Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
2001-03-16
2004-01-06
Duffy, Patricia A. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S265100, C424S266100, C424S269100
Reexamination Certificate
active
06673351
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to immunotherapeutic agents or therapeutic agents, compositions comprising those agents, and methods of use of those agents and compositions for the treatment and clinical remission of psoriasis.
BACKGROUND
Psoriasis is a chronic, genetically-influenced, remitting and relapsing scaly and inflammatory skin disorder of unknown etiology that affects 1 to 3 percent of the world's population. There are several types of psoriasis, including plaque, pustular, guttate and arthritic variants. There is at present no cure for psoriasis, but rather only suppressive therapy (Greaves and Weinstein, 1995, Drug Therapy, 332: 581-588). Indications for treatment may arise from local symptoms, for example, pain, itching, reduction of manual dexterity, severe problems with walking, and cosmetic problems such as prominent hand, leg, or facial lesions. Due to the toxicity of the available therapies, patients with limited disease will often decide to forego treatment beyond the avoidance of provoking factors.
The goal of current treatments has been to decrease the severity and extent of psoriasis to the point at which it no longer interferes substantially with the patient's occupation, well-being, or personal or social life. The initial treatment for stable plaque psoriasis of any severity is topical. In patients in which more than 20 percent of the skin is affected, however, topical treatment alone may be impractical and systemic therapy may also be indicated at the outset.
The topical treatment for plaque psoriasis incorporates the use of emollients, keratolytic agents, coal tar, anthralin, corticosteroids of medium to strong potency, and calpotriene. All of these treatments have variable efficacy, fail to prevent frequent relapses of the disease, exhibit side effects, and pose cosmetic problems of their own.
Systemic treatment has been used in patients with physically, socially, or economically disabling psoriasis that has not responded to topical treatment. The choices to date have been phototherapy or systemic drug therapy. Generally, systemic treatment has employed phototherapy with Ultraviolet B irradiation, photo chemotherapy which combines the photosensitizing drug methoxsalen with Ultraviolet A phototherapy (PUVA), methotrexate, etretinate, systemic corticosteroids, and cyclosporine. Each of these systemic treatments has variable efficacy and undesired side effects, and some of them are very toxic and present frequent relapses of the disease. Accordingly, there is at present a need for an effective psoriasis treatment that avoids the disadvantages associated with the currently available topical or systemic treatments.
SUMMARY OF THE INVENTION
The present invention provides compositions and methods for the treatment and clinical remission of psoriasis. In one aspect, polypeptides derived from particulate antigens of protozoans of the genus Leishmania are provided that can generate an immune is response in an individual resulting in abatement of the clinical symptoms of psoriasis. In one embodiment of this aspect, the polypeptides comprise at least one of the amino acid sequences recited in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14, or immunogenic variants thereof. An immunogenic variant of an amino acid sequence may be either a truncated version of the sequence that retains a substantial amount of the activity of the original, or an altered version of the sequence retaining such activity and having conservative amino acid substitutions and/or modifications.
In another embodiment of this aspect, the polypeptides comprise at least an immunogenic portion of an amino acid sequence of a protein, or an immunogenic variant thereof, the protein isolated from protozoans of the genus Leishmania and having an apparent molecular weight of 21, 33, 44, 50, 55, 58, 65, or 77 kDa as determined by sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE).
In yet another embodiment of this aspect, the polypeptides comprise at least an immunogenic portion of an amino acid sequence of a protein, or an immunogenic variant thereof, the protein isolated from protozoans of the genus Leishmania and having an apparent molecular weight after total reduction and alkylation of 73, 80, or 82 kDa as determined by SDS-PAGE.
In related aspects, the present invention provides nucleic acid sequences encoding such polypeptides, vectors incorporating such nucleic acid sequences, methods for the production of such polypeptides by transformation, transfection, or transduction of microbial host cells, and microbial host cells transformed by such vectors, transfected by such nucleic acid sequences, or transduced with such nucleic acid sequences.
In another aspect of the invention, immunotherapeutic agents incorporating one or more polypeptides of the present invention are provided. These immunotherapeutic agents may be polyvalent or monovalent, and may incorporate an adjuvant such as alumina to enhance the immune response obtained from an inoculated subject. In a preferred embodiment, the polyvalent immunotherapeutic agent contains polypeptide isolates from a mixture of four species of Leishmania, namely,
L
.(
L
)
amazonensis, L
.(
L
)
venezuelensis, L
.(
V
)
brasiliensis
, and
L
.(
L
)
chagasi
. Also in a preferred embodiment, the monovalent immunotherapeutic agent contains a polypeptide isolate from one of these four species.
In another aspect of the invention, methods for the treatment and clinical remission of psoriasis are provided. In one embodiment, such a method involves administration of a therapeutically effective amount of a pharmaceutical composition comprising one or more polypeptides of the present invention to a subject in order to induce an immune response resulting in abatement of the clinical symptoms of psoriasis. In a related embodiment, the method involves administration of a therapeutically effective amount of a pharmaceutical composition comprising one or more nucleic acid sequences of the present invention to a subject. The term “therapeutically effective” as used herein means a reduction of approximately 70-100% of Psoriasis Area and Severity Index as is understood by those skilled in the art.
Other aspects of the invention include the use of the nucleic acid sequences of the invention as probes for genetic analysis and as nucleic acid molecular weight markers, and the use of the polypeptides of the invention as molecular weight markers.
DETAILED DESCRIPTION OF THE INVENTION
The present invention concerns novel compositions and methods for the treatment and clinical remission of psoriasis. The compositions comprise immunogenic polypeptides or the nucleic acids encoding them. The polypeptides of the present invention can elicit an immune response in a warm-blooded animal, thereby inducing clinical remission of psoriasis. As used herein, the term “warm-blooded animal” includes humans. In one embodiment of the invention, the subject polypeptides can be isolated from Leishmania protozoa and, preferably, from killed Leishmania amastigote protozoa. The polypeptides of the subject invention can be obtained from protozoa of the Leishmania genus using standard protein isolation procedures which are known in the art. Also contemplated by the present invention are immunotherapeutic agents and pharmaceutical compositions incorporating the immunogenic polypeptides of the present invention. In one embodiment, a first-generation polyvalent immunotherapeutic agent is provided, comprising a polypeptide isolate of a mixture of a plurality of Leishmania species, such as
L
.(
L
)
amazonensis, L
.(
L
)
venezuelensis, L
.(
V
)
brasiliensis, L
.(
L
)
chagasi, L
.(
L
)
donovani, L
.(
L
)
infantum, L
.(
L
)
major, L
.(
L
)
panamensis, L
.(
L
)
tropica
, and
L
.(
L
)
guyanensis
. Preferably, the mixture comprises
L
.(
L
)
amazonensis, L
.(
L
)
venezuelensis, L
.(
V
)
brasiliensis
, and
L
.(
L
)
ch
Astralis, LLC
Bond Schoeneck & King , PLLC
Duffy Patricia A.
Williams Michael P.
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