Major histocompatibility complex-based chimeric receptors and uses thereof for treating autoimmune diseases
Inventors
Norville, Julie • Wood, Elizabeth
Assignees
Publication Number
US-11826385-B2
Publication Date
2023-11-28
Expiration Date
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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
The disclosure features a major histocompatibility complex (MHC)-based chimeric receptor (CAR) comprising 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 cytoplasmic domain, and the antigenic peptide is dependent on the autoimmune disorder and may be from myelin basic protein (MBP), proteolipid protein (PLP), insulin, glutamate decarboxylase, or other self-antigens described in Table 1. The disclosure also provides nucleic acids or nucleic acid sets encoding the MHC-based chimeric receptors, vectors carrying such nucleic acids, and genetically engineered immune cells (e.g., T cells) expressing the MHC-CAR for use in treating autoimmune diseases such as multiple sclerosis.
Genetically modified immune cells expressing the MHC-CAR may be further modified for suppressing endogenous T cell receptor activity, for expression of suicide or marker genes, or for lymph node or tertiary lymphoid organ delivery and retention by overexpressing molecules such as VAP-1, L-selectin, CCR7, or CXCR5. In some embodiments, the genetically modified immune cell may be a regulatory T cell (Treg), which can be CD25+ and optionally CD4+, and such Treg cells may further express chimeric receptors specific to CD19 or CS-1, chemokine receptors such as CCR6 or CXCR5, PD-1 pathway modifications, or display an antibody specific to MOG. The disclosure further provides methods for suppressing autoreactive immune cells in a subject having an autoimmune disease by administering an effective amount of genetically modified immune cells as described, and pharmaceutical compositions comprising such genetically modified immune cells for use in treating target autoimmune diseases.
Claims Coverage
One independent claim is presented covering a multi-polypeptide MHC-based chimeric receptor.
MHC class II heterodimeric chimeric receptor with antigenic peptide fused to one chain and a cytoplasmic signaling domain on one chain
A major histocompatibility complex (MHC)-based chimeric receptor comprising: (a) a first polypeptide comprising an extracellular domain of a first MHC class II; (b) a second polypeptide comprising an extracellular domain of a beta chain of a second MHC class II; wherein an antigenic peptide is fused to either the first polypeptide or the second polypeptide; and wherein either the first polypeptide or the second polypeptide, but not both, further comprises a cytoplasmic signaling domain.
The independent claim covers a two-polypeptide MHC class II-based chimeric receptor in which an antigenic peptide is fused to one polypeptide and a cytoplasmic signaling domain is present on one, but not both, polypeptides.
Stated Advantages
Therapies specifically targeting the pathologic immune cells responsible for multiple sclerosis and related autoimmune disorders would have improved therapeutic outcomes over available therapies.
Genetically engineered immune cells expressing the MHC-CAR can target autoreactive immune cells, thereby benefiting treatment of autoimmune diseases involving the autoreactive immune cells.
Genetically modified regulatory T (Treg) cells expressing an MHC-CAR may be used to inhibit pathogenicity at an early stage, control disease progression at a middle stage, or suppress pathology at a late stage of the disease.
Pharmaceutical compositions comprising genetically modified immune cells expressing MHC-CAR are provided for use in treating autoimmune diseases and for manufacturing a medicament for such treatment.
Documented Applications
Treatment of autoimmune diseases, explicitly exemplified by multiple sclerosis, using genetically engineered immune cells expressing MHC-CAR to target autoreactive immune cells.
Treatment of other autoimmune disorders explicitly listed in the specification, 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 enumerated in Table 1.
Use of genetically modified regulatory T cells (Treg) and/or cytotoxic lymphocytes (CTLs) expressing MHC-CARs to suppress autoreactive immune cells in subjects having or at risk for autoimmune disease, including distinct genetic modification profiles for early-stage, relapsing-remitting or early-stage progressive, and chronic progressive disease states.
Pharmaceutical compositions comprising genetically modified immune cells expressing MHC-CARs, together with a pharmaceutically acceptable carrier, for use in treating autoimmune disease and for manufacturing a medicament for such therapeutic use.
Administration approaches described conceptually in the specification, including autologous or allogeneic genetically modified immune cells, co-use with therapies such as anti-CD52 antibodies, and delivery to lymph node or tertiary lymphoid organ sites [procedural detail omitted for safety].
Interested in licensing this patent?