Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1999-10-19
2002-05-28
Chin, Christopher L. (Department: 1641)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S133100, C424S152100, C424S153100, C424S158100, C424S172100, C424S173100, C530S388230
Reexamination Certificate
active
06395274
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the field of recombinant DNA technology. This invention is directed to antibodies, and in particular, monoclonal antibodies that are capable of specifically binding to human interleukin-5. The invention concerns the development of such antibodies, as well as their diagnostic and therapeutic uses.
BACKGROUND OF THE INVENTION
I. Interleukin-5 and the Humoral Response to Microbial Infection
Antibodies are produced by the immune system of humans and animals in response to the presence of molecules that are considered “foreign.” Such molecules fall into two classes: “antigens” or “haptens.” An antigen is a molecule whose presence in an animal is capable of inducing the immune system to produce antibodies. In contrast, a hapten is capable of being bound by an antibody, but is not capable of eliciting antibody formation. Haptens are generally small molecules; when conjugated to a larger molecule, they can become antigens, and thus induce antibody formation. The nature and structure of antibodies, and the tenets of immunology are disclosed by Davis, B. D. et al. (In:
Microbiology
. 2d Ed., Harper & Row, NY (1973)).
The capacity to induce antibody formation in response to microbial infection depends upon a series of interactions among T cells, B cells, and macropghages. Each B cell is genetically programmed to produce cells that express an immunoglobulin (or antibody) that is capable of specific interaction with a distinct antigenic determinant on the infectious microbe. Such antibodies play a central role in the humoral response to infection (Takatsu, K.,
Microbial Rev
35: 593-606 (1991)).
The B cell response to an antigen is regulated by a helper T cell responding to, and specific for, the same antigen molecule (Takatsu, K.,
Microbial Rev
35:593-606 (1991)). The helper T cells recognize antigenic peptides in the context of class If major histocompatability complex (MHC) molecules that are arrayed on B cells, and secrete several soluble factors (“lymphokines”) which can induce growth and maturation of B cells (Howard, M. et al.,
Ann. Rev. Immunol
. 1:307-333 (1983); Kishimoto, T. et al.,
Ann. Rev. Immunol
. 3:133-157 (1985); Melchers, F. et al.,
Ann. Rev. Immunol
. 4:13-36 (1986); Takatsu, K.,
Microbial Rev
35:593-606 (1991)).
One of these soluble factors (termed, “T-cell-replacing factor” (“TRF”) was found to induce the terminal differentiation of activated B cells into antibody producing cells (Takatsu, K. et al.,
J. Immunol
. 124:2414-2422 (1980)). This factor was subsequently found to have an activity (termed “BCGF II”) that could promote DNA synthesis in certain B cell leukemic cells (Harada, N. et al.
J. Immunol
. 134:3944-3951 (1985)). Further research revealed the additional presence of an eosinophil differentiation factor capable of inducing eosinophil colony formation (Sanderson, C. J. et al.,
J. Exper. Med
. 162:60-74 (1985)). Ultimately, these factors were purified (Sanderson, C. J. et al.,
Proc. Natl. Acad. Sci
. (U.S.A.) 83:437-440 (1986)) and sequenced (Campbell, H. D. et al.,
Eur. J. Biochem
. 174:345-352 (1988); Kinashi, T. et al.
Nature
324:70-73 (1986)), and found to be derived from a single protein, termed “interleukin-5” (“IL-5”) (McKenzie, A. N. J. et al., In:
Interleukins: Molecular Biology and Immunology
. Chem. Immunol., Basel, Karger, vol. 51, pp 135-152 (1992), herein incorporated by reference).
The cDNA encoding murine IL-5/TRF/BCGFII was cloned by using SP6 expression vector system (Kinashi, T., et al.
Nature
324:70-73 (1986)). The amino acid sequence deduced from the nucleotide sequence of the entire IL-5 cDNA revealed that murine IL-5 consists of 133 amino acids including a hydrophobic signal sequence of 20 amino acids (Kinashi, T., et al.,
Nature
324:70-73 (1986)) with a molecular mass of 12.3 kDa. Thus, the mature human IL-5 protein has 113 amino acids, and is the same length as the mature murine IL-5. Comparison of the cDNA sequence of murine IL-5 with that of human shows a sequence homology of 77% at the DNA level and 70% at the protein level.
Interleukin-5 is a homodimeric glycoprotein. Investigations using reduced and alkylated IL-5 suggest that dimerization is essential for biological activity (Tsuroka, N., et al.,
Cell. Immunol
. 125:354-362 (1990)). Comparison of the two polypeptide sequences shows 81 identical amino acids, 25 conservative amino acid changes, with the remaining 7 (and the two N-terminal amino acids of the human protein sequence) as non-conservative changes. This high degree of similarity is reflected in the ability of the two proteins to cross-react With cells of other mammals (Sanderson, C. J., et al., In:
Colony Stimulating Factors: Molecular and Cellular Biology
, Marcel Dekker, NY, pp 231-256 (1990)). Despite their capacity to cross react, murine and human IL-5 display significant species specificity, with the murine material being approximately 100-fold more active against murine cells than the human molecule. Conversely, human IL-5 is approximately 20-fold more active in human bone marrow assays than murine IL-5 (McKenzie, A. N. J. et al., In:
Interleukins: Molecular Biology and Immunology
, Chem. Immunol., Basel, Karger, vol. 51, pp 135-152 (1992)).
Native IL-5 or recombinant IL-5 expressed in mammalian cells in heterogeneously glycosylated, with the mouse sequence containing three potential N-glycosylation sites, while the human sequence lacks on of these. Carbohydrate has been shown to be unnecessary for biological activity, although it is possible that it may perform some role in governing the half-life of the polypeptide in the circulation (McKenzie, A. N. J. et al., In:
Interleukins: Molecular Biology and Immunology
, Chem. Immunol., Basel, Karger, vol. 51, pp 135-152 (1992)).
Interleukin-5 promotes the growth of B-lineage cells. IL-5 acts on naturally activated B cells, on LPS-stimulated B cells, and on resting B cells to induce maturation and to propagate proliferation (Karasuyama, H. et al.,
J. Exper. Med
. 167:1377-1390 (1988)). IL-5 induces the increase in levels of secreted forms of &mgr;-mRNA in BCL
1
or resting as well as activated B cells (Webb, C. P. et al.
J. Immunol
. 143:3934-3939 (1989)). Murine IL-5 was found to cause an increase in the frequency of B cells both proliferating and 1 g secreting (Alderson, M. R. et al.,
J. Imunol
. 139:2656-2660 (1987)). IL-5 can induce antigen-specific and polyclonal IgA production in antigen-primed B cells and in LPS-stimulated B cells, respectively.
IL-5 also appears to promote immunoglobulin formation. Transgenic mice carrying the IL-5 gene exhibited elevated levels of IL-5 in the serum (2-10 ng/ml), and an increase in the levels of serum IgM and IgA. A marked increase in the number of peripheral blood white cells (PBL), of spleen cells and of peritoneal cells was also observed. Particularly, the increase in the numbers of eosinophils in PBL reached 70-fold those of age-matched control mice (Tominaga, A. et al.,
J. Exper., Med
. 144:1345-1352 (1990)). Antibodies to IL-5 mAbs have been isolated (Coffman, R. L. et al.,
Science
245:08-311 (1989)), and have been found to inhibit the antigent-specific primary IgM response induced by a cloned helper T cells in an MHC-restricted manner and also to inhibit polyclonal Ig-secretion (Rasmussen, R. et al.,
J. Immunol
. 140:705-712 (1988)).
Importantly, IL-5 also plays a role in the production and maturation of eosinophils. Eosinophils are immune system cells that accumulate in response to allergic inflammatory reactions. They ingest antibody-antigen complexes and thereby become degranulated. Since the granules contain substances capable of blocking the action of histamine, serotonin and bradykinin, all of which are involved in inflammation, it has been proposed that eosinophils protect the tissues of the host not only by phagocytizing and degrading cytotoxic antibody-antigen complexes but also by damping the effects of chemical mediators of the inflammatory response (Davis, B. D. et al. In:
Microbiology
, 2nd Edit., Harper & Row, NY (1973)). IL
Dickason Richard R.
Huston David P.
Huston Marilyn M.
Baylor College of Medicine
Chin Christopher L.
Fulbright & Jaworski
Grun James L.
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