Immunoglobulin constant region fc receptor binding agents

a technology of immunoglobulin and constant region, applied in the field of immunology, inflammation, tumor immunology, can solve the problems of insufficient sterility, lack of availability, presence of impurities, etc., and achieve the effect of broad application, treatment and prophylaxis of pathological conditions

Inactive Publication Date: 2012-12-06
GLIKNIK +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015]The present invention relates to biologically active biomimetic molecules, compositions comprising the same, and methods of using the same. These biomimetics have broad application for treating immunological and inflammatory disorders including but not limited to autoimmune diseases, and they have utility as bioimmunotherapy agents for cancer. Further, certain of these biomimetics also have utility as reagents, such as for use in immunological assays for testing immune cell function and in the diagnosis of disease. Moreover, the biomimetics and compositions of the present invention have the advantage of overcoming the above-listed limitations of hIVIG. The invention also relates to the treatment and prophylaxis of pathological conditions mediated by monocyte-derived cells, and more particularly to the use of stabilized functional portions of IgG Fc fragments for such treatment and prophylaxis.

Problems solved by technology

While hIVIG has been an effective clinical treatment, there are several shortcomings to hIVIG formulations, including the potential for inadequate sterility, the presence of impurities, lack of availability, and lot-to-lot variation.

Method used

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  • Immunoglobulin constant region fc receptor binding agents
  • Immunoglobulin constant region fc receptor binding agents
  • Immunoglobulin constant region fc receptor binding agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

Construct Design of Immunologically Active Biomimetics

[0345]A sequence encoding a Fc fragment monomer from human IgG1 (SEQ ID NO: 1) has been cloned into an expression vector (pCDNA 3.1D / V5 His TOPO Invitrogen) comprising selected restriction enzyme cleavage sites, an IgK signal (further defined below) and epitope tags to create the IgG1 monomer sequence {RestEnzSites-IgK signal-RestEnzSites-IgG1 (Hinge-CH2-CH3)-RestEnzSites-epitope tags (V5 and His)-STOP), shown in FIG. 17 (SEQ ID NO:19). The construct was transfected into CHO cells (CHO-002) for protein production. Additionally, we have designed several stradomer constructs with the general structures:

[0346](a) {RestEnzSites-IgK signal-RestEnzSites-IgG1(Hinge-CH2-CH3)-XbaI site-IgG1(Hinge-CH2-CH3)-STOP} (SEQ ID NO: 21) (see also FIG. 4A and FIG. 18);

[0347](b) {RestEnzSites-IgK signal-RestEnzSites-IgG1 (Hinge-CH2-CH3)-XbaI site-IgG1 (Hinge-CH2-CH3)-RestEnzSites-epitope tags (V5 and His)-STOP} (SEQ ID NO: 23) (see also FIG. 19);

[034...

example 2

Design and Testing of Immunologically Active Biomimetics Coated IVIG and Coated Fc stimulate Similar Phenotypic Changes

[0354]IVIG and Fc when coated onto the walls and floor of the wells of a sterile plate stimulate nearly identical changes in CD1a and CD86 levels on immature DC and delay the up regulation of CD11c. Because of the recognized critical role of DC in ITP, these data provide a rational model for evaluating the function of IVG mimetics such as stradomers. We also conclude that the fact that the phenotypic changes induced by IVIG are completely recapitulated by recombinant Fc suggest that the effects of IVIG on DC are highly likely to be Fc mediated.

Stradomer Generation

[0355]We have constructed stradomers of four different classes to mimic the effects of IVIG on immature DC. The serial stradomers, cluster stradomer units comprising cluster stradomers, core stradomer units comprising core stradomers, and Fc fragment stradomers shown below in Table 3 were each produced exce...

example 3

Heat Aggregated Biomimetics are More Potent than IVIG

[0380]A stradomer is a biologically active mimetic of aggregated immunoglobulin and especially of the aggregated Fc fragments of those immunoglobulin. In some instances, heat aggregation of the biomimetics described herein can increase biological activity. We conclude that heat-aggregated biomimetics as herein described can be as potent as IVIG.

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Abstract

IVIG replacement compounds are derived from recombinant and / or biochemical creation of immunologically active biomimetic(s). These replacement compounds are then screened in vitro to assess each replacement compound's efficiency at modulating immune function. Particular replacement compounds are selected for further in vivo validation and dosage / administration optimization. Finally, the replacement compounds are used to treat a wide range of diseases, including inflammatory and autoimmune diseases.

Description

[0001]This application is a continuation of U.S. application Ser. No. 12 / 602,609, filed Jun. 4, 2010 under 35 U.S.C. §371, which is a National Stage filing of PCT / US2008 / 065428, filed May 30, 2008, which claims priority to U.S. Provisional Appl. No. 61 / 015,547, filed Dec. 20, 2007, U.S. Provisional Appl. No. 61 / 015,127 filed Dec. 19, 2007, and U.S. Provisional Appl. No. 60 / 941,644, filed Jun. 1, 2007, all of which are incorporated herein by reference in their entirety.DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY[0002]The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: GLIK—002—05US_SeqList.txt, date recorded: May 11, 2012, file size 311 kilobytes)BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]This invention relates generally to the fields of immunology, inflammation, and tumor immunology. More specifically, the present inven...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/46A61K39/00
CPCA61K2039/505C07K16/00C07K16/065C07K16/32C07K2317/50C07K16/18C07K2317/53C07K2317/55C07K2319/00C07K2317/526C07K16/28C07K2317/52C07K2319/30A61P1/00A61P1/04A61P19/02A61P19/08A61P21/00A61P21/04A61P25/00A61P25/28A61P29/00A61P31/04A61P31/12A61P31/22A61P33/06A61P35/00A61P37/00A61P37/02A61P37/06A61P43/00A61P7/04A61P7/06A61P3/10Y02A50/30C07K16/283C07K16/2863C07K2317/35C07K2317/41C07K2317/524C07K2317/528C07K2317/71C07K2317/72C07K2317/73C07K2317/92C07K2318/00A61K2039/54A61K2039/57G01N2500/10G01N33/5047C07K16/06A61K39/395G01N33/53A61K39/39533
Inventor STROME, SCOTT E.SCHULZE, DAN H.BLOCK, DAVID S.
Owner GLIKNIK
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