System and methods relating to chimeric autoantibody receptors
Chimeric autoantibody receptors (CAARs) can include separate signaling and recognition constructs that are able to bind ligands that target autoantigens made of conventional amino acids, non-conventional amino acids, carbohydrates, or nucleic acids. Additionally, the present disclosure describes cells modified to express such constructs and the use of such constructs and/or cells in the treatment of autoimmune disease.
1. A system for selective depletion of autoreactive immune cells comprising:
at least one cell engineered to express at least one signaling construct comprising an intracellular signaling domain and a signaling protein binding domain,
at least one first recognition construct comprising
a first non-immunoglobulin moiety specific for binding with an autoreactive receptor expressed by a first target autoreactive immune cell and
a first recognition construct protein binding domain constructed to competitively bind to the signaling construct protein binding domain of the at least one engineered cell;
and at least one second recognition construct comprising
a second recognition construct protein binding domain constructed to competitively bind with to the signaling construct protein binding domain of the at least one engineered cell; and
a second non-immunoglobulin moiety specific for binding with an autoreactive receptor expressed by a second target autoreactive immune cell.
2. The system of claim 1 , wherein the first non-immunoglobulin moiety can bind to a target ligand found on a target cell associated with a medical condition selected from the group consisting of: autoimmune diseases, atopy, rheumatoid arthritis, cystic fibrosis, bronchiectasis, type I diabetes, celiac disease, inflammatory bowel disease, multiple sclerosis, autoimmunity, autoimmune response, vasculitis, myasthenia gravis, inflammatory diseases, inflammation, inflammatory response, neurological diseases, including Huntington's disease and Parkinson's disease, cardiovascular disease, including atherosclerosis, and infectious disease.
3. The system of claim 1 , wherein at least one of the first and the second non-immunoglobulin moiety is selected from the group consisting of: affimers, DARPins, aptamers, affibodies, spiegelmers, autoantigen, MHC-autoantigen, MHC fragment, complexed MHC-autoantigen, complexed MHC fragment, MHC-peptide, complexed MHC-peptide, fused MHC-peptide, autoantigen fragment, autoantigen-based constructs, sugar-based constructs, and lipid-based constructs.
4. The system of claim 2 , wherein the intracellular signaling domain is only activated when at least one of the at least one first recognition construct is bound to both the target ligand and the signaling protein binding domain of at least one of the at least one signaling constructs.
5. The system of claim 1 , wherein the intracellular signaling domain is configured to activate or inhibit effector functions of the at least one engineered cell.
6. The system of claim 1 , wherein the at least one engineered cell is selected from the group consisting of: T cells, NK cells, NKT cells, Treg, macrophages, a cell line, effector cells, allogenic cells, autologous cells, and stem-cell derivatives.
7. The system of claim 1 , wherein at least one of the at least one first recognition constructs and at least one of the at least one signaling constructs are used to make at least one logic gate.
8. The system of claim 1 , wherein the at least one engineered cell is further engineered to express at least one chimeric antigen receptor.
9. The system of claim 1 , wherein an affinity for the binding by the first non-immunoglobulin moiety with the first target autoreactive immune cell is an order of magnitude greater than an affinity for binding by the first non-immunoglobulin moiety with the second target autoreactive immune cell.
10. The system of claim 1 , wherein an affinity for the binding by the first non-immunoglobulin moiety with the first target autoreactive immune cell is two orders of magnitude greater than an affinity for binding by the first non-immunoglobulin moiety with the second target autoreactive immune cell.
11. The system of claim 1 , wherein an affinity for the binding by the second non-immunoglobulin moiety with the second target autoreactive immune cell is an order of magnitude greater than an affinity for binding by the second non-immunoglobulin moiety with the first target autoreactive immune cell.
12. The system of claim 1 , wherein an affinity for the binding by the second non-immunoglobulin moiety with the second target autoreactive immune cell is two orders of magnitude greater than an affinity for binding by the second non-immunoglobulin moiety with the first target autoreactive immune cell.
13. The system of claim 1 , wherein the autoreactive receptor expressed by the first target autoreactive immune cell comprises a T cell receptor and the autoreactive receptor expressed by the second target autoreactive immune cell comprises a B cell receptor.
14. A system for selective depletion of autoreactive immune cells comprising:
at least one cell engineered to express at least one signaling construct comprising an intracellular cell signaling domain and a signaling construct protein binding domain;
at least one first recognition construct comprising
a first non-immunoglobulin moiety specific for a first autoreactive receptor expressed by a target autoreactive immune cell and
a first recognition construct protein binding domain that competitively binds to the signaling construct protein binding domain of the at least one engineered cell; and
at least one second recognition construct comprising
a second non-immunoglobulin moiety specific for a second autoreactive receptor expressed by the target autoreactive immune cell, and
a second recognition construct protein binding domain that competitively binds with the signaling construct protein binding domain of the at least one engineered cell.
15. The system of claim 14 , wherein an affinity for binding by the first non-immunoglobulin moiety with the first autoreactive receptor is an order of magnitude greater than an affinity for binding by the first non-immunoglobulin moiety with the second autoreactive receptor.
16. The system of claim 14 , wherein an affinity for binding by the first non-immunoglobulin moiety with the first autoreactive receptor is two orders of magnitude greater than an affinity for binding by the first non-immunoglobulin moiety with the second autoreactive receptor.
17. A system for selective depletion of autoreactive immune cells comprising:
at least one cell engineered to express at least one signaling construct comprising an intracellular cell signaling domain and a signaling construct protein binding domain;
at least one first recognition construct comprising
a first non-immunoglobulin moiety with a first affinity for binding with a first ligand of a target autoreactive immune cell and
a first recognition construct protein binding domain that competitively binds to the signaling construct protein binding domain of the at least one engineered cell; and
at least one second recognition construct comprising
a second non-immunoglobulin moiety with a second affinity for binding with a second ligand of a second target autoreactive immune cell, and
a second recognition construct protein binding domain that competitively binds with the signaling construct protein binding domain of the at least one engineered cell.
18. The system of claim 17 , wherein each of the first affinity and the second affinity is an order of magnitude greater than an affinity for the first non-immunoglobulin moiety binding with a non-target cell.
19. The system of claim 17 , wherein the first affinity is an order of magnitude greater than an affinity for the first non-immunoglobulin moiety binding with the second ligand.
20. The system of claim 17 , wherein the ligand expressed by the first target autoreactive immune cell expresses a T cell receptor and the ligand expressed by the second target autoreactive immune cell expresses a B cell receptor.