Regulated biocircuit systems
The present invention provides regulatable biocircuit systems. Such systems provide modular and tunable protein expression systems in support of the discovery and development of therapeutic modalities.
1. A regulatable human T cell engineered to express an effector module or a population of regulatable human T cells engineered to express the effector module, wherein the effector module comprises:
a first component and a second component,
wherein said first component is a stimulus response element (SRE) comprising an FK506 binding protein (FKBP) destabilizing domain (DD), wherein the FKBP DD comprises mutations F36V and L106P and comprises SEQ ID NO: 213274 or comprises mutation E31G, F36V, R71G, and K105E and comprises SEQ ID NO: 213297 and
wherein said second component is a chimeric antigen receptor that recognizes a C19 antigen, and wherein said effector module is responsive to at least one stimulus.
2. The regulatable human T cell or population of regulatable human T cells of claim 1 , wherein the T cells are primary T cells.
3. The regulatable human T cell or population of regulatable human T cells of claim 1 , wherein the T cell is selected from the group consisting of cytotoxic T cells, helper T cells, memory T cells, regulatory T cells, tissue infiltrating T cells and combinations thereof.
4. The regulatable human T cell or population of regulatable human T cells of claim 1 , wherein the regulatable human T cell or population of regulatable human T cells is obtained from a subject suffering from, being treated for, diagnosed with, or suspected of having a disorder selected from the group consisting of an immune disorder including autoimmune disorders and a hyperproliferative condition including cancer, an infectious disease, a non-infectious disease, and graft vs. host disease.
5. The regulatable human T cell or population of regulatable human T cells of claim 1 , wherein the effector module comprises:
FKBP DD comprising mutations F36V L106P (SEQ ID NO: 213574), and further comprising CD8a leader, CD19 scFV, CD8a hinge, CD8a transmembrane domain, 41BB, and CD3zeta and having the amino acid sequence set forth in SEQ ID NO: 213412 or SEQ ID NO: 213414, or
FKBP DD comprising mutations E31G, F36V, R71G, and K105E (SEQ ID NO: 213297), and further comprising a CD8a leader, CD19 scFV, CD8a hinge, CD8a transmembrane domain, 41BB, CD3zeta, and a linker and having the amino acid sequence set forth in SEQ ID NO: 213417.
6. The regulatable human T cell or population of regulatable human T cells of claim 1 , wherein the at least one stimulus is Shield-1.
7. A pharmaceutical composition comprising the regulatable human T cell or population of regulatable human T cells of claim 1 .