Materials and methods for the development of an antigen-specific immune non-responsiveness state
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Publication Number
US-11801287-B2
Publication Date
2023-10-31
Expiration Date
Abstract
The present invention provides materials and methods for making a subject non-responsive to an antigen. Methods of the invention may comprise contacting the subject with the antigen and a compound that induces anergy. In some embodiments, the antigen may be an autoimmune antigen, examples of which include, but are not limited to acetylcholine receptor for myasthenia gravis, glutamic acid decarboxylase for type I diabetes mellitus and rheumatoid factor in rheumatoid arthritis. In some embodiments, the present invention provides a method of transplanting an organ, tissue, or cells into a subject (e.g. a mammal such as a human).
Core Innovation
The invention relates to inducing antigen-specific immune non-responsiveness (anergy) in a subject. The approach comprises administering an antigen to the subject and administering an effective amount of a compound selected from a group of compounds that prevents T cell activation and interferes with Lck-mediated T cell proximal signaling.
In particular, the compound prevents T cell activation by interfering with the binding of lymphocyte-specific protein tyrosine kinase (Lck) in the T cell to ITAM-2 ζ chain C terminal phosphotyrosine residues. By blocking this Lck association with CD3 ITAM-2 ζ chain C terminal phosphotyrosines, antigen-driven T cell activation is suppressed and antigen-specific anergy is induced.
The disclosed antigen contexts include autoimmune antigens such as acetylcholine receptor, glutamic acid decarboxylase, and rheumatoid factor for treating autoimmune diseases. The disclosure also addresses transplant settings, including organ/tissue/cell transplantation, graft-vs-host disease, and hyper-acute/chronic rejection, by administering such compounds to make a subject non-responsive to an antigen.
The document includes in vivo testing using the Popliteal Lymph Node Assay (PLNA) to show suppressed T cell activation and antigen-specific anergy upon re-challenge with the same antigen source versus a different source. The results described include reduced lymph node swelling upon re-challenge with the same antigen source (FVB) and preserved response upon re-challenge with a different source (SJL), supporting antigen-specific anergy induction by the disclosed compounds (e.g., compounds 72, 86, 241).
Claims Coverage
The independent claim covers making a subject non-responsive to an antigen by administering the antigen together with an effective amount of a compound that prevents T cell activation via interference with Lck binding to ITAM-2 ζ chain C terminal phosphotyrosine residues. Dependent claims further refine timing, specify autoimmune antigen examples, and constrain the effective amount within a defined dosing range or to a specific dose level.
Antigen and Lck/ITAM-2 ζ C terminal phosphotyrosine binding interference to induce non-responsiveness
Administering the antigen to the subject and administering an effective amount of a compound selected from the group, wherein the compound prevents T cell activation by interfering with the binding of lymphocyte-specific protein tyrosine kinase (Lck) in the T cell to ITAM-2 ζ chain C terminal phosphotyrosine residues.
Timing of compound administration relative to antigen
Administering the effective amount of the compound before, at the same time as, and/or after administration of the antigen.
Autoimmune antigen selection
Administering an autoimmune antigen selected from acetylcholine receptor, glutamic acid decarboxylase, and rheumatoid factor.
Defined dosing range for effective amount
Administering an effective amount within a defined dosing range of about 0.1 mg/kg body weight to about 100 mg/kg body weight.
Single-point effective dose level
Administering an effective amount of 1 mg/kg body weight.
Overall, the claim coverage centers on preventing T cell activation by interfering with Lck binding to ITAM-2 ζ chain C terminal phosphotyrosine residues to make the subject non-responsive to an antigen, with dependent claims adding timing relationships, specific autoimmune antigens, and dosing constraints.
Stated Advantages
Prevents T cell activation by interfering with the binding of Lck to ITAM-2 ζ chain C terminal phosphotyrosine residues.
Induces antigen-specific immune non-responsiveness (anergy) such that response is reduced upon re-challenge with the same antigen source but preserved upon re-challenge with a different source.
Documented Applications
Treating autoimmune diseases using autoimmune antigens selected from acetylcholine receptor, glutamic acid decarboxylase, and rheumatoid factor, together with compounds that interfere with Lck/ITAM-2 ζ chain C terminal phosphotyrosine signaling.
Suppressing transplant-related immune responses by making a subject non-responsive to an antigen in organ/tissue/cell transplantation settings, including graft-vs-host disease and hyper-acute/chronic rejection.
Demonstrated in vivo using the Popliteal Lymph Node Assay (PLNA), including re-challenge experiments showing reduced lymph node swelling upon re-challenge with the same antigen source (FVB) but preserved response with a different source (SJL).
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