Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 May 15;88(10):4181–4185. doi: 10.1073/pnas.88.10.4181

Reshaping a therapeutic CD4 antibody.

S D Gorman 1, M R Clark 1, E G Routledge 1, S P Cobbold 1, H Waldmann 1
PMCID: PMC51622  PMID: 1903536

Abstract

An immunosuppressive rat antibody (Campath-9) against human CD4 has been reshaped for use in the management of autoimmunity and the prevention of graft rejection. Two different forms of the reshaped antibody were produced that derive their heavy chain variable region framework sequences from the human myeloma proteins KOL or NEW. When compared to a chimeric form of the CD4 antibody, the avidity of the KOL-based reshaped antibody was only slightly reduced, whereas that of the NEW-based reshaped antibody was very poor. The successful reshaping to the KOL-based framework was by a procedure involving the grafting of human framework sequences onto the cloned rodent variable region by in vitro mutagenesis.

Full text

PDF
4182

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ballhausen W. G., Reske-Kunz A. B., Tourvieille B., Ohashi P. S., Parnes J. R., Mak T. W. Acquisition of an additional antigen specificity after mouse CD4 gene transfer into a T helper hybridoma. J Exp Med. 1988 Apr 1;167(4):1493–1498. doi: 10.1084/jem.167.4.1493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Benjamin R. J., Waldmann H. Induction of tolerance by monoclonal antibody therapy. Nature. 1986 Apr 3;320(6061):449–451. doi: 10.1038/320449a0. [DOI] [PubMed] [Google Scholar]
  3. Clark M. R., Waldmann H. T-cell killing of target cells induced by hybrid antibodies: comparison of two bispecific monoclonal antibodies. J Natl Cancer Inst. 1987 Dec;79(6):1393–1401. [PubMed] [Google Scholar]
  4. Cobbold S. P., Martin G., Waldmann H. The induction of skin graft tolerance in major histocompatibility complex-mismatched or primed recipients: primed T cells can be tolerized in the periphery with anti-CD4 and anti-CD8 antibodies. Eur J Immunol. 1990 Dec;20(12):2747–2755. doi: 10.1002/eji.1830201232. [DOI] [PubMed] [Google Scholar]
  5. Crowe J. S., Smith M. A., Cooper H. J. Nucleotide sequence of Y3-Ag 1.2.3. rat myeloma immunoglobulin kappa chain cDNA. Nucleic Acids Res. 1989 Oct 11;17(19):7992–7992. doi: 10.1093/nar/17.19.7992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Devereux J., Haeberli P., Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. doi: 10.1093/nar/12.1part1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Epp O., Lattman E. E., Schiffer M., Huber R., Palm W. The molecular structure of a dimer composed of the variable portions of the Bence-Jones protein REI refined at 2.0-A resolution. Biochemistry. 1975 Nov 4;14(22):4943–4952. doi: 10.1021/bi00693a025. [DOI] [PubMed] [Google Scholar]
  8. Gunning P., Leavitt J., Muscat G., Ng S. Y., Kedes L. A human beta-actin expression vector system directs high-level accumulation of antisense transcripts. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4831–4835. doi: 10.1073/pnas.84.14.4831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gutstein N. L., Wofsy D. Administration of F(ab')2 fragments of monoclonal antibody to L3T4 inhibits humoral immunity in mice without depleting L3T4+ cells. J Immunol. 1986 Dec 1;137(11):3414–3419. [PubMed] [Google Scholar]
  10. Hafler D. A., Ritz J., Schlossman S. F., Weiner H. L. Anti-CD4 and anti-CD2 monoclonal antibody infusions in subjects with multiple sclerosis. Immunosuppressive effects and human anti-mouse responses. J Immunol. 1988 Jul 1;141(1):131–138. [PubMed] [Google Scholar]
  11. Hale G., Dyer M. J., Clark M. R., Phillips J. M., Marcus R., Riechmann L., Winter G., Waldmann H. Remission induction in non-Hodgkin lymphoma with reshaped human monoclonal antibody CAMPATH-1H. Lancet. 1988 Dec 17;2(8625):1394–1399. doi: 10.1016/s0140-6736(88)90588-0. [DOI] [PubMed] [Google Scholar]
  12. Hale G., Hoang T., Prospero T., Watt S. M., Waldmann H. Removal of T cells from bone marrow for transplantation. Comparison of rat monoclonal anti-lymphocyte antibodies of different isotypes. Mol Biol Med. 1983 Oct;1(3):305–319. [PubMed] [Google Scholar]
  13. Herzog C., Walker C., Müller W., Rieber P., Reiter C., Riethmüller G., Wassmer P., Stockinger H., Madic O., Pichler W. J. Anti-CD4 antibody treatment of patients with rheumatoid arthritis: I. Effect on clinical course and circulating T cells. J Autoimmun. 1989 Oct;2(5):627–642. doi: 10.1016/s0896-8411(89)80002-2. [DOI] [PubMed] [Google Scholar]
  14. Hieter P. A., Max E. E., Seidman J. G., Maizel J. V., Jr, Leder P. Cloned human and mouse kappa immunoglobulin constant and J region genes conserve homology in functional segments. Cell. 1980 Nov;22(1 Pt 1):197–207. doi: 10.1016/0092-8674(80)90168-3. [DOI] [PubMed] [Google Scholar]
  15. Jones P. T., Dear P. H., Foote J., Neuberger M. S., Winter G. Replacing the complementarity-determining regions in a human antibody with those from a mouse. 1986 May 29-Jun 4Nature. 321(6069):522–525. doi: 10.1038/321522a0. [DOI] [PubMed] [Google Scholar]
  16. Lesk A. M., Boswell D. R., Lesk V. I., Lesk V. E., Bairoch A. A cross-reference table between the Protein Data Bank of macromolecular structures and the National Biomedical Research Foundation-Protein Identification Resource amino acid sequence data bank. Protein Seq Data Anal. 1989 Jul;2(4):295–308. [PubMed] [Google Scholar]
  17. Maddon P. J., Littman D. R., Godfrey M., Maddon D. E., Chess L., Axel R. The isolation and nucleotide sequence of a cDNA encoding the T cell surface protein T4: a new member of the immunoglobulin gene family. Cell. 1985 Aug;42(1):93–104. doi: 10.1016/s0092-8674(85)80105-7. [DOI] [PubMed] [Google Scholar]
  18. Madsen J. C., Superina R. A., Wood K. J., Morris P. J. Immunological unresponsiveness induced by recipient cells transfected with donor MHC genes. Nature. 1988 Mar 10;332(6160):161–164. doi: 10.1038/332161a0. [DOI] [PubMed] [Google Scholar]
  19. Mathieson P. W., Cobbold S. P., Hale G., Clark M. R., Oliveira D. B., Lockwood C. M., Waldmann H. Monoclonal-antibody therapy in systemic vasculitis. N Engl J Med. 1990 Jul 26;323(4):250–254. doi: 10.1056/NEJM199007263230407. [DOI] [PubMed] [Google Scholar]
  20. Orlandi R., Güssow D. H., Jones P. T., Winter G. Cloning immunoglobulin variable domains for expression by the polymerase chain reaction. Proc Natl Acad Sci U S A. 1989 May;86(10):3833–3837. doi: 10.1073/pnas.86.10.3833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Page M. J., Sydenham M. A. High level expression of the humanized monoclonal antibody Campath-1H in Chinese hamster ovary cells. Biotechnology (N Y) 1991 Jan;9(1):64–68. doi: 10.1038/nbt0191-64. [DOI] [PubMed] [Google Scholar]
  22. Poljak R. J., Nakashima Y., Chen B. L., Konigsberg W. Amino acid sequence of the VH region of a human myeloma immunoglobulin (IgG New). Biochemistry. 1977 Jul 26;16(15):3412–3420. doi: 10.1021/bi00634a019. [DOI] [PubMed] [Google Scholar]
  23. Qin S. X., Cobbold S., Benjamin R., Waldmann H. Induction of classical transplantation tolerance in the adult. J Exp Med. 1989 Mar 1;169(3):779–794. doi: 10.1084/jem.169.3.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Qin S. X., Wise M., Cobbold S. P., Leong L., Kong Y. C., Parnes J. R., Waldmann H. Induction of tolerance in peripheral T cells with monoclonal antibodies. Eur J Immunol. 1990 Dec;20(12):2737–2745. doi: 10.1002/eji.1830201231. [DOI] [PubMed] [Google Scholar]
  25. Queen C., Schneider W. P., Selick H. E., Payne P. W., Landolfi N. F., Duncan J. F., Avdalovic N. M., Levitt M., Junghans R. P., Waldmann T. A. A humanized antibody that binds to the interleukin 2 receptor. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10029–10033. doi: 10.1073/pnas.86.24.10029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Riechmann L., Clark M., Waldmann H., Winter G. Reshaping human antibodies for therapy. Nature. 1988 Mar 24;332(6162):323–327. doi: 10.1038/332323a0. [DOI] [PubMed] [Google Scholar]
  27. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schmidt W. E., Jung H. D., Palm W., Hilschmann N. Beitrag zur dreidimensionalen Strukturaufklärung der Antikörper. Die Primärstruktur des kristallisierbaren monoklonalen Immunoglobulins IgG1 KOL, I. Hoppe Seylers Z Physiol Chem. 1983 Jun;364(6):713–747. [PubMed] [Google Scholar]
  29. Takahashi N., Ueda S., Obata M., Nikaido T., Nakai S., Honjo T. Structure of human immunoglobulin gamma genes: implications for evolution of a gene family. Cell. 1982 Jun;29(2):671–679. doi: 10.1016/0092-8674(82)90183-0. [DOI] [PubMed] [Google Scholar]
  30. Tramontano A., Chothia C., Lesk A. M. Framework residue 71 is a major determinant of the position and conformation of the second hypervariable region in the VH domains of immunoglobulins. J Mol Biol. 1990 Sep 5;215(1):175–182. doi: 10.1016/S0022-2836(05)80102-0. [DOI] [PubMed] [Google Scholar]
  31. Verhoeyen M., Milstein C., Winter G. Reshaping human antibodies: grafting an antilysozyme activity. Science. 1988 Mar 25;239(4847):1534–1536. doi: 10.1126/science.2451287. [DOI] [PubMed] [Google Scholar]
  32. Wigler M., Pellicer A., Silverstein S., Axel R., Urlaub G., Chasin L. DNA-mediated transfer of the adenine phosphoribosyltransferase locus into mammalian cells. Proc Natl Acad Sci U S A. 1979 Mar;76(3):1373–1376. doi: 10.1073/pnas.76.3.1373. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES