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Breaking Immunological Tolerance with a Genetically Encoded Unnatural Amino Acid

a genetically encoded amino acid and immunological technology, applied in the field of immunology, can solve the problems of difficult for a subject to produce a robust antibody response to a variety, elicit strong/robust antibody responses, etc., and achieve the effect of increasing the immunogenicity of specific epitopes and inducing a strong immune respons

Inactive Publication Date: 2011-03-03
THE SCRIPPS RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0052]Immunological response or immune response: An “immunological response” or “immune response” to a moiety or composition thereof is the development in a subject of a cellular and / or antibody-mediated immune response to the moiety. Usually, an immunological response includes but is not limited to one or more of the following effects: the production of antibodies (preferably), B cells, helper T cells, suppressor T cells, and / or cytotoxic T cells and / or γδ T cells, directed specifically to one or more antigen of the moiety. In various embodiments, the subject will display either a therapeutic or prophylactic immunological response such that resistance to a new challenge with the moiety will be enhanced and / or the clinical severity of the disease state caused by / associated with the moiety is reduced.
[0061]Prophylactic treatment: A “prophylactic treatment” is a treatment administered to a subject who does not display signs or symptoms of a disease, pathology, or medical disorder, or displays only early signs or symptoms of a disease, pathology, or disorder, such that treatment is administered for the purpose of diminishing, preventing, or decreasing the risk of developing the disease, pathology, or medical disorder. A prophylactic treatment functions as a preventative treatment against a disease or disorder. A “prophylactic activity” is an activity of an agent, such an unnatural immunogen and / or antibody, or composition thereof, that, when administered to a subject who does not display signs or symptoms of a pathology, disease, or disorder (or who displays only early signs or symptoms of such) diminishes, prevents, or decreases the risk of the subject developing the pathology, disease, or disorder. A “prophylactically useful” agent or compound (e.g., an unnatural immunogen and / or antibody of the invention, refers to an agent or compound that is useful in diminishing, preventing, treating, or decreasing development of a pathology, disease, or disorder.

Problems solved by technology

A major challenge in modern medicine concerns the treatment of medical conditions that either do not elicit production of antibodies by a subject (e.g., due to the subject's immunological tolerance to self-antigens) or which do not elicit strong / robust antibody responses (e.g., certain bacterial / viral infections).
Furthermore, it can be difficult for a subject to produce a robust antibody response to a variety of viral and bacterial infections such as HIV, CMV, tuberculosis, and staphylococcus.

Method used

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  • Breaking Immunological Tolerance with a Genetically Encoded Unnatural Amino Acid
  • Breaking Immunological Tolerance with a Genetically Encoded Unnatural Amino Acid
  • Breaking Immunological Tolerance with a Genetically Encoded Unnatural Amino Acid

Examples

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example 1

Breaking Immunological Tolerance with a Genetically Encoded Unnatural Amino Acid

[0272]The ability to selectively induce a strong immune response against self-proteins, or increase the immunogenicity of specific epitopes in foreign antigens, would have a significant impact on the production of vaccines for cancer, protein-misfolding diseases, and infectious diseases. Here, we show that site-specific incorporation of an immunogenic unnatural amino acid into a protein of interest produces high-titer antibodies that cross-react with WT protein. Specifically, mutation of a single tyrosine residue (Tyr86) of murine tumor necrosis factor-α (mTNFα) to p-nitrophenylalanine (pNO2Phe) induced a high-titer antibody response in mice, whereas no significant antibody response was observed for a Tyr86→Phe mutant. The antibodies generated against the pNO2Phe are highly cross-reactive with native mTNFα and protect mice against lipopolysaccharide (LPS)-induced death. This approach may provide a genera...

example 2

Mechanistic Studies of the Immunochemical Termination of Tolerance with Unnatural Amino Acids

[0336]Example 2 characterizes the nature and durability of the polyclonal IgG antibody response created by incorporation of an unnatural amino acid(s) into TNFα and adds additional support for the generality of unnatural amino acid-induced (e.g., pNO2Phe-induced) loss of self-tolerance. Example 2 shows that the mutation of several surface residues of murine tumor necrosis factor-α (mTNFα) independently to p-nitrophenylalanine (pNO2Phe) lead to a T cell-dependent polyclonal and sustainable anti-mTNFα IgG autoantibody response lasting for at least 40 weeks. The Example shows that the antibodies bound multiple epitopes on mTNFα and protected mice from severe endotoxemia induced by lipopolysaccharide (LPS) challenge. Immunization of mice with a pNO2Phe43 mutant of murine retinol binding protein (RBP4) was also shown to elicit a high titer IgG antibody response, which was cross-reactive with wild...

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Abstract

The present invention comprises methods and compositions for producing and / or enhancing an immunological response in a subject against a target moiety such as a disease-related moiety by administration of an antigenic version of the target moiety having one or more unnatural amino acid and / or by administration of an antibody against a version of a target moiety having one or more unnatural amino acid which antibody is cross reactive with the natural target moiety.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to and benefit of U.S. Provisional Patent Application Ser. Nos. 61 / 065,148, filed on Feb. 8, 2008; 61 / 065,515, filed on Feb. 12, 2008; 61 / 135,947 filed Jul. 25, 2008; 61 / 137,676 filed Jul. 31, 2008; 61 / 203,948, filed Dec. 29, 2008; 61 / 065,147, filed Feb. 8, 2008; 61 / 065,590 filed Feb. 12, 2008; 61 / 135,969, filed Jul. 25, 2008; 61 / 137,635 filed Jul. 31, 2008; and 61 / 203,947, filed Dec. 29, 2008; the disclosures of which are incorporated herein in their entirety for all purposes.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT[0002]This invention was made with Government support under Grant No. HL-16411 from the National Institutes of Health (NIH) (5RO1GM62159). The United States Government has certain rights in this invention.FIELD OF THE INVENTION[0003]The current invention relates to the field of immunology. More specifically, the present invention provides comp...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/19A61K39/395C12P21/02C07K14/525A61P37/04A61P35/00A61P31/04A61P31/12A61P31/10A61P33/02
CPCA61K31/19C07K16/44C07K16/241A61K39/0008A61P25/28A61P31/04A61P31/10A61P31/12A61P33/00A61P33/02A61P35/00A61P37/02A61P37/04
Inventor GRUNEWALD, JANTSAO, MENG-LINPERERA, ROSHANLERNER, RICHARD A.SMIDER, VAUGHN V.SCHULTZ, PETER G.
Owner THE SCRIPPS RES INST
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