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FUSION PROTEINS OF NATURAL HUMAN PROTEIN FRAGMENTS TO CREATE ORDERLY MULTIMERIZED IMMUNOGLOBULIN Fc COMPOSITIONS

a technology of immunoglobulin and fusion proteins, which is applied in the field of immunology, autoimmunity, inflammation, tumor immunology, etc., can solve the problems of insufficient sterility, lack of availability of pooled human blood products, and high cost, and achieves broad application, high protein load, and enhanced ivig efficacy. effect of aggregate fraction

Inactive Publication Date: 2013-06-20
GLIKNIK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to a new alternative to IVIG that solves problems of high protein load, inconvenient patient dosing, infectious risk, and limited availability while maintaining the efficacy of IVIG. The invention is about biologically active fusion protein biomimetic molecules that consist of human immunoglobulin Fc and a single naturally occurring multimerization domain. These molecules have broad application for treating immunological and inflammatory disorders, including autoimmune diseases, and are also useful as laboratory reagents. The new molecules have improved properties over previous versions, including increased solubility, stability, and reduced risk of infection. The patent describes the use of these molecules in treating various disorders and also provides methods for their administration.

Problems solved by technology

While hIVIG has been an effective clinical treatment, there are several shortcomings to hIVIG treatments, including the potential for inadequate sterility, the presence of impurities or infectious agents including viruses and prions, lack of availability of this pooled human blood product, lot-to-lot variation, high expense, large protein load affecting renal function, and long administration time, generally over many hours and sometimes two consecutive days monthly.

Method used

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  • FUSION PROTEINS OF NATURAL HUMAN PROTEIN FRAGMENTS TO CREATE ORDERLY MULTIMERIZED IMMUNOGLOBULIN Fc COMPOSITIONS
  • FUSION PROTEINS OF NATURAL HUMAN PROTEIN FRAGMENTS TO CREATE ORDERLY MULTIMERIZED IMMUNOGLOBULIN Fc COMPOSITIONS
  • FUSION PROTEINS OF NATURAL HUMAN PROTEIN FRAGMENTS TO CREATE ORDERLY MULTIMERIZED IMMUNOGLOBULIN Fc COMPOSITIONS

Examples

Experimental program
Comparison scheme
Effect test

example 1

Production and Purification of the Stradomers

[0227]HEK293F cells (Invitrogen, Carlsbad, Calif.) or Chinese Hamster Ovary Cells (CHO) were used for stable expression of G045 / M045 and G051. The HEK293F or CHO cells were grown in suspension for scale up of protein expression.

[0228]Genes encoding G045c (SEQ ID NO:4), G045old (SEQ ID NO:7) G051 (SEQ ID NO:18), G019 (SEQ ID NO: 8), G028 (SEQ ID NO:9), G046 (SEQ ID NO: 10), G075 (SEQ ID NO: 20), G076 (SEQ ID NO: 21), G096 (SEQ ID NO: 28), G098 (SEQ ID NO: 24), G089 (SEQ ID NO: 27), or the corresponding murine sequences of the preceding stradomers. were cloned into a vector containing a neomycin resistance gene such as pcDNA3.3 from Invitrogen (Carlsbad, Calif.) and under the transcriptional control of the CMV promoter to facilitate high level expression of G045 or G051. Plasmid DNA for transfection were isolated from bacterial culture using a endotoxin free plasmid DNA isolation kit (Nucleobond, Macherey-Nagel). G045c / G045old and G051 enco...

example 2

Enhanced Efficacy of M045c Compared with M045old in a Mouse Model of Arthritis

[0234]Assessment of the efficacy of M045c compared to that of M045old in collagen induced arthritis was performed. At day 0 and day 21 DBA1 / J mice were immunized with Type II bovine collagen (Chondrex, Inc., Cat. 20021) with a 4 mg / ml solution emulsified with Incomplete Freund's Adjuvant (Sigma, Cat #5506). The mice were weighed weekly and scored daily for signs of arthritis. Each paw was scored and the sum of all four scores was recorded as the Arthritic Index (AI). The maximum possible AI was 16 as follows: 0=no visible effects of arthritis 1=edema and / or erythema of one digit 2=edema and / or erythema of 2 joints 3=edema and / or erythema of more than 2 joints 4=severe arthritis of the entire paw and digits including limb deformation and ankylosis of the joint. Starting at day 22 (treatment day 0) ten of the collagen immunized mice were sorted into treatment groups based upon average AI (3.3) and ten non-di...

example 3

Synergistic Effect of M045 and Prednisolone in a Mouse Model of Arthritis

[0237]Assessment of efficacy of M045c combined with low dose prednisolone in a collagen induced arthritis model was performed. Briefly at day 0 and day 21 DBA1 / J mice were immunized with Type II bovine collagen (Chondrex, Inc., Cat. 20021) with a 4 mg / ml solution emulsified with Incomplete Freund's Adjuvant (Sigma, Cat #5506). The mice were weighed weekly and scored daily for signs of arthritis. Each paw was scored and the sum of all four scores was recorded as the Arthritic Index (AI). The maximum possible AI was 16 as follows: 0=no visible effects of arthritis 1=edema and / or erythema of one digit 2=edema and / or erythema of 2 joints 3=edema and / or erythema of more than 2 joints 4=severe arthritis of the entire paw and digits including limb deformation and ankylosis of the joint. Starting at day 22 (treatment day 0) ten of the collagen immunized mice were sorted into treatment groups based upon average AI (3.3)...

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Abstract

The current invention involves a series of fully recombinant multimerized forms of immunoglobulin Fc which thereby present polyvalent immunoglobulin Fc to immune cell receptors. The fusion proteins exist as both homodimeric and highly ordered multimeric fractions, termed stradomers. In comparison to the homodimeric fraction, purified multimeric stradomers have higher affinity and avidity for Fc Rs with slower dissociation and are useful in the treatment and prevention of disease. The current invention demonstrates that directly linking IgG1 Fc regions to multimerization domains leads to enhanced multimerization and biological activity.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 61 / 368,465, filed Jul. 28, 2011, the contents of which are incorporated by reference herein in its 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—006—01US_SeqList_ST25.txt, date recorded: Jul. 26, 2011 file size 61 kilobytes).FIELD OF THE INVENTION[0003]This invention relates generally to the fields of immunology, autoimmunity, inflammation, and tumor immunology. More specifically, the present invention relates to biologically active biomimetic molecules comprising naturally linked immunoglobulin Fc domains, compositions comprising such biomimetics, and methods of making and using such biomimetics.[0004]The invention also relates to the treatment and prophylaxis...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K14/47
CPCA61K45/06C07K2317/35A61K31/573C07K2319/735C07K2319/73C07K2319/30A61K39/395C07K16/00C07K14/47A61K2039/505C07K2317/52C07K2317/92A61K2300/00A61P37/00
Inventor BLOCK, DAVID S.OLSEN, HENRIK
Owner GLIKNIK
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