Engineered cells and implantable elements for treatment of disease

{
  "publication_number": "US2026102435A1",
  "country": "US",
  "kind": "A1",
  "title": "Engineered cells and implantable elements for treatment of disease",
  "abstract": "Described herein are engineered mammalian cells comprising a reduction in the level or function of one or more of a major histocompatibility complex (MHC) class I protein complex component, optionally, a MHC class II protein complex component and/or CIITA, as well as one of an inflammatory cytokine and a pro-fibrotic factor, and methods of making and using the same.",
  "claims": [
    "1. An implantable element comprising an engineered mammalian cell comprising: (i) a reduction in the level or function of one or more of: (a) a major histocompatibility complex (MHC) class I protein complex; (b) a MHC class II protein complex; (c) class II major histocompatibility complex transactivator (CIITA); and (ii) a reduction in the level or function of one or more of: (d) an inflammatory cytokine; and (e) a pro-fibrotic factor, wherein the engineered mammalian cell comprises an exogenous nucleic acid encoding a therapeutic agent; and the implantable element comprises a polymer and a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: A is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - O -, - C(O)O -, - C(O) -, - OC(O) -, - N(R C) -, - N(R C)C(O) -, - C(O)N(R C) -, - N(R C)C(O)(C 1 -C 6 -alkylene)-, - N(R C)C(O)(C 1 -C 6 -alkenylene)-, - N(R C)N(R D) -, - NCN -, - C(═N(R C)(R D))O -, - S -, - S(O) x -, - OS(O) x -, - N(R C)S(O) x -, - S(O) x N(R C) -, - P(R F) y -, - Si(OR A) 2 -, - Si(R G)(OR A) -, - B(OR A) -, or a metal, each of which is optionally linked to an attachment group (e.g., an attachment group described herein) and is optionally substituted by one or more R 1; each of L 1 and L 3 is independently a bond, alkyl, or heteroalkyl, wherein each alkyl and heteroalkyl is optionally substituted by one or more R 2; L 2 is a bond; M is absent, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted by one or more R 3; P is absent, cycloalkyl, heterocyclyl, or heteroaryl, each of which is optionally substituted by one or more R 4; Z is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, - OR A, - C(O)R A, - C(O)OR A, - C(O)N(R C)(R D), - N(R C)CFv A, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 5; each R A, R B, R C, R D, R E, R F, and R G is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, azido, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 6; or R C and R D, taken together with the nitrogen atom to which they are attached, form a ring (e.g., a 5-7 membered ring), optionally substituted with one or more R 6; each R 1, R 2, R 3, R 4, R 5, and R 6 is independently alkyl, alkenyl, alkynyl, heteroalkyl halogen, cyano, azido, oxo, - OR A1, - C(O)OR A1, - C(O)R B1, - OC(O)R B1, - N(R C1)(R D1), - N(R C1)C(O)R B1, - C(O)N(R C1), SR E1, S(O) x R E1, - OS(O) x R E1, - N(R C1)S(O) x R E1, - S(O) x N(R C1)(R D1), - P(R F1) y, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted by one or more R 7; each R A1, R B1, R C1, R D1, R E1 and R F1 is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted by one or more R 7; each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl or heterocyclyl; x is 1 or 2; and y is 2, 3, or 4. 2. The implantable element of claim 1, comprising (i)(a). 3. The implantable element of any one of claims 1-2, comprising (i)(b). 4. The implantable element of any one of claims 1-3, comprising (i)(c). 5. The implantable element of any one of claims 1-4, comprising (ii)(d). 6. The implantable element of any one of claims 1-5, comprising (ii)(e). 7. The implantable element of any one of claims 1-6, comprising (i)(a) and one of (i)d) and (ii)(c). 8. The implantable element of any one of claims 1-7, comprising (i)(a) and both of (ii)(d) and (ii)(c). 9. The implantable element of any one of claims 1-8, comprising (i)(b) and one of (ii)(d) and (ii)(e). 10. The implantable element of any one of claims 1-9, comprising (i)(b) and both of (ii)(d) and (ii)(e). 11. The implantable element of any one of claims 1-10, comprising (i)(c) and one of (ii)(d) and (ii)(e). 12. The implantable element of any one of claims 1-11, comprising (i)(c) and both of (ii)(d) and (ii)(e). 13. The implantable element of any one of claims 1-12, wherein the reduction in the level or function in (i)(a) occurs in one or more of the MHC class I protein components selected from: (a-i) human leukocyte antigen (HLA) A; (a-ii) HLA-B; (a-iii) HLA-C; and (a-iv) beta-2-microglobulin (beta-2M). 14. The implantable element of claim 13, comprising (a-i). 15. The implantable element of any one of claims 13-14, comprising (a-ii). 16. The implantable element of any one of claims 13-15, comprising (a-iii). 17. The implantable element of any one of claims 13-16, comprising (a-iv). 18. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a mutation resulting in the reduction of the level of a component of the MHC class I complex, e.g., as compared to a reference standard. 19. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a lower-functioning or non-functioning variant of a component of the NHC class I complex, e.g., as compared to a reference standard. 20. The implantable element of any one of the preceding claims, wherein a level of a component of the MHC class I complex is silenced or knocked down, e.g., as compared to a reference standard. 21. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a reduction in the level of a MHC class I component by about 0.05%, 0.1%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, e.g., as compared to an engineered mammalian cell that is substantially identical to or identical to the engineered mammalian cell except that it does not comprise a reduction in the level of an MHC class I component, e.g., as compared to a reference standard. 22. The implantable element of any one of the preceding claims, wherein the reduction in the level or function in (i)(b) occurs in one or more of the MHC class I protein components selected from: (b-i) human leukocyte antigen (HLA) DP; (b-ii) HLA-DM; (b-iii) HLA-DOA; (b-iv) HLA-DOB; (b-v) HLA-DQ; and (b-vi) HLA-DR. 23. The implantable element of claim 22, wherein the MHC class II complex comprises (b-i). 24. The implantable element of any one of claims 22-23, wherein the MHC class II complex comprises (b-ii). 25. The implantable element of any one of claims 22-24, wherein the MHC class II complex comprises (b-iii). 26. The implantable element of any one of claims 22-25, wherein the MHC class II complex comprises (b-iv). 27. The implantable element of any one of claims 22-26, wherein the MHC class II complex comprises (b-v). 28. The implantable element of any one of claims 22-27, wherein the MHC class II complex comprises (b-vi). 29. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a mutation resulting in the reduction of a level of a component of the MHC class II complex, e.g., as compared to a reference standard. 30. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a lower-functioning or non-functioning variant of a component of the MHC class II component, e.g., as compared to a reference standard. 31. The implantable element of any one of the preceding claims, wherein expression of a component of the MHC class II complex is silenced or knocked down, e.g., as compared to a reference standard. 32. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a reduction in the level of a MHC class II component by about 0.05%, 0.1%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, e.g., as compared to the engineered mammalian cell not comprising a reduction in the level of an MHC class II component, e.g., as compared to a reference standard. 33. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a reduction in the function or expression of a class II major histocompatibility complex transactivator (CIITA). 34. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a mutation resulting in the reduction of expression of a component of the CIITA, e.g., as compared to a reference standard. 35. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a lower-functioning or non-functioning variant of a component of the CHITA, e.g., as compared to a reference standard. 36. The implantable element of any one of the preceding claims, wherein expression of the CIITA is silenced or knocked down, e.g., as compared to a reference standard. 37. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a reduction in the level of the CIITA by about 0.05%, 0.1%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or mere, e.g., as compared to an engineered mammalian cell that is substantially identical to or identical to the engineered mammalian cell except that it does not comprise a reduction in the level of CIITA, e.g., as compared to a reference standard. 38. The implantable element of any one of the preceding claims, wherein the inflammatory cytokine is selected from: (d-i) IL-6 (d-ii) IL-8; and (d-iii) MCP-1. 39. The implantable element of claim 38, wherein the inflammatory cytokine is (d-i). 41. The implantable element of any one of claims 38-39, wherein the inflammatory cytokine is (d-ii). 42. The implantable element of any one of claims 38-40, wherein the inflammatory cytokine is (d-ii). 43. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a mutation resulting in the reduction of expression of an inflammatory cytokine, e.g., as compared to a reference standard. 44. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a lower-functioning or non-functioning variant of an inflammatory cytokine, e.g., as compared to a reference standard. 45. The implantable element of any one of the preceding claims, wherein expression of an inflammatory cytokine is silenced or knocked down, e.g., as compared to a reference standard. 46. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a reduction in the level of an inflammatory cytokine by about 0.05%, 0.1%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, e.g., as compared to an engineered mammalian cell that is substantially identical to or identical to the engineered mammalian cell except that it does not comprise a reduction in the level of the inflammatory cytokine, e.g., as compared to a reference standard. 47. The implantable element of any one of the preceding claims, wherein the pro-fibrotic factor is selected from: (e-i) FGF-2; (e-ii) PDGF; and (e-iii) VEGFA. 48. The implantable element of claim 47, wherein the pro-fibrotic factor is (e-i). 49. The implantable element of any one of claims 47-48, wherein the pro-fibrotic factor is (e-ii). 50. The implantable element of any one of claims 47-49, wherein the pro-fibrotic factor is (e-iii). 51. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a mutation resulting in the reduction of expression of the pro-fibrotic factor, e.g., as compared to a reference standard. 52. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a lower-functioning or non-functioning variant of the pro-fibrotic factor e.g., as compared to a reference standard. 53. The implantable element of any one of the preceding claims, wherein expression of the pro-fibrotic factor is silenced or knocked down, e.g., as compared to a reference standard. 54. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a reduction in the level of a pro-fibrotic factor by about 0.05%, 0.1% 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, e.g., as compared to an engineered mammalian cell that is substantially identical to or identical to the engineered mammalian cell except that it does not comprise a reduction in the level of the pro-fibrotic factor, e.g., as compared to a reference standard. 55. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell is a human cell. 56. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises (n) an embryonic stem cell (ESC) or a cell derived therefrom or (b) an induced pluripotent stem cell (iPSC) or a cell derived therefrom. 57. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises a retinal pigment epithelial (RPE) cell, a CCD-33Lu cell, a MRC-5 cell, a MRC-9 cell, a MCF10a cell, or a cell derived from any of the preceding cells. 58. The implantable element of any one of the preceding claims, wherein the engineered mammalian cell comprises an RPE cell (e.g., an ARPE-19 cell). 59. The implantable element of any one of the preceding claims, wherein the exogenous nucleotide sequence is extrachromosomal. 60. The implantable element of any one of the preceding claims, wherein the exogenous nucleotide sequence is inserted into at least one location in the genome of the mammalian cell. 61. The implantable element of any one of the preceding claims, wherein the polymer comprises a polymer selected from alginate, hyaluronate, and chitosan. 62. The implantable element of any claim 61, wherein the polymer comprises alginate. 63. The implantable element of claim 62, wherein the alginate is a high guluronic acid (G) alginate or a high mannuronic acid (M) alginate. 64. The implantable element of any one of the preceding claims, wherein the polymer composition comprises at least one polymer covalently modified with a peptide. 65. The implantable element of claim 64, wherein the peptide comprises, consists essentially of or consists of GRGDSP, GGRGDSP or GGGRGDSP. 65. The implantable element of any one of claims the preceding claims, wherein the cell-containing compartment is surrounded by a barrier compartment comprising an alginate hydrogel and optionally a compound of Formula (I) (e.g., a compound of Formula (I) described herein) disposed on the outer surface of the barrier compartment. 66. The implantable element of any one of claims the preceding claims, wherein the polymer composition comprises an alginate covalently modified with a peptide, wherein the peptide consists essentially of or consists of GRGDSP or GGRGDSP, and wherein the barrier compartment comprises an alginate chemically modified with or a pharmaceutically acceptable salt thereof. 67. The implantable element of any one of the preceding claims, wherein the implantable element is spherical. 68. The implantable element of any one of the preceding claims, wherein the implantable element comprises a two-compartment hydrogel capsule. 69. The implantable element of any one of the preceding claims, wherein the implantable element is spherical with a diameter of about 0.75 mm to about 2 mm. 70. The implantable element of any one of the preceding claims, wherein the therapeutic agent is a protein, e.g., a hormone, a blood clotting factor, an antibody, or an enzyme. 71. An implantable element comprising: (i) an engineered ARPE cell capable of reducing the expression of beta-2M or CIITA and one of: (a) an inflammatory cytokine selected from IL-16, IL-8, and MCP-1; and (b) a pro-fibrotic factor selected from FGF-2, PDGF, and VEGFA; (ii) a polymer composition comprising an alginate covalently modified with one or more of: (c) a compound of Formula (I) (e.g., as described herein); and (d) a peptide. 72. An implantable element comprising: (i) an engineered ARPE cell capable of reducing the expression of beta-2M or CIITA and one of: (a) an inflammatory cytokine selected from IL-16, IL-8, and MCP-1; and (b) a pro-fibrotic factor selected from FGF-2, PDGF, and VEGFA; (ii) a polymer composition comprising an alginate covalently modified with one or more of: or a pharmaceutically acceptable salt thereof; and (d) a peptide comprising or consisting of GRGDSP or GGRGDSP. 73. The implantable element of any one of the preceding claims, formulated for implantation into a subject (e.g., into the intraperitoneal (IP) space, the peritoneal cavity, the omentum, the lesser sac, the subcutaneous fat). 74. The implantable element of claim 73, formulated for implantation into the IP space of a subject. 75. A preparation of implantable elements, wherein each implantable element in the preparation is an implantable element of arty one of claims 1-74. 76. A composition for use in treating a disease or disorder in a subject comprising an implantable element of any one of claims 1-74 or the preparation of claim 75, thereby treating the disease or disorder in the subject. 77. The composition for use of claim 76, wherein the disease or disorder is a lysosomal storage disease or a metabolic disorder. 78. The composition for use of any one of claims 76-77, wherein the subject is a human."
  ],
  "cpc": [
    "A61K 35/30",
    "A61K 38/22",
    "A61K 38/43",
    "A61K 47/36",
    "A61K 9/4816",
    "A61K 9/4833",
    "C07K 16/00",
    "C12N 2510/00",
    "C12N 5/0606",
    "C12N 5/0621",
    "C12N 5/0696",
    "C12N 5/10"
  ],
  "filing_date": "2023-10-11",
  "publication_date": "2026-04-16",
  "application_number": "US-202319120515-A"
}