Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-02-07
2002-07-16
Crouch, Deborah (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S455000
Reexamination Certificate
active
06420346
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to pharmaceutical compositions and methods for treating rheumatoid arthritis in an individual. More particularly, the present invention relates to DNA vaccination approaches which induce the breakdown of self-tolerance to cytokines and as such inhibit the progression of the disease.
Rheumatoid arthritis (RA) is an inflammatory disorder characterized by infiltration of leukocytes into the synovial tissue (ST) and synovial fluid (SF) of joints (Harris, 1990). Depending on the type of immunization, a single administration of complete Freund's adjuvant (CFA) may result in the development of a local inflammatory process or chronic poly adjuvant induced arthritis (AIA, also termed AA) which histologically and clinically resembles human RA (Holoshitz et al., 1983). In the scientific and medical communities, AIA is considered a reliable animal model for testing drugs and treatments for RA.
In both diseases proinflammatory cytokines and chemokines are believed to play a pivotal role in the attraction of leukocytes to the site of inflammation and in the initiation and progression of the inflammatory process. The role of proinflammatory cytokines, particularly TNF-&agr; and IL-1, in disease manifestation has been intensively studied and explored in experimental models that have been expanded to clinical trials (Arend and Dayer, 1995; Arend et al., 1994; Elliott et al., 1994; Feldmann et al., 1997; Moreland et al., 1997; Moreland et al., 1996; for a general review, see also, Feldmann et al., 1996). Other cytokines such as IL-4, TGF-&bgr;, IL-8, IL-17, IL-10, IL-11, IL-12 and IL-15 have also been implicated in the regulation of the disease. Such regulation can be attributed to either their direct effect on disease manifestation, their synergistic effect with other proinflammatory cytokines/chemokines, or their involvement in the regulation of chemokine transcription, and production (Badolato and Oppenheim, 1996; Badolato et al., 1997; Butler et al., 1999; Chabaud et al., 1998; Evans et al., 1998; Feldmann et al., 1996; Kasama et al., 1999; Ma et al., 1998; Parks et al., 1998; Sato et al., 1996; Schimmer et al., 1998; Schrier et al., 1998; Wahl et al., 1993).
Chemokines are chemoattractant cytokines that mediate leukocyte attraction and recruitment at the site of inflammation. Based on the positions of the first two cysteines, chemokines can be divided into four highly conserved but distinct supergene families, C—C, C-X-C, C and C-X3-C (Rollins, 1997; Sallusto et al., 1998; Ward et al., 1998). The C—C family is primarily involved in the activation of endothelium and chemoattraction of T cells and monocytes to the site of inflammation. The protective competence of anti-C—C chemokine based immunotherapy has been demonstrated in experimental autoimmune encephalomyelitis (EAE), and AA.
Neutralizing the activity of chemokines as a way to treat arthritis has been explored by several researchers. In a very recent study neutralizing antibodies to epithelial neutrophil activating peptide 78 (ENA-78) were found capable of inhibiting the development of AA if administered before but not after the onset of disease (Halloran et al., 1999). In another recent study Barnes et al. used anti-human RANTES to ameliorate AA in the Lewis rat (Barnes et al., 1998). Gong et al. used an antagonist of Monocyte Chemoattractant Protein 1 (MCP-1) to inhibit arthritis in the MRL-1pr mouse model (Gong et al., 1997). Using a streptococcal cell wall induced arthritis model it has been shown that anti-IL-4 and anti MCP-1 antibodies block the disease (Schimmer et al., 1998). The same study demonstrated that neutralizing IL-4 by itself, leads to a marked reduction in MCP-1 mRNA transcription at the autoimmune site and to inhibition of the development of disease which further implicates MCP-1 in playing an active role in arthritis development.
A major disadvantage in treating chronic diseases with xenogenic neutralizing antibodies lies in their immunogenicity. This has motivated investigators to develop chimeric humanized antibodies, and monoclonal antibodies engineered with human Ig heavy and light chain from yeast artificial chromosomes (YAC) (Green et al., 1994). However, following repeated immunization, these engineered antibodies do trigger an apparent allotypic response.
The present invention provides an alternative therapeutic approach to the treatment of rheumatoid arthritis. This approach utilizes ex-vivo or in-vivo DNA vaccination with either cell contained DNA or preferably naked DNA constructs which include an expressible cytokine, preferably chemokine, derived coding sequence(s). The approach of the present invention enables overexpression of the cytokine in the recipient subject, thereby eliciting an immune response which induces the breakdown of self-tolerance to these cytokine and as such inhibit the progression of the disease.
As is further described in the examples section below, this therapeutic approach is of great advantage over prior art methods since it results in the generation of immunity to autologous antigens, which immunity level corresponds with a disease state. This type of therapy is ideally suited for treating rheumatoid arthritis.
SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided a method of treating rheumatoid arthritis of an individual, the method comprising the step of expressing within the individual at least an immunologically recognizable portion of a cytokine from an exogenous polynucleotide encoding the at least a portion of the cytokine, wherein a level of expression of the at least a portion of the cytokine is sufficient to induce a formation of anti-cytokine immunoglobulins, the anti-cytokine immunoglobulins being for neutralizing or ameliorating an activity of a respective and/or cross reactive endogenous cytokine, to thereby treat rheumatoid arthritis.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising, as an active ingredient, a nucleic acid construct including a polynucleotide region encoding at least a portion of a cytokine and a pharmaceutically acceptable carrier.
According to further features in preferred embodiments of the invention described below, the cytokine is a chemokine.
According to still further features in the described preferred embodiments the chemokine is a C—C chemokine.
According to still further features in the described preferred embodiments the C—C chemokine is selected from the group consisting of MIP-1&agr;, MCP-1, MIP-1&bgr; and RANTES.
According to still further features in the described preferred embodiments the cytokine is TNF-&agr;.
According to still further features in the described preferred embodiments the step of expressing within the individual the at least an immunologically recognizable portion of the cytokine from the exogenous polynucleotide encoding the at least a portion of the cytokine is effected by administering the exogenous polynucleotide to the individual.
According to still further features in the described preferred embodiments the exogenous polynucleotide forms a part of a pharmaceutical composition.
According to still further features in the described preferred embodiments the pharmaceutical composition also includes a pharmaceutically acceptable carrier.
According to still further features in the described preferred embodiments the pharmaceutically acceptable carrier is selected from the group consisting of a viral carrier, a liposome carrier, a micelle carrier and a cellular carrier.
According to yet another aspect of the present invention there is provided a method of treating rheumatoid arthritis in an individual, the method comprising the step of administering to the individual cells expressing from an exogenous polynucleotide at least an immunologically recognizable portion of a cytokine, wherein a level of expression of the at least a portion of the cytokine is sufficient to induce a formation of anti-cytokine immunoglobulins, the anti-cytokine immun
Crouch Deborah
G. E. Ehrlich Ltd.
Rappaport Family Institute for Research in the Medical Sciences
Woitach Joseph T.
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