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...
Reexamination Certificate
2000-01-07
2001-09-18
Stucker, Jeffrey (Department: 1648)
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...
C424S130100, C424S141100, C435S326000, C435S331000, C530S350000, C530S388850, C530S389100
Reexamination Certificate
active
06291652
ABSTRACT:
INTRODUCTION
1. Field of the Invention
The field of this invention is Huntington's disease.
2. Background of the Invention
Huntington's Disease (HD) is a devastating neurological disease which usually presents in mid adult life and results in psychiatric disturbance, involuntary movement disorder, and cognitive decline associated with inexorable progression to death, typically 17 years following onset. HD is a progressive neurodegenerative disease striking principally medium spiny GABAergic neurons of the caudate nucleus of the basal ganglia. It affects about one in 10,000 individuals and is transmitted in an autosomal dominant fashion.
HD is associated with expansion of a CAG repeat within the HD gene. The HD gene is ubiquitously expressed and conserved across a wide range of species. The HD gene encompasses 67 exons, spans over 200 kb and is associated with two transcripts of 10.3 kb and 13.6 kb, differing with respect to their 3′ untranslated regions. Both messages are predicted to encode a 348 kilodalton protein containing 3144 amino acids. In addition, the HD gene encompasses a highly polymorphic CAG repeat which varies in number from 8 to 35 in normal individuals. CAG expansion beyond 36 CAG repeats is seen in persons with HD.
The increase in size of the CAG repeat in persons with HD shows a highly significant correlation with age of onset of clinical features. This association is particularly striking for persons with juvenile onset HD who have very significant expansion, usually beyond 50 repeats. The CAG repeat length in HD families does exhibit some instability that is particularly marked when children inherit the HD gene from affected fathers.
HD is one of an increasing number of disorders associated with trinucleotide repeat expansion, including myotonic dystrophy, fragile X syndrome, spinobulbar muscular atrophy (SBMA) and more recently spinocerebellar ataxia type 1 and X linked mental retardation. The common occurrence of the expanded trinucleotide repeat in each of these disorders suggests a common feature underlying their pathogenesis. There are however, still few clues as to how repeat expansion actually causes these illnesses.
As such, there is continued interest in the elucidation of underlying mechanisms of HD and similar diseases characterized by the presence of trinucleotide repeat expansions, such as polyglutamine expansions. Of use to these endeavors would be a highly specific antibody that specifically recognized mutant forms of proteins having polyglutamine expansions and did not appreciably bind to non-mutant proteins having such expansions.
Relevant Literature The 1C2 antibody is described in WO 97/17445. Also of interest are: Imbert et al., Nat. Genet. (November 1996) 14:285-291; Jones et al., J. Inherit. Metab. Dis. (June 1997) 20:125-138; Jou et al., Hum. Mol. Genet. (March 1995) 4:465-469; Li et al., Hum. Mol. Genet. (May 1998) 7:777-782; Li et al., Nature (November 1995) 378:398-402; Lunkes et al., Philos. Trans. R. Soc. Lund B. Biol. Sci. (June 1999) 354:1013-1019; Lunkes et al., Essays Biochem. (1998) 33:149-163; Takeuchi et al., Gene (December 1997) 204:71-77; Stevanin et al., Hum. Mol. Genet. (December 1996) 5:1887-1892; Trottier et al., Nature (November 1995) 378:403-406; Trottier et al., Nature Genet. (May 1995) 10:104-110; and Walling et al., J. Neurosci Res (November 1998) 54:301-308.
Intrabodies are described in U.S. Pat. Nos. 5,851,829 and 5,965,371. See also Ohage et al., J. Mol. Biol. (September 1999)291:1129-1134; Ohage et al., J. Mol. Biol. (September 1999) 291:1119-1128; and Chen et al., Hum. Gene Ther. (May 1994) 5:595-601.
SUMMARY OF THE INVENTION
Antibodies, as well as binding fragments and mimetics thereof (including intrabodies), that specifically bind to polyglutamine expansion containing proteins, e.g. mutant huntingtin protein, are provided. The subject binding agents, e.g. antibodies, fragments and mimetics thereof, etc., are characterized in that they bind to the polyglutamine expansion containing protein in a manner that differs from the 1C2 antibody, e.g. in terms of specificity, affinity, avidity, and the like. Also provided are methods of screening compounds for polyglutamine expansion protein binding modulation activity, as well as pharmaceutical compositions of such agents. In addition, methods and devices for screening samples for the presence of polyglutamine expansion containing proteins, e.g. mutant huntingtin protein, are provided. Finally, nucleic acids encoding the subject antibodies and methods for their expression, including in therapeutic treatment protocols, are provided.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
Antibodies, as well as binding fragments and mimetics thereof (including intrabodies), that specifically bind to polyglutamine expansion containing proteins, e.g. mutant huntingtin protein, are provided. The subject binding agents, e.g. antibodies, fragments and mimetics thereof, etc., are characterized in that they bind to the polyglutamine expansion containing protein in a manner that differs from the 1C2 antibody, e.g. in terms of at least one of specificity, affinity and avidity. Also provided are methods of screening compounds for polyglutamine expansion protein binding modulation activity, as well as pharmaceutical compositions of such agents. In addition, methods and devices for screening samples for the presence of polyglutamine expansion containing proteins, e.g. mutant huntingtin protein, are provided. Finally, nucleic acids encoding the subject antibodies and methods for their expression, including in therapeutic treatment protocols, are provided.
Before the subject invention is further described, it is to be understood that the invention is not limited to the particular embodiments of the invention described below, as variations of the particular embodiments may be made and still fall within the scope of the appended claims. It is also to be understood that the terminology employed is for the purpose of describing particular embodiments, and is not intended to be limiting. Instead, the scope of the present invention will be established by the appended claims.
In this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs.
A
NTIBODIES
As summarized above, antibodies that recognize proteins having polyglutamine expansions are provided. More specifically, antibody compositions containing one or more antibodies, usually a plurality of antibodies and more usually a large plurality of antibodies, which recognize proteins having polyglutamine expansions are provided. By “recognize” is meant that the antibodies bind to proteins having polyglutamine expansions. The subject antibodies are specific for proteins having polyglutamine expansions. As the subject antibodies are specific for proteins having polyglutamine expansions, they bind preferentially to polyglutamine expansion containing proteins, as compared to proteins that do not contain polyglutamine expansions. In many embodiments, the subject antibodies do not bind to any appreciable extent to proteins that do not contain a polyglutamine expansion.
The polyglutamine expansions of the proteins to which the antibodies of the subject invention bind are glutamine stretches of at least 35 glutamine residues, where the number of glutamine residues in the polyglutamine expansion domain of the proteins typically ranges from about 35 to 200, usually from about 35 to 175 and more usually from about 35 to 150. The polyglutamine expansion of the target protein may be a heteropolymer stretch or homopolymeric stretch. Where the polyglutamine expansion is a heteropolyglutamine expansion, the number of non-glutamine residues in the expansion is limited, where the number % of non-glutamine residues does not exceed about 10, usually does not exceed about 5 and m
Bozicevic, Field & Francis
Field Bret E.
Stucker Jeffrey
The Regents of the University of California
Winkler Ulrike
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