Chemistry: molecular biology and microbiology – Vector – per se
Reexamination Certificate
2000-01-18
2003-06-17
Low, Christopher S. F. (Department: 1653)
Chemistry: molecular biology and microbiology
Vector, per se
C536S023100, C536S023500, C536S024310, C530S300000, C530S326000, C530S327000, C514S04400A, C930S010000
Reexamination Certificate
active
06579715
ABSTRACT:
2. BACKGROUND OF THE INVENTION
Proteins are the major structural and regulatory components of life. In particular, secreted proteins, or circulating fragments or portions of other proteins, can interact with protein receptors to regulate and maintain a wide variety of biological and physiological processes. Often, such processes are mediated by protein ligands that interact with corresponding membrane receptor proteins that activate signal transduction and other pathways that control cell physiology, chemical release and communication, and gene expression. As such, protein/receptor interactions constitute preferred targets for drug intervention and for the design of therapeutic agents.
3. SUMMARY OF THE INVENTION
The present invention relates to the discovery, identification, and characterization of nucleotides that encode two novel mammalian proteins, and the corresponding amino acid sequences encoded by the disclosed nucleotide sequences. Both genes share limited similarity with the rat cortexin protein and are thus referred to as cortexin-like proteins (CLPs). The novel human protein described for the first time herein is referred to as human cortexin-like protein (HCLP). The novel human nucleic acid sequence described herein, encodes a protein of 81 amino acids in length (SEQ ID NO: 4), and the gene encoding the novel murine cortexin-like protein (MCLP) encodes a sequence of 82 amino acids (SEQ ID NO: 2). The described CLPs may lack one or more amino acids (cleaved from either end, or, more typically, the N-terminus, e.g., at a signal sequence or other proteolytic cleavage/processing site) when the CLPs are present in the cell membrane.
Given that the murine homolog of the described HCL has been identified, “knockout” ES cells have been produced using gene trap technology essentially as described in U.S. application Ser. No. 08/942,806, filed Oct. 2, 1997, herein incorporated by reference. Conventional methods (see, for example, PCT Applic. No. PCT/US98/03243, filed Feb. 20, 1998, herein incorporated by reference) can also be used to generate mutant animals by gene targeting. Accordingly, an additional aspect of the present invention includes knockout cells and animals having genetically engineered mutations in gene encoding the presently described proteins.
The invention encompasses the nucleotides presented in the Sequence Listing, host cells expressing such nucleotides, and the expression products of such nucleotides, and: (a) nucleotides that encode mammalian homologs of the described gene products; (b) nucleotides that encode one or more portions of the described genes that correspond to functional domains, and the polypeptide products specified by such nucleotide sequences, including but not limited to the novel regions of any active domain(s); (c) isolated nucleotides that encode mutant versions, engineered or naturally occurring, of the described proteins in which all or a part of at least one domain is deleted or altered, and the polypeptide products specified by such nucleotide sequences, including but not limited to soluble proteins and peptides in which all or a portion of the signal sequence in deleted; (d) nucleotides that encode chimeric fusion proteins containing all or a portion of a coding region of the disclosed genes, or one of its domains (e.g., a receptor/ligand binding domain, accessory protein/self-association domain, etc.) fused to another peptide or polypeptide.
The invention also encompasses agonists and antagonists of the described proteins, including small molecules, large molecules, mutant HCLPs, or portions thereof that compete with native HCLP, and antibodies, as well as nucleotide sequences (e.g., antisense and ribozyme molecules, and gene or regulatory sequence replacement constructs) that can be used to inhibit the expression of the described HCLP and MCLP products, or to enhance the expression of the corresponding genes (e.g., expression constructs that place the described gene under the control of a strong promoter system), and transgenic animals that express a HCLP or MCLP transgene, or “knock-outs” (which can be conditional) that do not express functional MCLP.
Further, the present invention also relates to methods for the use of the described genes and products for the identification of compounds that modulate, i.e., act as agonists or antagonists, of HCLP or MCLP expression and/or HCLP or MCLP activity. Such compounds can be used as therapeutic agents for the treatment of any of a wide variety of symptomatic representations of biological disorders or imbalances.
Additionally contemplated are therapeutic applications of the described HCLP as well as the use of HCLP in the production of a medicament for treatment of encephalopathy, and particularly dyscirculatory encephalopathy.
4. DESCRIPTION OF THE SEQUENCE LISTING AND FIGURES
The Sequence Listing provides the sequences of the described HCLP and MCLP open reading frames (ORFs), and the amino acid sequences encoded thereby.
5. DETAILED DESCRIPTION OF THE INVENTION
The presently described novel gene sequences are exemplary of a novel gene locus that, for the purposes of this disclosure, shall generically be referred to as the cortexin-like protein (CLP) gene. Depending upon the context of the disclosure the term CLP (or as modified by a designation of species, e.g., HCLP or MCLP) may interchangeably be used in conjunction with language denoting the CLP amino acid sequence (of the CLP protein or any portion thereof), or the CLP nucleotide sequence (of a CLP gene or any portion thereof).
The HCLP and MCLP described for the first time herein, are novel proteins that are expressed, inter alia, in brain and testis. The described proteins have structural motifs typical of integral membrane proteins, and are presumed to be such, but CLPs, or proteolytic cleavage products thereof, can also exert biological effect by acting as ligands that interact with cell surface receptors. Because such ligands/secreted proteins are considered to be more likely to effect some biological activity (via their cognate receptors), the genes encoding such proteins (and the proteins encoded thereby as well as the uses and formulations thereof) have been the subjects of intense scientific and commercial scrutiny (see, for example, Applic. Ser. Nos. PCT/US98/04858 (from 60/068,368, 60/057,765, 60/048,970, 60/040,762 and others listed on the face of the application) filed Mar. 12, 1998, Ser. No. 09/040,963, filed Mar. 18, 1998, PCT/US98/05255 (corresponding to Ser. No. 60/041,263), filed Mar. 18, 1998, all of which are herein incorporated by reference in their entirety).
The invention encompasses the use of the described HCLP nucleotides, HCLP (and peptide fragments thereof), as well as antibodies, preferably humanized monoclonal antibodies, or binding fragments, domains, or fusion proteins thereof, or antiidotypic variants derived therefrom, that bind HCLP (which can, for example, also act as HCLP agonists or antagonists), other antagonists that inhibit binding activity or expression, or agonists that activate HCLP receptor activity or increase HCLP expression, in the diagnosis and/or treatment of disease.
In particular, the invention described in the subsections below encompasses HCLP and MCLP polypeptides or peptides corresponding to functional domains of HCLP or MCLP, mutated, truncated or deleted HCLPs or MCLPs (e.g., HCLPs or MCLPs missing one or more functional domains or portions thereof), HCLP or MCLP fusion proteins (e.g., HCLP or MCLP, or a functional domain of HCLP or MCLP, fused to an unrelated protein or peptide such as an immunoglobulin constant region, i.e., IgFc), nucleotide sequences encoding such products, and host cell expression systems that can produce such HCLP or MCLP products.
The invention also encompasses antibodies and anti-idiotypic antibodies (including Fab fragments), antagonists and agonists of HCLP, as well as compounds or nucleotide constructs that inhibit expression of a HCLP or MCLP gene (transcription factor inhibitors, antisense and ribozyme molecules, or gene or regulatory sequ
Friedrich Glenn
Nehls Michael C.
Lexicon Genetics Incorporated
Low Christopher S. F.
Schnizer Holly
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