REGULATED BIOCIRCUIT SYSTEMS

Abstract

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.

Claims

1. A biocircuit system comprising at least one effector module, said at least one effector module each comprising (a) a first component and a second component wherein each of said first said second component is independently selected from the group consisting of a peptide, peptide complex, peptide-protein complex, protein, fusion protein, protein complex, protein-protein complex, and wherein said first component is a stimulus response element (SRE) comprising (i) one or more regions derived from a payload, said payload having a sequence selected from the group consisting of SEQ ID NO: 1-102450, and 212852-213270; (ii) one or more regions derived from a Target of a ligand binding partner pair listed in Table 2 or Table 3; (iii) one or more regions derived from an antibody listed in Table 5; or (iv) an SRE listed in Table 4, and wherein said second component is a payload construct comprising (i) a payload, said payload having a sequence selected from the group consisting of SEQ ID NO: 1-102450, and 212852-213270 or functional fragment thereof; (ii) a Target of a ligand binding partner pair listed in Table 2, Table 3 or functional fragment thereof; or (iii) an antibody listed in Table 5 or a functional fragment thereof; and wherein said effector module is responsive to at least one stimulus.

2-3. (canceled)

4. The biocircuit system of claim 1, wherein said biocircuit system is selected from the group consisting of a DD biocircuit system, a Dimer biocircuit system, a CAR biocircuit system, a Receptor biocircuit system, and a Cell biocircuit system.

5. (canceled)

6. The biocircuit system of claim 1, wherein the at least one effector module further comprises a signal sequence selected from those listed in Table 6.

7. The biocircuit system of claim 1, wherein the at least one effector module further comprises a cleavage and/or processing feature selected from those listed in Table 7.

8. The biocircuit system of claim 1, wherein the at least one effector module further comprises a targeting and/or penetrating peptide selected from those listed in Tables 8 or 10.

9. The biocircuit system of claim 1, wherein the at least one effector module further comprises a linker selected from those listed in Tables 9, 11 or 12.

10-20. (canceled)

21. The biocircuit system of claim 1, wherein the stimulus is selected from the group consisting of a ligand, an externally added or endogenous metabolite, the presence or absence of a defined ligand, pH, temperature, light, ionic strength, cellular location, subject site, microenvironment, the presence or concentration of one or more cations or one or more anions, an effector module, a concentration gradient of ions, biomolecules or the like, and the presence or concentration of one or more metal ions.

22. The biocircuit system of claim 21, wherein the stimulus is a ligand and said ligand is selected from the group consisting of any of the ligands of Tables 1-3.

23. The biocircuit system of claim 22, wherein the ligand is selected from the group consisting of a protein, peptide, nucleic acid, lipid, lipid derivative, sterol, steroid, metabolite, metabolite derivative, and small molecule.

24. (canceled)

25. The biocircuit system of claim 23, wherein the ligand is a small molecule.

26. The biocircuit system of claim 25, wherein the small molecule is cell permeable.

27-35. (canceled)

36. A polynucleotide comprising: (a) a first region encoding a stimulus response element (SRE) selected from the group consisting of a peptide, a peptide complex, a peptide-protein complex, a protein, a fusion protein, a protein complex, and a protein-protein complex, said SRE comprising; (i) one or more regions derived from a payload, said payload having a sequence selected from the group consisting of SEQ ID NO: 102451-204900; (ii) one or more regions derived from a Target of a ligand binding partner pair listed in Table 2, Table 3; or (iii) an SRE listed in Table 4, and (b) a second region encoding one or more payload constructs and wherein said a payload construct comprises (i) a payload, said payload having a sequence selected from the group consisting of SEQ ID NO: 102451-204900 or functional fragment thereof, or (ii) an antibody listed in Table 5 or a functional fragment thereof; and (c) optionally, a third region encoding at least one member of the group consisting of a linker, modifier, signal sequence; binding domain, regulatory motif, dimerization domain, and cleavage site.

37. The polynucleotide of claim 36, wherein at least one region of said polynucleotide is codon optimized.

38. The polynucleotide of claim 37, wherein the region encoding said first component of the effector module is codon optimized.

39. The polynucleotide of claim 37, wherein the region encoding said second component of the effector module is codon optimized.

40. The polynucleotide of claim 36 which is a DNA molecule.

41. The polynucleotide of claim 40 having a third region selected from the group consisting of the DNA sequence of any of the microRNAs listed in Table 13, the reverse complement of the microRNAs listed in Table 13, and the microRNA anti-seed region of any of the microRNAs listed in Table 13.

42. The polynucleotide of claim 36 which is a messenger RNA (mRNA).

43. The polynucleotide of claim 42, wherein the mRNA contains region selected from the group consisting of the sequence of the reverse complement of the microRNAs listed in Table 13, and the microRNA anti-seed region of any of the microRNAs listed in Table 13.

44-46. (canceled)

47. An expression vector comprising the polynucleotide of claim 36.

48-52. (canceled)

53. A regulatable human T cell or T cell population engineered to express an effector module.

54. The regulatable human T cell or T cell population of claim 53, wherein the effector module encodes a chimeric antigen receptor (CAR).

55. The regulatable human T cell or T cell population of claim 53, wherein the T cells are primary T cells.

56. The regulatable human T cell or T cell population of claim 53, 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 lymphocytes and combinations thereof.

57. The regulatable human T cell or T cell population of claim 53, wherein the T cell population is obtained from a subject suffering from, being treated for, diagnosed with, at risk of developing, or suspected of having a disorder selected from the group consisting of an immune disorder (including autoimmune disorders), a hypoproliferative condition including cancer, an infectious disease, a non-infectious disease, and graft vs. host disease.

58-65. (canceled)

66. A method of treating a patient in need, the method comprising administration of the regulatable human T cell or T cell population of claim 53.

67. The method of claim 66, wherein the treatment comprises adoptive immunotherapy.

68. The method of claim 66 further comprising expanding the regulatable human T cell or T cell population prior to the step of administration.

69-71. (canceled)

Description

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