Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1997-05-12
2001-02-06
Hutzell, Paula K. (Department: 1646)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S007100, C424S184100, C424S085100, C536S024300, C536S024330
Reexamination Certificate
active
06183951
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates generally to the fields of autoimmunity and inflammatory bowel disease and more specifically to serological and genetic methods for predicting the responsiveness of clinical subtypes of Crohn's disease to anti-Th1 cytokine therapies such as anti-TNF-&agr; therapeutics.
2. Background Information
Inflammatory bowel disease (IBD) is the collective term used to describe two gastrointestinal disorders of unknown etiology: Crohn's disease (CD) and ulcerative colitis (UC). The course and prognosis of IBD, which occurs world-wide and is reported to afflict as many as two million people, varies widely. Onset of IBD is predominantly in young adulthood with diarrhea, abdominal pain, and fever the three most common presenting symptoms. The diarrhea may range from mild to severe, and anemia and weight loss are additional common signs of IBD. Ten percent to fifteen percent of all patients with IBD will require surgery over a ten year period. In addition, patients with IBD are at increased risk for the development of intestinal cancer. Reports of an increasing occurrence of psychological problems, including anxiety and depression, are perhaps not surprising symptoms of what is often a debilitating disease that strikes people in the prime of life.
Crohn's disease is a classification representing a number of distinct disease subtypes that affect the gastrointestinal tract and produce similar symptoms. The heterogeneity underlying CD is reflected in variable responses of CD patients to particular treatment strategies: available anti-inflammatory and steroid therapies are effective in treating some patients with CD, while other patients have moderate to severe disease that is refractory to current medical treatment. Anti-Th1 cytokine therapies are a new treatment option for patients with such refractory disease. However, the response to anti-Th1 cytokine therapy, such as an anti-TNF-&agr; therapeutic, is unpredictable. Although about 65% of those with severe Crohn's disease respond dramatically to anti-Th1 cytokine therapy, the remaining 35% of patients with similar clinical characteristics demonstrate a small or negligible response.
Methods for predicting whether a patient with CD will respond to anti-Th1 cytokine therapy would represent a major clinical advance that would aid in the therapeutic management of CD. Such methods would be advantageous in saving the cost of treating those having an unresponsive subtype of CD and would eliminate the disappointment of those needlessly undergoing such therapy. Such methods also would advance medical management of CD by identifying a subgroup of non-responsive patients for whom alternative treatment modalities must be sought. Unfortunately, methods of stratifying CD into clinical subtypes having predictable responses to anti-Th1 cytokine therapy are currently not available. Thus, there is a need for such methods. The present invention satisfies this need and provides related advantages as well.
SUMMARY OF THE INVENTION
The present invention provides genetic and serological methods of diagnosing clinical subtypes of Crohn's disease with characteristic responsiveness to anti-Th1 cytokine therapies such as anti-TNF-&agr; therapeutics. The invention provides, for example, a method of diagnosing a clinical subtype of Crohn's disease having an inferior clinical response to anti-Th1 cytokine therapy by determining whether perinuclear anti-neutrophil antibody (pANCA) is present in a patient with CD, where the presence of pANCA indicates a clinical subtype of CD having an inferior clinical response to anti-Th1 cytokine therapy. The present invention also provides a method of diagnosing a clinical subtype of Crohn's disease having a particular clinical response to anti-Th1 cytokine therapy by determining whether speckling anti-pan polymorphonuclear antibody (SAPPA) is present in a patient with CD, where the presence of SAPPA indicates a clinical subtype of CD having a superior clinical response to anti-Th1 cytokine therapy.
In addition, the invention provides a method of diagnosing a clinical subtype of Crohn's disease having an inferior clinical response to anti-Th1 cytokine therapy by determining the presence or absence of a TNFa10b4c1d3e3 haplotype in a patient with CD, where the presence of the TNFa10b4c1d3e3 haplotype indicates a clinical subtype of CD having an inferior clinical response to anti-Th1 cytokine therapy. The present invention also provides a method of diagnosing a clinical subtype of Crohn's disease having an inferior clinical response to anti-Th1 cytokine therapy by determining the presence or absence of a TNFa11b4c1d3e3 haplotype in a patient with CD, where the presence of the TNFa11b4c1d3e3 haplotype indicates a clinical subtype of CD having an inferior clinical response to anti-Th1 cytokine therapy.
The invention further provides a method of diagnosing a clinical subtype of CD having an inferior clinical response to anti-Th1 cytokine therapy by determining the presence or absence of a homozygous TNF-&bgr; 1111 haplotype at the TNFc, aa13L, aa26 and NcoI loci in a patient with CD, where the presence of the homozygous TNF-&bgr; 1111 haplotype indicates a clinical subtype of CD having an inferior clinical response to anti-Th1 cytokine therapy.
In addition, there is provided a novel TNF-&bgr; nucleotide sequence SEQ ID NO: 13, which has a polymorphism at the nucleotide corresponding to amino acid 13 of the TNF-&bgr; leader sequence. The invention also provides an allele-specific oligonucleotide primer for detection of the polymorphic TNF-&bgr; sequence SEQ ID NO: 13, which has at least 15 nucleotides of SEQ ID NO: 13 shown in
FIG. 4B
, including the nucleotide at position 207 of SEQ ID NO: 13.
Also provided herein are combined serological and genetic methods of diagnosing a clinical subtype of Crohn's disease having a particular clinical response to anti-Th1 cytokine therapy. The invention provides a method of diagnosing a clinical subtype of CD having a particular clinical response to anti-Th1 cytokine therapy by determining whether SAPPA is present in a patient with CD, determining whether pANCA is present in the patient, determining the presence or absence of a TNFa10b4c1d3e3 haplotype in the patient and determining the presence or absence of a TNFa11b4c1d3e3 haplotype in the patient, where the presence of SAPPA indicates a clinical su b type of CD having a superior clinical response to anti-Th1 cytokine therapy, the presence of pANCA indicates a clinical subtype of CD having an inferior clinical response to anti-Th1 cytokine therapy, the presence of the TNFa10b4c1d3e3 haplotype independently indicates a clinical subtype of CD having an inferior clinical response to anti-Th1 cytokine therapy and the presence of the TNFa11b4c1d3e3 haplotype independently indicates a clinical subtype of CD having an inferior clinical response to anti-Th1 cytokine therapy.
In addition, the present invention provides kits for diagnosing a clinical subtype of CD having a particular clinical response to anti-Th1 cytokine therapy. The kits of the invention include neutrophil and one or more oligonucleotide primers complementary to a nucleotide sequence flanking a TNF microsatellite locus selected from the group consisting of TNFa, TNFb, TNFc, TNFd and TNFe. The kits can include, for example, neutrophil and pairs of oligonucleotide primers complementary to nucleotide sequences flanking each of the TNFa, TNFb, TNFc, TNFd and TNFe loci. The neutrophil can be, for example, alcohol-fixed neutrophil. If desired, one or more secondary antibodies selective for ANCA also can be included in the kits of the invention.
REFERENCES:
patent: WO 95/31575 (1995-11-01), None
patent: WO 96/12189 (1996-04-01), None
Broekroelofs et al., “Anti-Neutrophil Cytoplasmic Antibodies (ANCA) in Sera from Patients with Inflammatory Bowel Disease (IBD),”Dig. Dis. Sci.39:545-549 (1994).
Cambridge et al., “Anti-neutrophil Antibodies in Inflammatory Bowel Disease: Prevale
Barry Mary J.
Plevy Scott E.
Targan Stephan R.
Taylor Kent
Campbell & Flores LLP
Hutzell Paula K.
Lazar-Wesley Eliane
Prometheus Laboratories Inc.
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