Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
1999-10-19
2002-04-16
Smith, Lynette R. F. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S009100, C424S265100, C435S069100, C435S069300, C530S350000, C530S395000
Reexamination Certificate
active
06372219
ABSTRACT:
BACKGROUND OF THE INVENTION
In one of its life-stages the parasite
Schistosoma mansoni
(
S. mansoni
), which causes the tropical disease schistosomiasis, has the unique ability to penetrate intact, unabraded human skin. After gaining entry into the host, the parasite spends over 48 hrs in various layers of the skin without eliciting any marked tissue response. This subdued inflammatory response is largely responsible for the parasite's ability to pass through the skin virtually undetected by its human host.
Other schistosomes such as
Trichobilharia oceltata
(a bird parasite) which also can penetrate intact human skin, causes a severe inflammatory response in the skin (commonly called swimmer's itch) which results in the parasite's elimination from the host. Therefore, suppression of inflammatory responses in the skin appears to be crucial for the survival of schistosomes in its human host. Because
Schistosoma mansoni
does not elicit such a response, it would be useful to determine the mechanisms by which the inflammatory response is reduced or suppressed and to exploit such mechanisms as anti-inflammatory therapeutics for treating any inflammatory condition.
SUMMARY OF THE INVENTION
The present invention is directed to an isolated purified polypeptide designated Sm 16.8 or variants, fragments, derivatives, homologs or analogs thereof. The variants, fragments, derivatives, homologs or analogs may have a biological activity of Sm 16.8 and/or be immunologically active, that is, capable of inducing antibody formation, the antibodies being directed to one or more epitopes of the Sm 16.8 polypeptide.
Antibodies that specifically bind to polypeptides of the present invention are also within the scope of the present invention. Such antibodies may serve as therapeutics and/or diagnostic products. The antibodies may be polyclonal or monoclonal.
More particularly, the invention is directed to a polypeptide having a molecular weight of 16.8 kDa on a non-reducing SDS-polyacrylamide gel and has an isoelectric point of 5.9. The polypeptide of the present invention is obtainable from the parasite
Schistosoma mansoni
and may be a secretion/excretion product of the schistosome.
Also, comprehended by the invention are DNAs encoding the polypeptides of the present invention as well as vectors comprising the DNAs of the invention, host cells transformed with the vector and expression products derived therefrom. Host cells may be procaryotic or eucaryotic host cells.
The invention is also directed to vaccines comprising one or more polypeptides according to the present invention which may also include suitable adjuvants, diluents or carrier substances, the vaccines being useful for immunoprophylaxis of schistosomiasis.
Pharmaceutical compositions comprising Sm 16.8 variants, fragments, derivatives, homologs or analogs of the polypeptide in combination with pharmaceutically acceptable diluents, adjuvants and carriers are also contemplated by the present invention.
The invention is further directed to methods of suppressing or preventing inflammation by administering to a subject an anti-inflammatory dose of a polypeptide or pharmaceutical compositions according to the present invention.
Methods for treating inflammation associated diseases such as cutaneous disease are also within the scope of the invention. Such methods comprise administering to a subject a therapeutically effective dose of a polypeptide or pharmaceutical composition according to the present invention. The polypeptides may be administered topically, for example, in a suitable cream, lotion or salve that may include excipients useful in transporting the biologically active polypeptides into the skin.
Methods for treating systemic diseases characterized by inflammatory processes, using the polypeptides of the invention are also contemplated by the present invention. Such diseases may be autoimmune diseases.
DETAILED DESCRIPTION OF THE INVENTION
During penetration into the skin, parasites such as those of the species
Schistosoma
continuously excrete/secrete substances (ES) into their surroundings in order to aid their passage and/or as part of their metabolism.
These ES products are known to contain different types of proteins and lipids, many of whose function are not fully known. By culturing these parasites (i.e., schistosomes) in vitro ES products have been collected, purified and analyzed for their functional capabilities. One of the major components of the ES products are proteins. Given that
S. mansoni
and
T. ocellata
differ in their ability to induce inflammation in the skin, the proteins in the ES products of the two parasites were analyzed in an attempt to identify whether ES products of
S. mansoni
contain any factors that have the capacity to modulate inflammatory responses in human skin that are not contained in the ES products of
T. ocellata
. These studies revealed the presence of a protein in the secretions of
S. mansoni
but not
T. oceltata
, that has the ability to suppress inflammation.
Cytokines, natural hormone like substances produced by many cells in the skin, may play a central role in initiating, promoting or suppressing inflammation. Cytokines such as Interleukin-1&agr;(IL-1&agr;) and IL-1&bgr; promote inflammation, whereas, cytokines such as IL-1ra suppress inflammation. In the skin, cells such as keratinocytes, Langerhans cells, lymphocytes or mast cells can produce an array of pro-inflammatory cytokines upon activation. Yet, penetration and migration of
S. mansoni
through the skin fails to induce any inflammatory, response.
Keratinocytes constitute over 95% of the cells in human skin. It has been shown repeatedly that depending upon the stimulus, human keratinocytes may produce the pro-inflammatory cytokine IL-1&agr; or the anti-inflammatory cytokine IL-1ra. Production of large quantities of IL-1ra locally results in the suppression of inflammatory responses.
The immunological basis for many cutaneous diseases such as atopic dernatitis, urticaria, contact sensitivity, cutaneous allergic conditions and psoriasis, is the accumulation of inflammatory cells in the epidermis and dermis. Any drug that can reduce or suppress accumulation of inflammatory cells in the skin will alleviate the clinical symptoms associated with these diseases.
Other inflammatory diseases are associated with the inflammatory processes in other organs of the body and are likewise susceptible to treatment with certain anti-inflammatory drugs.
A
Schistosoma mansoni
derived protein, Sm 16.8, that selectively up regulates IL-1ra production in human keratinocytes was identified and characterized. When added to human keratinocyte cultures at a concentration of 5 &mgr;g/1×10
5
cells, Sm 16.8 stimulated the production of IL-1ra within 4 hrs. Intracellular message (mRNA) for IL-1ra in these cells increased from 4 hrs after treatment and attained maximum values within 8 hrs. Statistically significant amounts of IL-1ra were also found intracellularly and in the culture supernatants of human keratinocytes after treatment with Sm 16.8. IL-1ra is a natural antagonist of IL-1, in that it competes with IL-1&agr;and IL-1&bgr; for the IL-1 receptor. Binding of IL-1&agr; or IL-1&bgr; to IL-1 receptors expressed on many cells results in a cascade of events leading to inflammation. However, binding of IL-1ra to IL-1 receptors fails to induce any receptor mediated responses. Therefore, occupancy of all available IL-1 receptors by IL-1ra results in the blocking of all IL-1 mediated responses. Since, IL-1ra binds to IL-1 receptors with affinity equal to or higher than those of IL-1&agr; or IL-1&bgr; and, since the dissociation rate constant of IL-1ra from IL-1 receptors is several-fold lower than that for IL-1&agr; and IL-1&bgr;, a higher concentration of IL-1ra in the local microenvironment can effectively block all the IL-1 mediated responses including inflammation. Given evidence that Sm 16.8 can stimulate a 100-400 fold increase in IL-1ra production from human keratinocytes, which are the major cell type in the
Kalyanasundaram Ramaswamy
Salafsky Bernard
Shibuya Takeshi
Baskar Padma
Marshall Gerstein & Borun
Smith Lynette R. F.
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