Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
2000-01-05
2002-03-19
Ulm, John (Department: 1646)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S252300, C435S320100, C530S350000, C536S023500
Reexamination Certificate
active
06358707
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to newly identified polypeptides and polynucleotides encoding such polypeptides, to their use in therapy and in identifying compounds which may be agonists, antagonists and/or inhibitors which are potentially useful in therapy, and to production of such polypeptides and polynucleotides.
BACKGROUND OF THE INVENTION
The drug discovery process is currently undergoing a fundamental revolution as it embraces ‘functional genomics’, that is, high throughput genome- or genebased biology. This approach is rapidly superceding earlier approaches based on ‘positional cloning’. A phenotype, that is a biological function or genetic disease, would be identified and this would then be tracked back to the responsible gene, based on its genetic map position.
Functional genomics relies heavily on the various tools of bioinformatics to identify gene sequences of potential interest from the many molecular biology databases now available. There is a continuing need to identify and charcterize further genes and their elated polypeptides/proteins, as targets for drug discovery.
Platelets and platelet membrane glycoproteins play a significant role in inflammatory and thrombotic reactions. Specific anti-platelet autoantibodies and alloantbodies to membrane glycoproteins, such as GPIb, GPIIb, and GPIIIa, among others have been identified in patients with clinical disorders like drug-dependent thrombocytopenia purpura, post transfusion purpura, septicemia, neonatal isoimmune thrombocytopenia, and chronic immune thrombocytope, among others (Woods, et al. 1984a Blood, 64:156-160; Woods, et al. 1984b, Blood, 63: 368-375; Kickler, et al. 1988 Blood 71: 894-898; Christie, et al. 1987 Br. J. Haematol, 67: 213-219). Autoantibodies against such cell surface antigens interact with platelets and cause platelet aggregation. Identification of these self antigens has helped elucidate the molecular mechanism underlying the cell activation. Several auto-antibodies activate platelets either via an FcgRII (CD32) receptor mediated process (Rubinstein, et al. 1991, J. Immunol. 147: 3040-3046; Horsewood, et al. 1991, Blood 78:1019-1026) or as F(ab′)2 fragments without the necessity of an intact IgG molecule. Korneck, et al. in 1991 (J. Biol. Chem. 265: 10042-10048) had previously reported a monoclonal antibody, mAb F11 which recognized two membrane proteins of 32 and 35 kd, termed the F11 antigen. Partial peptide sequencing of the purified F11 antigen was also reported (Naik, et al. 1995 Biochem. J., 310: 155-162) and its ability to induce vesicular secretion and aggregation in human platelets has been studied.
The F11 antigen is a novel platelet membrane surface glycoprotein which is cross-linked with the FcgRII receptor when platelets are activated by the stimulatory mAb F11. While the physiological and pathophysiological significance of F11 antigen remains to be completely explored, such proteins clearly represent putative targets for therapeutic intervention in a wide range of distinct pathological, inflammatory and thrombotic conditions.
SUMMARY OF THE INVENTION
The present invention relates to F11 antigen, in particular F11 antigen polypeptides and F11 antigen polynucleotides, recombinant materials and methods for their production. In another aspect, the invention relates to methods for using such polypeptides and polynucleotides, including the treatment of cardiopulmonary diseases including atherosclerosis, restenosis, CHF, stroke, angiogenesis, systemic/pulmonary hypertension, adult respiratory distress syndrome, fibrotic vasculopathies, and COPD, endocrinolological disease (diabetes), neurological
eurodegenerative conditions, hematopoietic, oncological, auto-immunological including inflammatory diseases, psoriasis, lupus, arthritis, Crohn's, inflammatory bowel syndrome, thrombocytopeinas, thrombosis, septicemia, urological/reproductive and hepatorenal (glomerulopathies) diseases, hereinafter referred to as “the Diseases”, amongst others. In a further aspect, the invention relates to methods for identifying agonists and antagonists/inhibitors using the materials provided by the invention, and treating conditions associated with F11 antigen imbalance with the identified compounds. In a still further aspect, the invention relates to diagnostic assays for detecting diseases associated with inappropriate F11 antigen activity or levels.
DESCRIPTION OF THE INVENTION
In a first aspect, the present invention relates to F11 antigen polypeptides. Such peptides include isolated polypeptides comprising an amino acid sequence which has at least 70% identity, preferably at least 80% identity, more preferably at least 90% identity, yet more preferably at least 95% identity, most preferably at least 97-99% identity, to that of SEQ ID NO:2 over the entire length of SEQ ID NO:2. Such polypeptides include those comprising the amino acid of SEQ ID NO:2.
Further peptides of the present invention include isolated polypeptides in which the amino acid sequence has at least 70% identity, preferably at least 80% identity, more preferably at least 90% identity, yet more preferably at least 95% identity, most preferably at least 97-99% identity, to the amino acid sequence of SEQ ID NO:2 over the entire length of SEQ ID NO:2. Such polypeptides include the polypeptide of SEQ ID NO:2.
Further peptides of the present invention include isolated polypeptides encoded by a polynucleotide comprising the sequence contained in SEQ ID NO: 1.
Polypeptides of the present invention are believed to be members of the F11-antigen gene family of polypeptides. They are therefore of interest because this is a novel receptor involved in platelet aggregation, vascular disease and thrombosis. These properties are hereinafter referred to as “F11 antigen activity” or “F11 antigen polypeptide activity” or “biological activity of F11 antigen”. Also included amongst these activities are antigenic and immunogenic activities of said F11 antigen polypeptides, in particular the antigenic and immunogenic activities of the polypeptide of SEQ ID NO:2. Preferably, a polypeptide of the present invention exhibits at least one biological activity of F11 antigen.
The polypeptides of the present invention may be in the form of the “mature” protein or may be a part of a larger protein such as a fusion protein. It is often advantageous to include an additional amino acid sequence which contains secretory or leader sequences, pro-sequences, sequences which aid in purification such as multiple histidine residues, or an additional sequence for stability during recombinant production.
The present invention also includes include variants of the aforementioned polypeptides, that is polypeptides that vary from the referents by conservative amino acid substitutions, whereby a residue is substituted by another with like characteristics. Typical such substitutions are among Ala, Val, Leu and Ile; among Ser and Thr; among the acidic residues Asp and Glu; among Asn and Gln; and among the basic residues Lys and Arg; or aromatic residues Phe and Tyr. Particularly preferred are variants in which several, 5-10, 1-5, 1-3, 1-2 or 1 amino acids are substituted, deleted, or added in any combination.
Polypeptides of the present invention can be prepared in any suitable manner. Such polypeptides include isolated naturally occuring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well understood in the art.
In a further aspect, the present invention relates to F11 antigen polynucleotides. Such polynucleotides include isolated polynucleotides comprising a nucleotide sequence encoding a polypeptide which has at least 70% identity, preferably at least 80% identity, more preferably at least 90% identity, yet more preferably at least 95% identity, to the amino acid sequence of SEQ ID NO:2, over the entire length of SEQ ID NO:2. In this regard, polypeptides which have at least 97% identity are highly preferred, whilst
Gupta Shalley Kant
Pillarisetti Kodandaram
Han William T.
King William T.
Ratner & Prestia
SmithKline Beecham Corporation
Ulm John
LandOfFree
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