Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Patent
1994-08-10
1998-11-24
Hutzell, Paula K.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
5303879, 5303881, 43524027, 435 7021, C07K 1600, C12P 2108, C12N 512
Patent
active
058408568
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the field of assaying platelet factor 4 superfamily members (hereafter "PF4A") and the preparation of agonists and antagonists to the members of this family, in particular, antibodies to these receptors.
2. Description of Background and Related Art
While interleukin-8 was initially identified as a chemoattractant for neutrophils, and was known to bind a receptor on neutrophils (Samanta et including the stimulation of degranulation and the upregulation of the cell adhesion molecule MAC-1 and of the complement receptor CR1. Oppenheim et al., Annu. Rev. Immunol., 9: 617-648 (1991).
IL-8 is secreted by many cell types in response to pro-inflammatory stimuli such as IL-1.beta., TNF, and endotoxin and is a member of a family of ten or more pro-inflammatorycytokines with an M.sub.r .about.10,000. Oppenheim et al., supra. This larger family of proteins is called the platelet factor 4 superfamily. Wolpe et al., FASEB J., 3: 2565-73 (1989). Some members of the platelet factor 4 superfamily, in general the subset referred to as C-X-C peptides (including IL-B), possess neutrophil agonist activity, e.g. neutrophil activating protein-2 (NAP-2), platelet factor 4 are encoded by genes on human chromosome 4. Other members of this family, the C-C peptides, encoded by genes on human chromosome 17, are not neutrophil agonists, and include RANTES, macrophage chemotactic and activating factor (MCAF). Hereafter "PF4A" means the PF4 superfamily. Oppenheim et al., supra.
The IL-8 receptors are members of the superfamily of seven transmembrane, G-protein linked receptors. Taylor, Biochem. J., 272: 1 (1990). This family of receptors includes several hundred different receptors among which the .beta.-adrenergic receptor (Strader et al., FASEB, 3: 1825 types of IL-8 receptors have been described: type A (IL8R-A) (Holmes et acid identity and have 29-34% sequence homology to C5a and fMet-Leu-Phe. Holmes et al., supra. IL8R-A has a high affinity (2 nM) for IL-8 only, while IL8R-B has a high affinity (2 nM) for both IL-8 and MGSA. The function and expression level of each receptor on these cells have yet to be determined.
It is an object of this invention to identify receptors for the PF4A superfamily (hereinafter "PF4AR").
It is another object of this invention to obtain DNA encoding or hybridizing to these receptors, and to express the receptors in host cells.
It is an additional object of this invention to provide isolates of PF4AR for diagnostic and therapeutic purposes.
A still further object is to obtain DNA encoding variants of such receptors and to prepare such variants in recombinant cell culture.
A yet further object is to identify and prepare antibodies to receptors for the PF4A superfamily (hereinafter "PF4AR").
It is still another object to provide a method for treating or preventing an inflammatory response in a mammal using an antibody to such receptors.
These and other objects of this invention will be apparent from the specification as a whole.
SUMMARY OF THE INVENTION
These objects are accomplished, in one aspect, by providing an isolated novel PF4AR polypeptide, including polypeptides that are related structurally to the PF4AR. Members of this class of polypeptide are hereafter generically termed PF4AR, and include derivatives and variants thereof.
Either the whole PF4AR molecule or fragments thereof (which also may be synthesized by chemical methods) fused (by recombinant expression or in vitro covalent methods) to an immunogenic polypeptide are used to immunize an animal to raise antibodies against a PF4AR epitope. Anti-PF4AR antibodies are recovered from the serum of immunized animals. Alternatively, monoclonal antibodies are prepared from cells of the immunized animal in conventional fashion.
Thus, in a further aspect, the invention provides an antibody that is capable of binding a PF4AR polypeptide, preferably one that does not cross-react with a receptor capable of binding another PF4 superfamily member. More preferably, the antibo
REFERENCES:
Federsppiel et al., "Molecular cloning of the cDNA and chromosomal localization of the gene for a putative seven-transmembrane segment (7-TMS) receptor isolated from human spleen" Genomics 16:707-712 (1993).
Feng, Yu et al., "HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor" Science 272:872-877 (1996).
Herzog et al., "Molecular cloning, characterization, and localization of the human homolog to the reported bovine NPY Y3 receptor: lack of NPY binding and activation" DNA and Cell Biology 12(6):465-471 (1993).
Jazin et al., "A proposed bovine neuropeptide Y (NPY) receptor cDNA clone, or its human homologue, confers neither NPY binding sites nor NPY responsiveness on transfected cells" Regulatory Peptides 47:247-258 (1993).
Loetscher et al., "Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes" Journal of Biological Chemistry 269(1):232-237 (1994).
Nomura, H. et al., "Molecular cloning of cDNAs encoding a LD78 receptor and putative leukocyte chemotactic peptide receptors" International Immunology 5(10):1239-1249 (1993).
Chuntharapai Anan
Hebert Caroline
Kim K. Jin
Lee James
Ebert Ray F.
Genentech Inc.
Hutzell Paula K.
Love Richard B.
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