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Improved methods and compounds for eliminating immune responses to therapeutic agents

A therapeutic and kit technology, applied in chemical instruments and methods, medical raw materials derived from mammals, vaccines, etc., can solve problems such as reducing transgenic efficiency

Active Publication Date: 2018-07-17
IMCYSE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, viral proteins expressed by these vectors elicit an immune response, reducing transgene efficiency and preventing readministration of the transgene

Method used

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  • Improved methods and compounds for eliminating immune responses to therapeutic agents
  • Improved methods and compounds for eliminating immune responses to therapeutic agents
  • Improved methods and compounds for eliminating immune responses to therapeutic agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0225] Example 1: Therapeutic Antibodies

[0226] Many viruses contain common class II restricted T cell epitopes, an example is hepatitis C virus. Peptide sequence 1247 to 1261 (QGYK VLVLNPSVAA T) [SEQ ID NO:12] and 1535 to 1550 (TTVRLRA YMNTPGLPV )[SEQ ID NO: 13] simultaneously covers 12 of more than 15 DRB haplotypes, accounting for more than 85% of the general population.

[0227] Therefore, a vaccination strategy was established using a mixture of two peptides covering a minimal binding sequence for a class II-restricted epitope and a thiol reductase motif.

[0228] Peptides 1247-1261 contain the MHC class II binding sequence at positions 1251-1260 (underlined in SEQ ID NO: 12).

[0229] Peptides 1535-1550 contain minimal MHC class II binding sequence at positions 1542-1550 (underlined in SEQ ID NO: 13).

[0230] Two peptides were prepared for vaccination in which the redox motif and epitope sequence were separated by a VR dipeptide linker:

[0231] CPYC-VR-VLVLNPS...

Embodiment 2

[0237] Example 2: Erythropoietin

[0238] Erythropoietin (EPO), a 166 amino acid residue long polypeptide, is the major mediator of hypoxia-induced erythropoiesis and is produced by the kidney in adults (±80%). Hypoxia leads to increased production of EPO, which then circulates in the plasma and binds to receptors expressed on erythroid progenitors, leading to terminal differentiation of these precursors and an increase in erythrocytes.

[0239] Although human recombinant EPO is a weak immunogen, its repeated use, eg in renal insufficiency, glycosylation or slight differences in the production procedure can lead to the generation of specific neutralizing antibodies. Since EPO is the sole mediator of erythropoiesis due to hypoxia, the presence of a neutralizing immune response was considered a dramatic event.

[0240] One approach to prevent this unwanted immune response is to vaccinate individuals in need of EPO with promiscuous class II-restricted T-cell epitopes linked to t...

Embodiment 3

[0247] Example 3: α-galactosidase

[0248] Fabry disease is a lysosomal storage disease in which glycosphingolipids accumulate in various tissues due to the absence of alpha-galactosidase, a lysosomal hydrolase. It is an X-linked gene defect disorder affecting ± 1 in 100,000 individuals. Current treatment for Fabry disease consists of periodic infusions of alpha-galactosidase. However, more than 25% of patients undergoing such treatment develop an immune response to the enzyme, preventing further use of the enzyme and putting patients at risk of various complications, including stroke.

[0249] Recombinant alpha-galactosidases can be modified to contain the sequence of a class II restricted promiscuous T cell epitope added at the amino terminus of the molecule. Administration of this modified α-galactosidase molecule to individuals previously inoculated with this promiscuous epitope containing a thiol reductase motif, thereby triggering the generation of peptide-specific cyt...

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Abstract

The invention describes a kit of parts of polypeptides. The kit comprises: a) a peptide comprising : a1) an MHC class II T cell epitope or a CD1 d-restricted NKT cell epitope, and a2) a [CST]-X(2)-C [SEQ ID NO:7] or C-X(2)-[CST] [SEQ ID NO:8] oxidoreductase motif sequence immediately adjacent to said epitope or separated by at most 7 amino acids from said epitope, and b) a polypeptide comprising:b1) a therapeutic protein and b2) the epitope defined in a1), wherein the epitope sequence is a sequence which differs from the sequence of the protein of b1). The therapeutic protein, in combinationwith the peptide, is used to prevent an immune response against the therapeutic protein.

Description

technical field [0001] The present invention relates to modified proteins for use in replacement therapy, gene therapy and gene vaccination (gene immunization). [0002] The invention also relates to compounds and methods for preventing immune responses to proteins used in replacement therapy, gene therapy and genetic vaccination. Background technique [0003] Proteins used as therapeutics often elicit an immune response, preventing further use. Examples are factor VIII in the treatment of hemophilia A patients and antibodies specific for cytokines (eg anti-TNF-α antibody) or for cell surface markers (eg anti-CD20 antibody). On average, 30% of patients treated with this agent developed detectable concentrations of antibodies in peripheral blood. In addition, a substantial proportion of patients required higher than expected doses of therapeutic agents, suggesting that subdetectable concentrations of antibodies may neutralize the activity of the agent and / or increase its cl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/00C12N9/02A61K35/12
CPCA61K38/00A61K39/001C12N9/0004A61K2035/122C07K2319/40A61K39/39A61K2039/55505A61K2039/55516A61K2039/572A61K2039/627A61K2039/70C07K14/70539A61P43/00
Inventor 让-玛丽·圣-雷米卢克·范德·埃尔斯特文森特·卡利尔
Owner IMCYSE
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