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Interleukin-1 Conjugates and Uses Thereof

a technology of interleukin-1 and conjugates, applied in the field of medicine, public health, immunology, molecular biology and virology, can solve the problems of high cost of goods, potential patient compliance problems, kineret® prescribing information, etc., to inhibit the development of atherosclerosis symptoms, reduce the pro-inflammatory activity of il-1 in vivo, and improve the effect of treatment

Inactive Publication Date: 2011-02-03
CYTOS BIOTECHNOLOGY AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]We have, now, surprisingly found that the inventive compositions and vaccines, respectively, comprising at least one IL-1 molecule, are not only capable of inducing immune responses against IL-1, and hereby in particular antibody responses, but are, furthermore, capable of neutralizing the pro-inflammatory activity of IL-1 in vivo. In addition we have surprisingly found that IL-1 molecule, when covalently linked to the VLP in accordance with the invention, can protect from inflammation and from clinical signs of arthritis in a mouse model of rheumatoid arthritis. Moreover, we have found that the inventive compositions protected mice better from the development of arthritis symptoms than the recombinant IL-1 receptor antagonist Kineret®, which is approved for the treatment of human rheumatoid arthritis (Example 7). Furthermore, we surprisingly found that compositions of the invention were able to inhibit the development of atherosclerotic symptoms, when injected into genetically susceptible mice (Example 4) and therefore are an efficient treatment for atherosclerosis. Furthermore, we demonstrated that IL-1α is involved in the pathogenesis of atherosclerosis.
[0009]Furthermore, the present invention provides a method to administering the vaccine composition to a human or an animal, preferably a mammal. The inventive vaccine composition is capable of inducing strong immune response, in particular antibody response, typically and preferably without the presence of at least one adjuvant. Thus, in one preferred embodiment, the vaccine is devoid of an adjuvant. The avoidance of using adjuvant may reduce a possible occurrence of unwanted inflammatory T cell responses.
[0010]In one preferred embodiment, the VLP is a VLP of an RNA bacteriophage. In a further preferred embodiment said RNA bacteriophage is an RNA bacteriophage selected from the group consisting of: Qβ, fr, GA and AP205. In a further preferred embodiment said VLP of an RNA bacteriophage comprised by the composition and the vaccine composition, respectively, is recombinantly produced in a host and the VLP of an RNA bacteriophage is essentially free of host RNA, preferably host nucleic acid. It is advantageous to reduce, or preferably to eliminate, the amount of host RNA to avoid unwanted T cell responses as well as other unwanted side effects, such as fever.

Problems solved by technology

A recombinant version of IL-1ra (anakinra, Kineret®) is efficacious in reducing inflammation and preventing tissue damage in several inflammatory disorders, but the need for high systemic concentrations and the short half life of the drug require frequent (daily) administrations of high doses (˜100 mg), resulting in high cost of goods and potential patient compliance problems (Kineret® prescribing information, Amgen; Granowitz E. V. et al.

Method used

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  • Interleukin-1 Conjugates and Uses Thereof
  • Interleukin-1 Conjugates and Uses Thereof

Examples

Experimental program
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example 1

Cloning, Expression and Purification of Murine IL1α117-270 and IL-1β119-269

[0156]The nucleotide sequence encoding amino acids 117-270 of murine IL-1α was amplified by PCR from a cDNA library of TNFα-activated murine macrophages using oligonucleotides IL1α1 (5′-ATATATGCTAGCCCCTTACACCTACCAGAGTGATTTG-3′; SEQ ID NO:24) and IL1α2 (5′-ATATATCTCGAGTGATATCTGGAAGTCTGTCATA GAG-3′; SEQ ID NO:25). Using the same cDNA library, the nucleotide sequence encoding amino acids 119-269 of the murine IL-1β precursor was amplified with oligonucleotides IL1β1 (5′-ATATATGCTAGCCCCCATTAGACAGCTGCACTACAGG-3′; SEQ ID NO:26) and IL1β2 (5′-ATATATCTCGAGGGAAGACACAGATTCCATGGTGAAG-3′; SEQ ID NO: 27). Both DNA fragments were digested with NheI and XhoI, and cloned into the expression vector pModEC1 (SEQ ID NO:29)

[0157]The vector pModEC1 (SEQ ID NO:29) is a derivative of pET22b(+) (Novagen Inc.), and was constructed in two steps. In a first step the multiple cloning site of pET22b(+) was changed by replacing the origi...

example 2

A. Coupling of Mouse IL-1β119-269 to Qβ Virus-like Particles

[0159]A solution containing 1.3 mg / ml of the purified murine IL-1β119-269 protein from EXAMPLE 1 (SEQ ID NO:66) in PBS pH 7.2 was incubated for 60 min at room temperature with an equimolar amount of TCEP for reduction of the C-terminal cysteine residue.

[0160]A solution of 6 ml of 2 mg / ml Qβ capsid protein in PBS pH 7.2 was then reacted for 60 min at room temperature with 131 μl of a SMPH solution (65 mM in DMSO). The reaction solution was dialysed at 4° C. against three 3 l changes of 20 mM HEPES, 150 mM NaCl pH 7.2 over 24 hours. Seventy-five μl of the derivatized and dialyzed Qβ solution was mixed with 117 μl H2O and 308 μl of the purified and pre-reduced mouse IL-1β119-269 protein and incubated over night at 15° C. for chemical crosslinking. Uncoupled protein was removed by tangential flow filtration against PBS using cellulose ester membranes with a molecular weight cutoff of 300.000 Da.

[0161]Coupled products were analy...

example 3

A. Coupling of Mouse IL-1α117-270 to Qβ Virus-like Particles

[0169]A solution containing 1.8 mg / ml of the purified IL-1α117-270 protein from EXAMPLE 1 (SEQ ID NO:65) in PBS pH 7.2 was incubated for 60 min at room temperature with an equimolar amount of TCEP for reduction of the C-terminal cysteine residue.

[0170]A solution of 6 ml of 2 mg / ml Qβ capsid protein in PBS pH 7.2 was then reacted for 60 minutes at room temperature with 131 μl of a SMPH solution (65 mM in DMSO). The reaction solution was dialyzed at 4° C. against three 3 l changes of 20 mM HEPES, 150 mM NaCl pH 7.2 over 24 hours. Seventy-five μl of the derivatized and dialyzed Qβ solution was mixed with 192 μl H2O and 233 μl of the purified and pre-reduced mouse IL-1α117-270 protein and incubated over night at 15° C. for chemical crosslinking. Uncoupled protein was removed by tangential flow filtration against PBS using cellulose ester membranes with a molecular weight cutoff of 300.000 Da.

[0171]Coupled products were analyzed...

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Abstract

The present invention is related to the fields of molecular biology, virology, immunology and medicine. The invention provides a composition comprising an ordered and repetitive antigen array, wherein the antigen is an IL-1 protein, an IL-1 mutein or an IL-1 fragment. More specifically, the invention provides a composition comprising a virus-like particle, and at least one IL-1 protein, IL-1 mutein or at least one IL-1 fragment linked thereto. The invention also provides a process for producing the composition. The compositions of the invention are useful in the production of vaccines for the treatment of inflammatory diseases, and chronic autoimmune diseases, genetic diseases and cardiovascular diseases. The composition of the invention efficiently induces immune responses, in particular antibody responses. Furthermore, the compositions of the invention are particularly useful to efficiently induce self-specific immune responses within the indicated context.

Description

FIELD OF THE INVENTION[0001]The present invention is in the fields of medicine, public health, immunology, molecular biology and virology. The invention provides compositions comprising a virus-like particle (VLP) or a virus particle and at least one antigen, wherein said antigen is an Interleukin-1 (IL-1) protein, an IL-1 fragment or peptide or an IL-1 mutein covalently linked to the VLP or the virus particle. The invention also provides a process for producing the compositions. The compositions of this invention are useful in the production of vaccines for the treatment of various human disorders, including rheumatoid arthritis osteoarthritis and others. The compositions of the invention hereby induce efficient immune responses, in particular antibody responses.RELATED ART[0002]IL-1 is a potent proinflammatory cytokine produced by various cell types, including macrophages, dendritic cells, B-cells and T-cells (Dinarello C. A., 1991. Blood 77(8):1627-1652). It consists of two molec...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00C07K14/54A61P25/00A61P19/00A61P19/06A61P9/10A61P37/08A61P29/00
CPCA61K38/00A61K2039/5258A61K2039/6075C07K14/005C12N2795/18123C07K2319/00C12N7/00C12N2795/18122C07K14/545A61P1/04A61P17/04A61P17/06A61P19/00A61P19/02A61P19/06A61P19/08A61P19/10A61P25/00A61P25/08A61P25/16A61P25/28A61P29/00A61P29/02A61P37/00A61P37/02A61P37/06A61P37/08A61P9/00A61P9/10A61K39/385A61K39/395C12N7/04
Inventor BACHMANN, MARTINSPOHN, GUNTHERTISSOT, ALAIN
Owner CYTOS BIOTECHNOLOGY AG
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