Nature Biotechnology
16, 535 - 539 (1998)
doi:10.1038/nbt0698-535
Human antibodies by designTristan J. Vaughan1, *, Jane K. Osbourn1
& Philip R. Tempest1
1Cambridge Antibody Technology, The Science Park, Melbourn, Cambridgeshire, SG8 6JJ, UK.
*Corresponding author (e-mail: tris.vaughan@camb-antibody.co.uk). Monoclonal antibodies (Mabs) have long been considered a good class of natural drugs, both because they mimic their natural role in the body and because they have no inherent toxicity. Although rodent Mabs are readily generated, their widespread use as therapeutic agents has been hampered because they are recognized as foreign by the patient. Evidently, clinical Mabs should be as human as possible and results with some of the more recently developed chimerized and humanized Mabs are testimony to this. Mabs that are entirely human are now being produced from phage display and transgenic mice. The first fully human Mabs generated by phage display have already entered clinical trials, and together with recent advances in these technologies, may finally realize the full potential of antibodies.
REFERENCES
- Kohler, G. and Milstein, C. 1975. Continuous cultures of fused cells secreting antibody of pre-defined specificity. Nature 256: 495−497. | PubMed | ISI | ChemPort |
- Johnson, K.S. and Glover, D.R. 1998. Antibodies come in from the cold. Innovations in Pharmaceutical Technology. In press.
- Larrick, J.W., Wallace, E.F., Coloma, M.J., Bruderer, U., Lang, A.B., and Fry, K.E. 1992. Therapeutic human antibodies derived from PCR amplification of B-cell variable regions. Immunol. Rev. 130: 69−85. | PubMed | ISI | ChemPort |
- Adair, J.R. and Bright, S.M. 1995. Progress with humanized antibodies—an update. Expert Opinion on Investigational Drugs 4: 863−870.
- Neuberger, M.S., Williams, G.T., and Fox, R.O. 1994. Recombinant antibodies possessing novel effector functions. 1984. Nature 312: 604−608.
- Boulianne, G.L., Hozumi, N., and Shulman, M.J. 1984. Production of functional chimeric mouse/human antibody. Nature 312: 643−646. | Article | PubMed | ISI | ChemPort |
- LoBuglio, A.F., Wheeler, R.H., Trang, J., Haynes, A., Rogers, K., Harvey, E.B. et al. 1989. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc. Natl. Acad. Sci. USA 86: 4220−4224. | PubMed | ChemPort |
- Khazaeli, M.B., Saleh, M.N., Liu, T.P., Meredith, R.F., Wheeler, R.H., Baker, T.S. et al. 1991. Pharmacokinetics and immune response of 131l-chimeric mouse/human B72.3 (human
 4) monoclonal antibody in humans. Cancer Research 51: 5461−5466. | PubMed | ISI | ChemPort |
- Elliott, M.J., Maini, R.N., Feldmann, M., Long-Fox, A., Charles, P., Bijl, H. et al. 1994. Repeated therapy with monoclonal antibody to tumour necrosis factor
 (cA2) in patients with rheumatoid arthritis. Lancer 344: 1125−1127. | Article | ChemPort |
- Jones, P.T., Dear, P.H., Foote, J., Neuberger, M.S., and Winter, G. 1986. Replacing the complimentarity-determining regions in a human antibody with those from a mouse. Nature 321: 522−525. | Article | PubMed | ISI | ChemPort |
- Riechmann, L., Clark, M., Waldmann, H., and Winter G. 1988. Reshaping human antibodies for therapy. Nature 332: 323−327. | Article | PubMed | ISI | ChemPort |
- Padlan, E.A. 1994. Anatomy of the antibody molecule. Mol. Immunol. 31: 169−217. | Article | PubMed | ISI | ChemPort |
- Graziano, R.F., Tempest, P.R., White, P., Kelar, T., Deo, Y., Ghebremariam, H. et al. 1995. Construction and characterization of a humanized anti--immunoglobulin receptor type I (FcRI) monoclonal antibody. J. Immunol. 155: 4996−5002. | PubMed | ISI | ChemPort |
- Foote, J. and Winter, G. 1992. Antibody framework residues affecting the conformation of the hypervariable loops. J. Mol. Biol. 224: 487−499. | PubMed | ISI | ChemPort |
- Queen, C., Schneider, W.P., Selick, H.E., Payne, P.W., Landolfi, N.F., Duncan, J.F. et al. 1989 A humanized antibody that binds to the interleukin 2 receptor. Proc. Natl. Acad. Sci. USA 86: 10029−10033. | PubMed | ChemPort |
- Padlan, E.A. 1991. A possible procedure for reducing the immunogenicity of antibody variable domains while preserving their ligand-binding properties. Mol. Immunol. 28: 489−498. | Article | PubMed | ISI | ChemPort |
- Roguska, M.A., Pederson, J.T., Keddy, C.A., Henry, A.H., Searle, S.J., Lambert, J.M. et al. 1994. Humanization of murine monoclonal antibodies through variable domain resurfacing. Proc. Natl. Acad. Sci. USA 91: 969−973. | PubMed | ChemPort |
- Hale, G., Dyer, M.J., Clark, M.R., Phillips, J.M., Marcus, R., Riechmann, L. et al. 1988. Remission induction in non-Hodgkin lymphoma with reshaped human monoclonal antibody CAMPATH-1H. Lancer ii: 1394−1399. | Article |
- Matteson, E.L., Yokum, D.E., St Clair, E.W., Achkar, A.A., Thakor, M.S., Jacobs, M.R. et al. 1995. Treatment of active refractory rheumatoid arthritis with humanized monoclonal antibody CAMPATH-1H administered by daily subcutaneous injection. Arthritis and Rheumatism 38: 1187−1193. | PubMed | ISI | ChemPort |
- Weinblatt, M.E., Maddison, P.J., Bulpitt, K.J., Hazelman, B.L., Urowitz, M.B., Sturrock, R.D. et al. 1995. CAMPATH-1H, a humanized monoclonal antibody, in refractory rheumatoid arthritis: an intravenous dose-escalation study. Arthritis and Rheumatism 38: 1589−1594. | PubMed | ISI | ChemPort |
- Caron, P.C., Jurcic, J.G., Scott, A.M., Finn, R.D., Divgi, C.R., Graham, M.C. et al. 1994. A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity. Blood 83: 1760−1768. | PubMed | ISI | ChemPort |
- Hakimi, J., Mould, D., Waldmann, T.A., Queen, C., Anasetti, C, and Light, S. 1997. Development of Zenapax: a humanized anti-Tac antibody, pp. 277−300 in Antibody therapeutics. Harris, W.J. and Adair, J.R. (eds.). CRC Press, Boca Raton, FL. | ChemPort |
- Aujame, L., Geoffroy, F. and Sodoyer, R. 1997. High affinity human antibodies by phage display. Human Antibodies 8: 155−168. | PubMed | ChemPort |
- McCafferty, J., Griffiths, A.D., Winter, G. and Chiswell, D.J. 1990. Phage antibodies: Filamentous phage displaying antibody variable domains. Nature 348: 552−554. | Article | PubMed | ISI | ChemPort |
- Winter, G., Griffiths, A.D., Hawkins, R.E. and Hoogenboom, H.R. 1994. Making antibodies by phage display technology. Annu. Rev. Immunol. 12: 433−455. | Article | PubMed | ISI | ChemPort |
- Griffiths, A.D., Williams, S.C., Hartley, O., Tomlinson, I.M., Waterhouse, P., and Crosby, W.L. et al. 1994. Isolation of high affinity human antibodies directly from large synthetic repertoires. EMBO J. 13: 3245−3260. | PubMed | ISI | ChemPort |
- Vaughan, T.J., Williams, A.J., Pritchard, K., Osbourn, J.K., Pope, A.R., Earnshaw, J.C. et al. 1996. Human antibodies with sub-nanomolar affinities isolated from a large non-immunized phage display library. Nature Biotechnology 14: 309−314. | Article | PubMed | ChemPort |
- Schier, R., McCall, A., Adams, G.P., Marshall, K.W., Merrit, H., Yim, M. et al. 1996. Isolation of picomolar anti-c-erbB-2 single chain Fv by molecular evolution of the complementarity determining regions in the centre of the antibody binding site. J. Mol. Biol. 263: 551−567 | Article | PubMed | ISI | ChemPort |
- Xie, M.-H., Yuan, J., Adams, C., and Gurney, A. 1997. Direct demonstration of MuSK involvement in acetylcholine receptor clustering through identification of agonist ScFv. Nature Biotechnology 15: 768−771. | Article | PubMed | ISI | ChemPort |
- Hawkins, R.E. and Winter, G. 1992. Cell selection strategies for making antibodies from variable gene libraries: tapping the memory pool. Eur. J. Immunol. 22: 867−870. | PubMed | ISI | ChemPort |
- Thompson, J., Pope, A., Tung-Chan, J.S., Hollis, G., Mark, G., and Johnson, K.S. 1996. Affinity maturation of a high-affinity human monoclonal antibody against the third hypervariable loop of human immunodeficiency virus: use of phage display to improve affinity and broaden strain reactivity. J. Mol. Biol. 256: 77−88. | Article | PubMed | ISI | ChemPort |
- Yang, W.P., Green, K., Pinz-Sweeney, S., Briones, A.T., Burton, D.R., and Barbas, C.F. 1995. CDR walking mutagenesis for the affinity maturation of a potent human anti-HIV-1 antibody into the picomolar range. J. Mol. Biol. 254: 392−403. | Article | PubMed | ISI | ChemPort |
- Parsons, H.L., Earnshaw, J.C., Wilton, J., Johnson, K.S., Schueler, P.A., Mahoney, W., and McCafferty, J. 1996. Directing phage selections towards specific epitopes. Protein Eng. 9: 1043−1049. | PubMed | ISI | ChemPort |
- Osbourn, J.K., Derbyshire, E.J., Vaughan, T.J., Field, A.W., and Johnson, K.S. 1998. Pathfinder selection; in situ isolation of novel antibodies. Immunotechnology 3: 293−302. | Article | PubMed | ISI | ChemPort |
- Siegel, D. 1995. Isolation of human anti-red blood cell antibodies by repertoire cloning. Annals of the New York Academy of Science 764: 547−558. | ISI | ChemPort |
- Kruif, J., Terstappen, L., Boel, E., and Logtenberg, T. 1995. Rapid selection of cell subpopulation-specific human monoclonal antibodies from a synthetic phage antibody library. Proc. Natl. Acad. Sci. USA 92: 3938−3942. | PubMed |
- Jespers, L.S., Roberts, A., Mahler, S.M., and Winter, G., Hoogenboom, H.R. 1994. Guiding the selection of human antibodies from phage display repertoires to a single epitope of an antigen. Bio/Technology 12: 899−903. | Article | PubMed | ISI | ChemPort |
- Nissim, A., Hoogenboom, H.R., Tomlinson, I.M., Flynn, G., Midgley, C., Lane, D. et al. 1994. Antibody fragments from a "single pot" phage display library as immunological reagents. EMBO J. 13: 692−698. | PubMed | ISI | ChemPort |
- Wang, L., Radic, M.Z., Siegel, D., Chang, T., Bracy, J., and Galili, U. 1997. Cloning of anti-Gal Fabs from combinatorial phage display libraries: structural analysis and comparison of Fab expression in pComb3H and pComb8 phage. Mol. Immunol. 34: 609−618. | Article | PubMed | ISI | ChemPort |
- Griffiths, A.D., Malmqvist, M., Marks, J.D., Bye, J.M., Embleton, M.J., McCafferty, J. et al. 1993. Human anti-self antibodies with high specificity from phage display libraries. EMBO J. 12: 725−734. | PubMed | ISI | ChemPort |
- Cai, X., and Garen, A. 1995. Anti-melanoma antibodies from melanoma patients immunized with genetically modified autologous tumour cells: selection of specific antibodies from single-chain Fv fusion phage libraries. Proc. Natl. Acad. Sci. USA 92: 6537−6541. | PubMed | ChemPort |
- Pasqualini, R. and Ruoslahti, E. 1996. Organ targeting in vivo using phage display peptide libraries. Nature 380: 364−366. | Article | PubMed | ChemPort |
- Hoogenboom, H.R. 1995. Designing and optimizing library selection strategies for generating high-affnity antibodies. Trends in Biotechnology 15: 62−70. | Article |
- Marks, J.D., Griffiths, A.D., Malmqvist, M., Clackson, T.P., Bye, J.M., and Winter, G. 1992. By-passing immunisation: building high affinity human antibodies by chain shuffling. Bio/Technology 10: 779−783. | Article | PubMed | ISI | ChemPort |
- Low, N.M., Holliger, P., and Winter, G. 1996. Mimicking somatic hypermutation; affinity maturation of antibodies displayed on bacteriophage using a bacterial mutator strain. J. Mol. Biol. 250: 359−368. | Article |
- Patten, P.A., Howard, R.J., and Stemmer, W.P. 1997. Applications of DNA shuffling to Pharmaceuticals and vaccines. Curr. Opin. Biotechnol. 8: 724−733. | Article | PubMed | ISI | ChemPort |
- Hawkins, R.E., Russell, S.J., and Winter, G. 1992. Selection of phage antibodies by binding affinity: mimicking affinity maturation. J. Mol. Biol. 226: 889−896. | Article | PubMed | ISI | ChemPort |
- CAT initiates first clinical trial. SCRIP. 1997. No. 2258:pg 7.
- Brüggemann, M., and Neuberger, M.S. 1996. Strategies for expressing human antibody repertoires in transgenic mice. Immunol. Today 17: 391−397. | Article | PubMed | ISI | ChemPort |
- Jakobovits, A. 1995. Production of fully human antibodies by transgenic mice. Curr. Opin. Biotechnol. 6: 561−566. | Article | PubMed | ISI | ChemPort |
- Brüggemann, M. and Taussig, M.J. 1997. Production of human antibody repertoires in transgenic mice. Curr. Opin. Biotechnol. 8: 455−458. | Article | PubMed | ISI |
- www.mrc-cpe.ac.uk/imt-doc/public/INTRO.html—Tomlinson, I.M., Williams, S.C., Corbett, S.J., Cox, J.P.L., and Winter, G.. 1997. V Base: the database of human antibody genes. MRC Centre for Protein Engineering, Cambridge, UK.
- Lonberg, N., Taylor, L.D., Harding, F.A., Trounstine, M., Higgins, M., Schramm, S.R. et al. 1994. Antigen-specific human antibodies from mice comprising four distinct genetic modifications. Nature 368: 856−859. | Article | PubMed | ISI | ChemPort |
- Brüggemann, M., Caskey, H.M., Teale C., Waldmann, H., Williams, G.T., Suran, M.A. et al. 1989. A repertoire of monoclonal antibodies with human heavy-chains from transgenic mice. Proc. Natl. Acad. Sci. USA 86: 6709−6713. | PubMed | ISI | ChemPort |
- Wagner, S.D., Popov, A.V., Davies, S.L., Xian, J., Neuberger, M.S., and Brüuggemann, M. 1994. The diversity of antigen-specific monoclonal antibodies from transgenic mice bearing human immunoglobulin gene miniloci. Eur. J. Immunol. 42: 2672−2681.
- Green, L.L., Hardy, M.H., Maynard-Currie, C.E., Tsuda, H., Louie, D.M., Mendez, M.J. et al. 1994. Antigen-specific human monoclonal antibodies from mice engineered with human Ig heavy and light chain YACS. Nature Genet. 7: 13−21. | Article | PubMed | ISI | ChemPort |
- Popov, A.V., Bützler, C., Frippiat, J-P., Lefranc, M.P., and Brüggemann, M. 1996. Assembly and extension of yeast artificial chromosomes to build up a large locus. Gene 177: 195−205. | Article | PubMed | ISI | ChemPort |
- Mendez, M.J., Green, L.L., Corvalan, J.R.F., Jia, X.-C., Maynard-Currie, C.E., Yang, X-d.et al. 1997. Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat. Gen. 15: 146−156. | ISI | ChemPort |
- Fishwild, D.M., O'Donnell, S.L., Bengoechea, T., Hudson, D.V., Harding, F.S.L. et al. 1996 High-avidity human IgK monoclonal antibodies from a novel strain of minilocus transgenic mice. Nature Biotechnology 14: 845−851. | Article | PubMed | ISI | ChemPort |
- Marks, J.D., Hoogenboom, H.R., Bonnert, T.P., McCafferty, J., Griffiths, A.D., and Winter, G. 1991. By-passing immunisation: human antibodies from V-gene libraries displayed on phage. J. Mol. Biol. 222: 581−597. | PubMed | ISI | ChemPort |
- Nisonoff, A., Hopper, J.E., and Spring, S.B. 1975. p. 5 in The antibody molecule. Academic Press, New York.
|
