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Competitive inhibitors of invariant chain expression and/or ectopic clip binding

a competitive inhibitor and invariant chain technology, applied in the field of immunology, can solve the problems of unappreciated full impact of these molecules on immune signaling and activation, etc., and achieve the effect of easy synthesis and effective targeting methods

Inactive Publication Date: 2020-03-05
UNIV OF COLORADO THE REGENTS OF
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides methods for targeting a protein called CLIP by using a peptide that substitutes for it in a MHC molecule. The invention offers new peptides for this purpose and also discusses a method for identifying other peptides that can replace CLIP. These peptides are short and easy to make.

Problems solved by technology

Despite the fact that this “chaperone” role for invariant chain and CLIP has been identified, the full impact of these molecules on immune signaling and activation has not been appreciated by the prior art, nor has their been any sense from the prior art that anything useful would be served by inhibiting invariant chain expression or ectopic CLIP binding.
Despite the fact that this “chaperone” role for invariant chain and CLIP has been identified, the full impact of these molecules on immune signaling and activation has not been appreciated by the prior art, nor has their been any sense from the prior art that anything useful would be served by inhibiting invariant chain expression or ectopic CLIP binding

Method used

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  • Competitive inhibitors of invariant chain expression and/or ectopic clip binding
  • Competitive inhibitors of invariant chain expression and/or ectopic clip binding
  • Competitive inhibitors of invariant chain expression and/or ectopic clip binding

Examples

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example 1

Identification of CLIP Inhibitors

[0392]Peptide that are able to displace CLIP were identified using computer based analysis. Thus, examples of “ideal” MHC class II binding peptides were generated according to the invention. Analysis of the binding interaction between MHC class II and CLIP was used to identify other molecules that may bind to MHC class II and displace CLIP. The methods described herein are based on feeding peptide sequences into software that predicts MHC Class II binding regions in an antigen sequence using quantitative matrices as described in Singh, H. and Raghava, G. P. S. (2001), “ProPred: prediction of HLA-DR binding sites.”Bioinformatics, 17(12), 1236-37.

[0393]Because MHC class II HLA-DR can bind to peptides of varying length an analysis of MHC class II HLA-DR-CLIP binding was performed. Since the alpha chain of HLA-DR is much less polymorphic than the beta chain of HLA-DR, the HLA-DR beta chain (hence, HLA-DRB) was studied in more detail. Peptide binding data...

example 2

B-Cell Apoptosis after Coxsackievirus Infection

[0410]During the course of Coxsackievirus infection, animals that recover from the virus without subsequent autoimmune sequalae have high percentages of splenic B cell apoptosis during the infection in vivo (FIG. 1). Those animals susceptible to Coxsackievirus-mediated autoimmune disease have non-specifically activated B cells that do not undergo apoptosis, at least not during acute infection, nor during the time period prior to autoimmune symptoms indicating that a common feature in the development of autoimmune disease is failure of non-specifically activated B cells to die.

example 3

Activated B Cells in HIV Disease Mediate NK Cell Activation

[0411]We experimentally induced polyclonal activation of peripheral blood human B cells in an antigen-independent fashion using a combination of CD40 engagement (CD40Ligand bearing fibroblasts) and culture in recombinant IL-4. We isolated the activated B cells and return them to co-culture with autologous peripheral blood mononuclear cells (PBMCs). After five days of co-culture, we observed a striking increase in the percentage of activated NK cells in the PBMC culture (NK cells accounting for up to 25-50%, FIG. 2a, of the surviving PBMCs), and a dramatic apoptotic loss of the activated B cells (FIG. 2b). These data indicate that antigen—independent activated B cells in HIV disease initially activate NK cells.

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Abstract

The invention relates to methods for modulating the immune function through targeting of CLIP molecules. The result is wide range of new therapeutic regimens for treating, inhibiting the development of, or otherwise dealing with, a multitude of illnesses and conditions, including autoimmune disease, cancer, Alzheimer's disease, allergic disease, transplant and cell graft rejection, HIV infection and other viral, bacterial, and parasitic infection, and AIDS. Methods are also provided for preparing a peptide having the property of being able to displace CLIP by feeding one or more peptide sequences into software that predicts MHC Class II binding regions in an antigen sequence and related products.

Description

RELATED APPLICATIONS[0001]This application is a continuation application of U.S. application Ser. No. 15 / 232,856, filed Aug. 10, 2016 which is a continuation of U.S. application Ser. No. 14 / 609,127, filed on Jan. 29, 2015, which is a divisional application which claims the benefit under 35 U.S.C. § 120 of U.S. application Ser. No. 12 / 739,459, filed on Jan. 10, 2011, now U.S. Pat. No. 8,957,031 issued Feb. 17, 2015, entitled “COMPETITIVE INHIBITORS OF INVARIANT CHAIN EXPRESSION AND / OR ECTOPIC CLIP BINDING”, which is a National Stage application of PCT / US2008 / 012078, filed Oct. 23, 2008, which claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Ser. No. 61 / 000,152, filed on Oct. 23, 2007, and U.S. Provisional Application Ser. No. 61 / 135,964, filed on Jul. 25, 2008, both entitled “COMPETITIVE INHIBITORS OF INVARIANT CHAIN EXPRESSION AND / OR ECTOPIC CLIP BINDING,” and U.S. Provisional Application Ser. No. 61 / 137,150, filed on Jul. 25, 2008 and entitled...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/08G16B15/00G16B20/00G16B35/00G16C20/60C07K7/06A61K39/00
CPCY02A50/411A61K38/08Y02A50/401G16B35/00A61K38/00G16B15/00Y02A50/409C07K7/06G16C20/60G16B20/00A61K39/0011A61P1/04A61P19/02A61P21/04A61P25/00A61P27/02A61P29/00A61P31/04A61P31/12A61P31/14A61P31/18A61P33/00A61P33/02A61P33/06A61P35/00A61P37/02A61P37/06A61P37/08A61P43/00A61P7/06Y02A50/30G16B20/30G16B20/50G16B20/20A61K39/4613A61K39/464838
Inventor NEWELL-ROGERS, MARTHA KARENNEWELL, EVAN
Owner UNIV OF COLORADO THE REGENTS OF
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