Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Using tissue cell culture to make a protein or polypeptide
Patent
1993-08-13
1998-06-16
Feisee, Lila
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Using tissue cell culture to make a protein or polypeptide
435 691, 4351721, 4351723, 4241331, 5303873, 536 2353, C12P 2104, C12N 1500, C07K 1600, A61K 39395
Patent
active
057668868
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates, in general, to methods for preparing a modified antibody variable domain by determining the amino acid residues of the antibody variable domain which may be modified without diminishing the native affinity of the domain for antigen while reducing its immunogenicity with respect to a heterologous species; to methods of preparation of and use of antibody variable domains having modifications at the identified residues which are useful for administration to heterologous species; and to the variable regions so modified. More particularly, the invention relates to the preparation of modified mouse antibody variable domains, which are modified for administration to humans, the resulting antibody variable domains themselves, and the use of such "humanized" antibodies in the treatment of diseases in humans.
BACKGROUND
Application of unmodified mouse monoclonal antibodies in human therapy is problematic for three reasons. First, an immune response against the mouse antibodies is mounted in the human body. Second, the antibodies have a reduced half-life in the human circulatory system. Third, the mouse antibody effector domains may not efficiently trigger the human immune system.
There are three methods which have attempted to eliminate the foregoing problems. Junghans et al., Cancer Res., 50, 1495-1502 (1990) and other publications describe the utilization of genetic engineering techniques to link DNA encoding murine variable regions to DNA encoding human constant regions, creating constructs which when expressed generate a hybrid mouse/human antibody.
Also by genetic engineering techniques, the genetic information from murine hypervariable complementarity determining regions (CDRs) may be inserted in place of the DNA encoding the CDRs of a human monoclonal antibody to generate a construct encoding a human antibody with murine CDRs. This technique is known as "CDR grafting". See, e.g., Jones et al., Nature, 321, 522-525 (1986); Junghans et al., supra.
Protein structure analysis may be used to "add back" murine residues, again by genetic engineering, to first generation variable regions generated by CDR grafting in order to restore lost antigen binding capability. Queen et al., Proc. Natl. Acad. Sci. USA, 86, 10029-10033 (1989); Co, et al., Proc. Natl. Acad. Sci. USA, 88, 2869-2873 (1991) describe versions of this method. The foregoing three methods are techniques to "humanize" mouse monoclonal antibodies.
As a result of the humanization of mouse monoclonal antibodies, specific binding activity of the resulting humanized antibodies may be diminished or even completely abolished. For example, the binding affinity of the modified antibody described in Queen et al., supra, is reported to be reduced three-fold; in Co et al., supra, is reported to be reduced two-fold; and in Jones et al., supra, is reported to be reduced two- to three-fold. Other reports describe order-of-magnitude reductions in binding affinity. See, e.g., Tempest et al., Bio/Technology, 9, 266-271 (1991); Verhoeyen et al., Science, 239, 1534-1536 (1988).
A system for differentiating between the various subsets of T Cells, based upon cell surface antigens, is the Clusters of Differentation System (hereinafter referred to as the "CD System"). The CD System represents standard nomenclature for molecular markers of leukocyte cell differentation molecules. See Leukocyte Typing III White Cell Differentiation Antigens (Michael, ed. Oxford Press 1987), which is incorporated herein by reference.
So-called "pan T cell" markers (or antigens) are those markers which occur on T Cells generally and are not specific to any particular T cell subset(s). Pan T Cell markers include CD2, CD3, CD5, CD6, and CD7. The CD5 cluster antigen, for example, is one of the pan T markers present on about 85-100% of the human mature T lymphocytes and a majority of human thymocytes. CD5 is also present on a subset, about 20%, of B cells. Extensive studies using flow cytometry, immunoperoxidase staining, and red cell lysis have d
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Fishwild Dianne M.
Kohn Fred R.
Little, II Roger G.
Studnicka Gary M.
Feisee Lila
Lucas John
Xoma Corporation
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