Major histocompatibility complex-based chimeric receptors and uses thereof for treating autoimmune diseases
Inventors
Norville, Julie • Wood, Elizabeth
Assignees
Publication Number
US-12421293-B2
Publication Date
2025-09-23
Expiration Date
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Abstract
Major histocompatibility complex-based chimeric receptors (MHC-CAR) for use in targeting autoreactive immune cells. Also provided herewith are genetically engineered immune cells expressing the MHC-CAR for use in treating autoimmune diseases such as multiple sclerosis.
Core Innovation
Major histocompatibility complex-based chimeric receptors (MHC-CAR) for use in targeting autoreactive immune cells are disclosed. The MHC-based chimeric receptor comprises an extracellular domain of a MHC molecule conjugated to an antigenic peptide from an antigen involved in an autoimmune disease and a cytoplasmic signaling domain, at least one co-stimulatory domain, or a combination thereof. The MHC-based CAR may further comprise a hinge domain located between the extracellular domain and the signaling domain, and the antigenic peptide may be from myelin basic protein (MBP), proteolipid protein (PLP), insulin, glutamate decarboxylase, or other self-antigens described in Table 1. The MHC-CAR constructs may be class I or class II MHC based and can be configured as single-chain or multi-chain constructs.
Autoimmune diseases are characterized by abnormal immune responses against self-antigens, leading to damage or disruption of tissues. Multiple sclerosis (MS) is described as a central nervous system autoimmune disease in which activated autoreactive T cells invade the blood brain barrier, initiating an inflammatory response that leads to myelin destruction and axonal loss, and the patent states that therapies specifically targeting the pathologic immune cells responsible for MS would have improved therapeutic outcomes over available therapies. The disclosure further notes that this strategy could be extended to other immune disorders with similar mechanisms, including rheumatoid arthritis. The background emphasizes B cell and T cell roles in disease and the potential benefit of targeting those pathologic cells.
Also provided are genetically engineered immune cells expressing the MHC-CAR for use in treating autoimmune diseases such as multiple sclerosis. The genetically modified immune cell examples include T cells (including regulatory T cells, which can be CD25+ and optionally CD4+), and may further include modifications such as suppression of endogenous T cell receptor activity, disruption of CD52, expression of a suicide gene or marker gene (e.g., RQR8 or GFP), and engineered traits for lymph node or tertiary lymphoid organ delivery and retention or trafficking to sites of inflammation. Methods disclosed include administering an effective amount of genetically modified immune cells expressing MHC-CAR (autologous or allogeneic) to a subject having an autoimmune disease, and pharmaceutical compositions comprising such genetically modified immune cells for use in treating autoimmune diseases are provided.
Claims Coverage
Two independent claims are identified. Four main inventive features are extracted from the independent claims.
Extracellular MHC domain conjugated to an antigenic peptide
An extracellular domain of an MHC molecule conjugated to an antigenic peptide from an antigen involved in an autoimmune disease.
Cytoplasmic signaling domain or co-stimulatory domain
A cytoplasmic signaling domain, at least one co-stimulatory domain, or a combination thereof.
Class i MHC with alpha-chain extracellular domain fused to peptide
Wherein the MHC molecule is a class I MHC; and wherein the extracellular domain of the chimeric receptor comprises an extracellular domain of the alpha chain of the class I MHC, which is fused to the antigenic peptide.
Genetically modified immune cell expressing the MHC-CAR
A genetically modified immune cell which expresses an MHC-based chimeric receptor comprising (i) an extracellular domain of an MHC molecule conjugated to an antigenic peptide from an antigen involved in an autoimmune disease; and (ii) a cytoplasmic signaling domain, at least one co-stimulatory domain, or a combination thereof, wherein the MHC molecule is a class I MHC and the extracellular domain comprises the alpha chain fused to the antigenic peptide.
The independent claims cover MHC-based chimeric receptors having an MHC extracellular domain conjugated to an antigenic peptide combined with intracellular signaling and/or co-stimulatory domains, with specific embodiments reciting class I MHCs where the alpha-chain extracellular domain is fused to the antigenic peptide, and genetically modified immune cells (e.g., T cells) that express these MHC-CARs.
Stated Advantages
Therapies specifically targeting the pathologic immune cells responsible for MS would have improved therapeutic outcomes over available therapies.
Therapeutic treatments that target B cells either directly or indirectly have proven beneficial in treatment of autoimmune diseases such as MS.
Genetically engineered immune cells expressing MHC-CAR can be used to target autoreactive immune cells, thereby benefiting treatment of autoimmune diseases involving the autoreactive immune cells.
Documented Applications
Treatment of multiple sclerosis using genetically engineered immune cells expressing MHC-CAR, including Treg cells and cytotoxic lymphocytes (CTLs), and methods for administering such cells to a subject having MS.
Treatment of other autoimmune disorders explicitly listed in the patent, including systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis, Sjögren's syndrome, systemic sclerosis, ankylosing spondylitis, Type 1 diabetes, autoimmune thyroid diseases (Grave's and Hashimoto's), myasthenia gravis, inflammatory bowel disease (Crohn's or ulcerative colitis), psoriasis, and diseases included in Table 1.
Use of genetically modified immune cells expressing MHC-CAR for manufacturing a medicament and pharmaceutical compositions comprising such genetically modified immune cells and a pharmaceutically acceptable carrier for treating an autoimmune disease.
Administration modalities and treatment contexts explicitly described: autologous or allogeneic genetically modified immune cells; administration to a lymph node; co-treatment contexts including subjects undergoing therapy comprising an antibody specific to CD52; and stage-specific Treg or CTL modifications for early-stage, relapsing-remitting or progressive forms of MS as described in the patent.
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