Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 11 to 14 amino acid residues in defined sequence
Reexamination Certificate
1994-11-18
2001-12-11
Borin, Michael (Department: 1631)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
11 to 14 amino acid residues in defined sequence
C530S326000, C530S328000, C530S329000, C514S014800, C514S015800, C514S016700, C514S017400
Reexamination Certificate
active
06329499
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to methods for treating multiple sclerosis by using peptide analogues of human myelin basic protein.
BACKGROUND OF THE INVENTION
Multiple sclerosis (MS) is a chronic, inflammatory disease that affects approximately 250,000 individuals in the United States. Although the clinical course may be quite variable, the most common form is manifested by relapsing neurological deficits, in particular, paralysis, sensory deficits, and visual problems.
The inflammatory process occurs primarily within the white matter of the central nervous system and is mediated by T lymphocytes, B lymphocytes, and macrophages. These cells are responsible for the demyelination of axons. The characteristic lesion in MS is called the plaque due to its macroscopic appearance.
Multiple sclerosis is thought to arise from pathogenic T cells that somehow evaded mechanisms establishing self-tolerance, and attack normal tissue. T cell reactivity to myelin basic protein may be a critical component in the development of MS. The pathogenic T cells found in lesions have restricted heterogeneity of antigen receptors (TCR). The T cells isolated from plaques show rearrangement of a restricted number of V&agr; and V&bgr; gene segments. In addition, the TCRs display several dominant amino acid motifs in the third complementarity determining region (CDR), which is the major antigen contact site. All together, three CDR3 motifs have been identified in T cell clones known to recognize an epitope within amino acids 86-106 of myelin basic protein. These motifs were found in 44% of rearranged TCR sequences involving one particular V&bgr; gene rearranged in T cells isolated from brain of two patients with MS.
A definitive treatment for MS has not been established. Historically, corticosteroids and ACTH have been used to treat MS. Basically, these drugs reduce the inflammatory response by toxicity to lymphocytes. Recovery may be hastened from acute exacerbations, but these drugs do not prevent future attacks or prevent development of additional disabilities or chronic progression of MS (Carter and Rodriguez,
Mayo Clinic Proc
. 64:664, 1989; Weiner and Hafler,
Ann. Neurol
. 23:211, 1988). In addition, the substantial side effects of steroid treatments make these drugs undesirable for long-term use.
Other toxic compounds, such as azathioprine, a purine antagonist, cyclophosphamide, and cyclosporine have been used to treat symptoms of MS. Like corticosteroid treatment, these drugs are beneficial at most for a short term and are highly toxic. Side effects include increased malignancies, leukopenias, toxic hepatitis, gastrointestinal problems, hypertension, and nephrotoxicity (Mitchell,
Cont. Clin. Neurol
. 77:231, 1993; Weiner and Hafler, supra). Antibody based therapies directed toward T cells, such as anti-CD4 antibodies, are currently under study for treatment of MS. However, these agents may cause deleterious side effects by immunocompromising the patient.
More recently, cytokines such as IFN-&ggr; and IFN-&bgr; have been administered in attempts to alleviate the symptoms of MS. However, a pilot study involving IFN-&ggr; was terminated because 7 of 18 patients treated with this drug experienced a clinical exacerbation within one month after initiation of treatment. Moreover, there was an increase in the specific response to MBP (Weiner and Hafler, supra).
Betaseron, a modified beta interferon, has recently been approved for use in MS patients. Although Betaseron treatment showed some improvement in exacerbation rates (Paty et al.,
Neurology
43:662, 1993), there was no difference in the rate of clinical deterioration between treated and control groups (IFNB MS Study Group,
Neurology
43:655, 1993; Paty et al., supra). Side effects were commonly observed. The most frequent of such side effects were fever (40%-58% of patients), flu-like symptoms (76% of patients), chills (46% of patients), mylagias (41% of patients), and sweating (23% of patients). In addition, injection site reactions (85%), including inflammation, pain, hypersensitivity and necrosis, were common (IFNB MS Study Group, supra; Connelly,
Annals of Pharm
. 28:610, 1994).
In view of the problems associated with existing treatments of MS, there is a compelling need for improved treatments which are more effective and are not associated with such disadvantages. The present invention exploits the use of peptide analogues which antagonize a T cell response to human myelin basic protein to effectively treat MS, while providing other related advantages.
SUMMARY OF THE INVENTION
The present invention provides peptide analogues comprising at least 7 amino acids selected from residues 86 to 99 of human myelin basic protein (SEQ. ID No:3) in which either L-lysine at position 91, L-threonine at position 95, or L-arginine at position 97 is altered to another amino acid. In one embodiment, L-lysine at position 91 is altered and one to three additional L-amino acids selected from residues 86, 87, 88, 95, 98 or 99 are altered to another amino acid. In a second embodiment, L-threonine at position 95 is altered and one to three additional amino acids selected from residues 86, 87, 88, 91, 98 and 99 or 86, 87, 88, 97, 98, and 99 are altered to another amino acid. In a third related embodiment, L-arginine at position 97 is altered and one to three additional amino acids selected from residues 86, 87, 88, 95, 98 or 99 are altered to another amino acid. The peptide analogues preferably contain double or triple alterations. In preferred aspects of the invention, the peptide analogues have altered residues 91, 95 or 97 to alanine and the additional amino acids are altered to the corresponding D-form amino acid.
In other embodiments, peptide analogues comprise at least seven amino acids selected from residues 86 to 99 of human myelin basic protein (SEQ. ID No:3) in which either L-lysine at position 91, L-threonine at position 95, or L-arginine at position 97 is altered to another amino acid, and in addition the N-terminal and C-terminal amino acids are altered in order to reduce proteolysis upon administration of the peptide analogue. In a preferred aspect, the N-and C-terminal amino acids are of the D-form.
In other embodiments, the peptide analogues comprise at least seven amino acids selected from residues 86 to 99 of human myelin basic protein (SEQ. ID No:3) in which either L-lysine at position 91, L-threonine at position 95, or L-arginine at position 97 is altered to another amino acid and in addition up to three other amino acid alterations are made. Any residue within 86-99 may be altered except that in a peptide analogue in which residue 91 is altered, residue 97 may not be altered. Likewise, in a peptide analogue in which residue 97 is altered, residue 91 may not be altered.
Other embodiments provide peptide analogues comprising at least seven amino acids selected from residues 86 to 99 of human myelin basic protein (SEQ. ID NO:3) in which either L-lysine at position 91, L-threonine at position 95, or L-arginine at position 97 is altered to another amino acid. In preferred aspects, residue 91, 95 or 97 are altered to either alanine or the corresponding D-amino acid.
Further aspects of the present invention provide a pharmaceutical composition comprising a peptide analogue according to the embodiments set out above in which the peptide analogue is contained in a physiologically acceptable carrier or diluent.
Further aspects of the present invention provide methods of treating multiple sclerosis by administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a peptide analogue comprising at least seven amino acids selected from residues 86 to 99 of human myelin basic protein (SEQ. ID No:3) in which residues 91, 95 or 97 are altered to another amino acid. Additionally, one to three additional amino acids may be altered or the N-and C-ends are altered to reduce proteolysis upon administration.
These and other aspects of the invention will become evident upon reference to the followin
Conlon Paul J.
Gaur Amitabh
Ling Nicholas
Steinman Lawrence
Borin Michael
Neurocrine Biosciences Inc.
Seed Intellectual Property Law Group PLL
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