
  66. Jones PT, Dear PH, Foote J, et al. Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature. 1986;321:522–525. doi: 10.1038/321522a0. [DOI] [PubMed] [Google Scholar]
  67. Kauffman CL, Araia N, Toichi E, et al. 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. 2004;123:1037–1044. doi: 10.1111/j.0022-202X.2004.23448.x. [DOI] [PubMed] [Google Scholar]
  68. Kasper LH, Everitt D, Leist TP. A phase I trial of an interleukin-12/23 monoclonal antibody in relapsing multiple sclerosis. Curr Med Res Opin. 2006;22:1671–1678. doi: 10.1185/030079906X120931. [DOI] [PubMed] [Google Scholar]
  69. Keler T, Halk E, Vitale L, et al. Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques. J Immunol. 2003;171:6251–6259. doi: 10.4049/jimmunol.171.11.6251. [DOI] [PubMed] [Google Scholar]
  70. Klimm B, Schnell R, Diehl V, et al. Current treatment and immunotherapy of Hodgkin’s lymphoma. Haematologica. 2005;90:1680–1692. [PubMed] [Google Scholar]
  71. Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256:495–497. doi: 10.1038/256495a0. [DOI] [PubMed] [Google Scholar]
  72. Korman AJ, Peggs KS, Allison JP. Checkpoint blockade in cancer immunotherapy. Adv Immunol. 2006;90:297–339. doi: 10.1016/S0065-2776(06)90008-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007;356:580–592. doi: 10.1056/NEJMoa062382. [DOI] [PubMed] [Google Scholar]
  74. Kuroiwa Y, Tomizuka K, Shinohara T, et al. Manipulation of human minichromosomes to carry greater than megabase-sized chromosome inserts. Nat Biotechnol. 2000;18:1086–1090. doi: 10.1038/80287. [DOI] [PubMed] [Google Scholar]
  75. Kuroki M, Yamada H, Shibaguchi H, et al. 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. 2005;25:3733–3739. [PubMed] [Google Scholar]
  76. Kuus-Reichel K, Grauer LS, Karavodin LM, et al. Will immunogenicity limit the use, efficacy, and future development of therapeutic monoclonal antibodies. Clin Diagn Lab Immunol. 1994;1:365–372. doi: 10.1128/cdli.1.4.365-372.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Lammerts van Bueren JJ, Bleeker WK, Bogh HO, et al. 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. 2006;66:7630–7638. doi: 10.1158/0008-5472.CAN-05-4010. [DOI] [PubMed] [Google Scholar]
  78. Larrick JW, Bourla JM. Prospects for the therapeutic use of human monoclonal antibodies. J Biol Response Mod. 1986;5:379–393. [PubMed] [Google Scholar]
  79. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734–1736. doi: 10.1126/science.271.5256.1734. [DOI] [PubMed] [Google Scholar]
  80. Lenz H-J, Van Cutsem E, Khambata-Ford S, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irenotecan, oxaloplatin, and fluoropyrimidines. J Clin Onc. 2006;24:4914–4921. doi: 10.1200/JCO.2006.06.7595. [DOI] [PubMed] [Google Scholar]
  81. Lonberg N. Human antibodies from transgenic animals. Nat Biotechnol. 2005;23:1117–1125. doi: 10.1038/nbt1135. [DOI] [PubMed] [Google Scholar]
  82. Lonberg N, Huszar D. Human antibodies from transgenic mice. Int Rev Immunol. 1995;13:65–93. doi: 10.3109/08830189509061738. [DOI] [PubMed] [Google Scholar]
  83. Lonberg N, Taylor LD, Harding FA, et al. Antigen-specific human antibodies from mice comprising four distinct genetic modifications. Nature. 1994;368:856–859. doi: 10.1038/368856a0. [DOI] [PubMed] [Google Scholar]
  84. Ma D, Hopf CE, Malewicz AD, et al. Potent antitumor activity of an auristatin-conjugated, fully human monoclonal antibody to prostate-specific membrane antigen. Clin Cancer Res. 2006;12:2591–2596. doi: 10.1158/1078-0432.CCR-05-2107. [DOI] [PubMed] [Google Scholar]
  85. Maitta RW. Protective and nonprotective human immunoglobulin M monoclonal antibodies to Cryptococcus neoformans glucuronoxylomannan manifest different specificities and gene use profiles. Infect Immun. 2004;72:4810–4818. doi: 10.1128/IAI.72.8.4810-4818.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Maker AV, Phan GQ, Attia P, et al. 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. 2005;12:1005–1016. doi: 10.1245/ASO.2005.03.536. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Maker AV, Attia P, Rosenberg SA. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol. 2005b;175:7746–7754. doi: 10.4049/jimmunol.175.11.7746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Maker AV, Yang JC, Sherry RM, et al. Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother. 2006;29:455–463. doi: 10.1097/01.cji.0000208259.73167.58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Mannon PJ, Fuss IJ, Mayer L, et al. Anti-interleukin-12 antibody for active Crohn’s disease. N Engl J Med. 2004;351:2069–2079. doi: 10.1056/NEJMoa033402. [DOI] [PubMed] [Google Scholar]
  90. Mansour SL, Thomas KR, Capecchi MR. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature. 1988;336:348–352. doi: 10.1038/336348a0. [DOI] [PubMed] [Google Scholar]
  91. Martin PL, Jiao Q, Cornacoff J, Hall W, et al. 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. 2005;11:6959–6965. doi: 10.1158/1078-0432.CCR-04-2623. [DOI] [PubMed] [Google Scholar]
  92. McCafferty J, Griffiths AD, Winter G, et al. Phage antibodies: filamentous phage displaying antibody variable domains. Nature. 1990;348:552–554. doi: 10.1038/348552a0. [DOI] [PubMed] [Google Scholar]
  93. McCloskey RV, Straube RC, Sanders, et al. Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group. Ann Intern Med. 1994;121:1–5. doi: 10.7326/0003-4819-121-1-199407010-00001. [DOI] [PubMed] [Google Scholar]
  94. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821–31. doi: 10.1056/NEJMoa044459. [DOI] [PubMed] [Google Scholar]
  95. Melnikova VO, Bar-Eli M. Bioimmunotherapy for melanoma using fully human antibodies targeting MCAM/MUC18 and IL-8. Pigment Cell Res. 2006;19:395–405. doi: 10.1111/j.1600-0749.2006.00331.x. [DOI] [PubMed] [Google Scholar]
  96. Mendez MJ, Green LL, Corvalan JRF, et al. Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat Genet. 1997;15:146–156. doi: 10.1038/ng0297-146. [DOI] [PubMed] [Google Scholar]
  97. Mian BM, Dinney CPN, Bermejo CE, et al. 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. 2003;9:3167–3175. [PubMed] [Google Scholar]
  98. Mori E, Thomas M, Motoki K, et al. Human normal hepatocytes are susceptible to apoptosis signal mediated by both TRAIL-R1 and TRAIL-R2. Cell Death Differ. 2004;11:203–207. doi: 10.1038/sj.cdd.4401331. [DOI] [PubMed] [Google Scholar]
  99. Morrison SL, Johnson MJ, Herzenberg LA, et al. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc Natl Acad Sci USA. 1984;81:6851–6855. doi: 10.1073/pnas.81.21.6851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Mukherjee J, Chios K, Fishwild D, et al. Human Stx2-specific monoclonal antibodies prevent systemic complications of Escherichia coli O157:H7 infection. Infect Immun. 2002;70:612–619. doi: 10.1128/iai.70.2.612-619.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Mukherjee J, Chios K, Fishwild D, et al. Production and characterization of protective human antibodies against Shiga toxin 1. Infect Immun. 2002b;70:5896–5899. doi: 10.1128/IAI.70.10.5896-5899.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Nagy A, Gerstenstein M, Vinterstein K, et al. Manipulating the Mouse Embryo, A Laboratory Manual. 3rd edn. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2003. [Google Scholar]
  103. Nicholson IC, Zou X, Popov AV, et al. 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. 1999;163:6898–6906. [PubMed] [Google Scholar]
  104. Nozawa S, Aoki D, Tsukazaki K, et al. HMMC-1: a humanized monoclonal antibody with therapeutic potential against Mullerian duct-related carcinomas. Clin Cancer Res. 2004;10:7071–7078. doi: 10.1158/1078-0432.CCR-04-0802. [DOI] [PubMed] [Google Scholar]
  105. Olsson L, Andreasen RB, Ost A, et al. Antibody producing human-human hybridomas. II. Derivation and characterization of an antibody specific for human leukemia cells. J Exp Med. 1984;159:537–550. doi: 10.1084/jem.159.2.537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Ostendorf T, van Roeyen CRC, Peterson JD, et al. A fully human monoclonal antibody (CR002) identifies PDGF-D as a novel mediator of mesangioproliferative glomerulonephritis. J Am Soc Nephrol. 2003;14:2237–2247. doi: 10.1097/01.asn.0000083393.00959.02. [DOI] [PubMed] [Google Scholar]
  107. Parren PW, Warmerdam PA, Boeije LC, et al. 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. 1992;90:1537–1546. doi: 10.1172/JCI116022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Parry R, Schneider D Hudson D, et al. Identification of a novel prostate tumor target, mindin/RG-1, for antibody-based radiotherapy of prostate cancer. Cancer Res. 2005;65:8397–8405. doi: 10.1158/0008-5472.CAN-05-1203. [DOI] [PubMed] [Google Scholar]
  109. Pendley C, Schantz A, Wagner C. Immunogenicity of therapeutic monoclonal antibodies. Curr Opin Mol Ther. 2003;5:172–179. [PubMed] [Google Scholar]
  110. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA. 2003;100:8372–8377. doi: 10.1073/pnas.1533209100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Popov AV, Zou X, Xian J, et al. A human immunoglobulin lambda locus is similarly well expressed in mice and humans. J Exp Med. 1999;189:1611–1620. doi: 10.1084/jem.189.10.1611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Ramakrishna V, Treml JF, Vitale L, et al. Mannose receptor targeting of tumor antigen pmel17 to human dendritic cells directs anti-melanoma T cell responses via multiple HLA molecules. J Immunol. 2004;172:2845–2852. doi: 10.4049/jimmunol.172.5.2845. [DOI] [PubMed] [Google Scholar]
  113. Rathanaswami P, Roalstad S, Roskos L, et al. Demonstration of an in vivo generated subpicomolar affinity fully human monoclonal antibody to interleukin-8. Biochem Biophys Res Commun. 2005;334:1004–1013. doi: 10.1016/j.bbrc.2005.07.002. [DOI] [PubMed] [Google Scholar]
  114. Reuben JM, Lee BN, Li C, et al. Biologic and immunomodulatory events after CTLA4 blockade with ticilimumab in patients with advanced malignant elanoma. Cancer. 2006;106:2437–2444. doi: 10.1002/cncr.21854. [DOI] [PubMed] [Google Scholar]
  115. Ribas A, Camacho LH, Lopez-Berestein G, et al. 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. 2005;23:8968–8977. doi: 10.1200/JCO.2005.01.109. [DOI] [PubMed] [Google Scholar]
  116. Ribas A, Glaspy JA, Lee Y, et al. Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy. J Immunother. 2004;27:354–367. doi: 10.1097/00002371-200409000-00004. [DOI] [PubMed] [Google Scholar]
  117. Roost HP, Bachmann MF, Haag A, et al. Early high-affinity neutralizing anti-viral IgG responses without further overall improvements of affinity. Proc Natl Acad Sci USA. 1995;92:1257–1261. doi: 10.1073/pnas.92.5.1257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  118. Rowinski EK, Schwartz GH, Gollob JA, 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. doi: 10.1200/JCO.2004.11.061. [DOI] [PubMed] [Google Scholar]
  119. Sanderson K, Scotland R, Lee P, et al. 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. 2005;23:741–750. doi: 10.1200/JCO.2005.01.128. [DOI] [PubMed] [Google Scholar]
  120. Schedl A, Larin Z, Montoliu L, et al. A method for the generation of YAC transgenic mice by pronuclear microinjection. Nucleic Acids Res. 1993;21:4783–4787. doi: 10.1093/nar/21.20.4783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Schuler W, Bigaud M, Brinkmann V, et al. Efficacy and safety of ABI793, a novel human anti-human CD154 monoclonal antibody, in cynomolgus monkey renal allotransplantation. Transplantation. 2004;77:717–726. doi: 10.1097/01.tp.0000116563.72763.83. [DOI] [PubMed] [Google Scholar]
  122. Schwartzberg PL, Goff SP, Robertson EJ. Germ-line transmission of a c-abl mutation produced by targeted gene disruption in ES cells. Science. 1989;246:799–803. doi: 10.1126/science.2554496. [DOI] [PubMed] [Google Scholar]
  123. Sheoran AS, Chapman-Bonofiglio S, Harvey BR, et al. 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. 2005;73:4607–4613. doi: 10.1128/IAI.73.8.4607-4613.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  124. Simoons ML, de Boer MJ, van den Brand MJ, et al. Randomized trial of a GPIIb/IIIa platelet receptor blocker in refractory unstable angina. European Cooperative Study Group. Circulation. 1994;89:596–603. doi: 10.1161/01.cir.89.2.596. [DOI] [PubMed] [Google Scholar]
  125. Skov L, Kragbelle K, Zachariae C, et al. HuMax-CD4: a fully human monoclonal anti-CD4 antibody for the treatment of psoriasis vulgaris. Arch Dermatol. 2003;139:1433–1439. doi: 10.1001/archderm.139.11.1433. [DOI] [PubMed] [Google Scholar]
  126. Spalding BJ. FDA setback flattens Centocor. Nat Bio. 1992;10:616. [Google Scholar]
  127. Strauss WM, Dausman J, Beard C, et al. Germ line transmission of a yeast artificial chromosome spanning the murine alpha 1(I) collagen locus. Science. 1993;259:1904–1907. doi: 10.1126/science.8096090. [DOI] [PubMed] [Google Scholar]
  128. Suarez E, Y á ñez R, Barrios Y, Díaz-Espada F. Human monoclonal antibodies produced in transgenic BABkappa,lambda mice recognising idiotypic immunoglobulins of human lymphoma cells. Mol Immunol. 2004;41:519–526. doi: 10.1016/j.molimm.2004.03.035. [DOI] [PubMed] [Google Scholar]
  129. Suzuki N, Aoki D, Tamada Y, et al. HMOCC-1, a human monoclonal antibody that inhibits adhesion of ovarian cancer cells to human mesothelial cells. Gynecol Oncol. 2004;95:290–298. doi: 10.1016/j.ygyno.2004.06.024. [DOI] [PubMed] [Google Scholar]
  130. Tai YT, Li X, Tong X, et al. Human anti-CD40 antagonist antibody triggers significant antitumor activity against human multiple myeloma. Cancer Res. 2005;65:5898–5906. doi: 10.1158/0008-5472.CAN-04-4125. [DOI] [PubMed] [Google Scholar]
  131. Taylor LD, Carmack CE, Schramm SR, et al. A transgenic mouse that expresses a diversity of human sequence heavy and light chain immunoglobulins. Nucleic Acids Res. 1992;20:6287–6295. doi: 10.1093/nar/20.23.6287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  132. Taylor LD, Carmack CE, Huszar D, et al. Human immunoglobulin transgenes undergo rearrangement, somatic mutation and class switching in mice that lack endogenous IgM. Int Immunol. 1994;6:579–591. doi: 10.1093/intimm/6.4.579. [DOI] [PubMed] [Google Scholar]
  133. Teeling JL, French RR, Cragg MS, et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood. 2004;104:1793–1800. doi: 10.1182/blood-2004-01-0039. [DOI] [PubMed] [Google Scholar]
  134. Teeling JL, Mackus WJ, Wiegman LJJM, et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol. 2006;177:362–371. doi: 10.4049/jimmunol.177.1.362. [DOI] [PubMed] [Google Scholar]
  135. Thompson RH, Allison JP, Kwon ED. Anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) immunotherapy for the treatment of prostate cancer. Urol Oncol. 2006;24:442–447. doi: 10.1016/j.urolonc.2005.08.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  136. Toichi E, Torres G, McCormick TS. An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis. J Immunol. 2006;177:4917–4926. doi: 10.4049/jimmunol.177.7.4917. [DOI] [PubMed] [Google Scholar]
  137. Tomizuka K, Yoshida H, Uejima H, et al. Functional expression and germline transmission of a human chromosome fragment in chimaeric mice. Nat Genet. 1997;16:133–143. doi: 10.1038/ng0697-133. [DOI] [PubMed] [Google Scholar]
  138. Tomizuka K, Shinohara T, Yoshida H, et al. 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. 2000;97:722–727. doi: 10.1073/pnas.97.2.722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  139. Tomlinson IM, Walterb G, Jonesc PT, et al. The imprint of somatic hypermutation on the repertoire of human germline V genes. J Mol Biol. 1996;256:813–817. doi: 10.1006/jmbi.1996.0127. [DOI] [PubMed] [Google Scholar]
  140. Trikha M, Zhou Z, Nemeth JA, et al. CNTO 95, a fully human monoclonal antibody that inhibits alpha v integrins, has antitumor and antiangiogenic activity in vivo. Int J Cancer. 2004;110:326–335. doi: 10.1002/ijc.20116. [DOI] [PubMed] [Google Scholar]
  141. Tse KF, Jeffers M, Pollack VA, et al. CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma. Clin Cancer Res. 2006;12:1373–1382. doi: 10.1158/1078-0432.CCR-05-2018. [DOI] [PubMed] [Google Scholar]
  142. Tzipori S, Sheoran A, Akiyoshi D, et al. Antibody therapy in the management of shiga toxin-induced hemolytic uremic syndrome. Clin Microbiol Rev. 2004;17:926–941. doi: 10.1128/CMR.17.4.926-941.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  143. van Royen-Kerkhof A, Sanders EA, Walraven V, et al. A novel human CD32 mAb blocks experimental immune haemolytic anaemia in FcgammaRIIA transgenic mice. Br J Haematol. 2005;130:130–137. doi: 10.1111/j.1365-2141.2005.05571.x. [DOI] [PubMed] [Google Scholar]
  144. Villadsen LS, Schuurman J, Beurskens F, et al. Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model. J Clin Invest. 2003;112:1571–1580. doi: 10.1172/JCI18986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  145. Villadsen LS, Skov L, Dam TN, et al. In situ depletion of CD4+ T cells in human skin by Zanolimumab. Arch Dermatol Res. 2007;298:449–455. doi: 10.1007/s00403-006-0710-0. [DOI] [PubMed] [Google Scholar]
  146. Vitale L, Blanset D, Lowy I, et al. Prophylaxis and therapy of inhalational anthrax by a novel monoclonal antibody to protective antigen that mimics vaccine-induced immunity. Infect Immun. 2006;74:5840–5847. doi: 10.1128/IAI.00712-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  147. Wagner EF, Stewart TA, Mintz B. The human beta-globin gene and a functional viral thymidine kinase gene in developing mice. Proc Natl Acad Sci USA. 1981a;78:5016–5020. doi: 10.1073/pnas.78.8.5016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  148. Wagner TE, Hoppe PC, Jollick JD, et al. Microinjection of a rabbit beta-globin gene into zygotes and its subsequent expression in adult mice and their offspring. Proc Natl Acad Sci USA. 1981b;78:6376–6380. doi: 10.1073/pnas.78.10.6376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  149. Wang Y, Hailey J, Williams D, et al. 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. 2005;4:1214–1221. doi: 10.1158/1535-7163.MCT-05-0048. [DOI] [PubMed] [Google Scholar]
  150. Weinblatt ME, Keystone EC, Furst DE, et al. 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. 2003;48:35–45. doi: 10.1002/art.10697. [DOI] [PubMed] [Google Scholar]
  151. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003;21:3940–3947. doi: 10.1200/JCO.2003.05.013. [DOI] [PubMed] [Google Scholar]
  152. Wu Y, Zhong Z, Huber J, et al. Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer. Clin Cancer Res. 2006;12:6573–6584. doi: 10.1158/1078-0432.CCR-06-0831. [DOI] [PubMed] [Google Scholar]
  153. Xu JL, Davis MM. Diversity in the CDR3 region of V(H) is sufficient for most antibody specificities. Immunity. 2000;13:37–45. doi: 10.1016/s1074-7613(00)00006-6. [DOI] [PubMed] [Google Scholar]
  154. Yamamura K-I, Kudo A, Ebihara T, et al. Cell-type-specific and regulated expression of a rearranged human gamma1 heavy-chain immunoglobulin gene in transgenic mice. Proc Natl Acad Sci USA. 1986;83:2152–2156. doi: 10.1073/pnas.83.7.2152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  155. Yang X-D, Jia X-C, Corvalan JR, et al. 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. [PubMed] [Google Scholar]
  156. Yang X-D, Corvalen JR, Wang P, et al. Fully human anti-interleukin-8 monoclonal antibodies: potential therapeutics for the treatment of inflammatory disease states. J Leukoc Biol. 1999b;66:401–410. doi: 10.1002/jlb.66.3.401. [DOI] [PubMed] [Google Scholar]
  157. Yang X-D, Jia X-C, Corvalan JR, et al. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol. 2001;38:17–23. doi: 10.1016/s1040-8428(00)00134-7. [DOI] [PubMed] [Google Scholar]
  158. Zijlstra M, Li E, Sajjadi F, et al. Germ-line transmission of a disrupted beta 2-microglobulin gene produced by homologous recombination in embryonic stem cells. Nature. 1989;342:435–438. doi: 10.1038/342435a0. [DOI] [PubMed] [Google Scholar]
  159. Zou YR, Muller W, Gu H, et al. Cre-loxP-mediated gene replacement: a mouse strain producing humanized antibodies. Curr Biol. 1994;4:1099–1103. doi: 10.1016/s0960-9822(00)00248-7. [DOI] [PubMed] [Google Scholar]

Articles from Therapeutic Antibodies are provided here courtesy of Nature Publishing Group

RESOURCES