JP-2022533092-A5 -

Dates

Publication Date

20230519

Application Date

20200512

Description

In some embodiments, the polynucleotide is one of the polynucleotides described in the preceding embodiments. In some embodiments, the CAAR is one of the CAARs described in the previous embodiments. In some embodiments, the autoantibody-mediated NMJ disease is myasthenia gravis (MG). In some other embodiments, the subject is human. In some embodiments, the genetically modified cell is a T cell. In some embodiments, the modified cell targets a B cell. [Invention 1001] A polynucleotide encoding a chimeric autoantibody receptor (CAAR), wherein the CAAR comprises an extracellular domain containing an acetylcholine receptor (AChR) autoantigen or a fragment thereof, and optionally a transmembrane domain, an intracellular domain of a costimulatory molecule, and/or a signaling domain. [Invention 1002] The polynucleotide of the present invention 1001, wherein the AChR autoantigen or a fragment thereof is derived from the α subunit of AChR. [Invention 1003] The polynucleotide of the present invention 1001, wherein the AChR autoantigen or a fragment thereof is encoded by a nucleic acid sequence comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO: 3, 5, 7, 22, 23, 29, 33, and 42. [Invention 1004] The polynucleotide of the present invention 1001, wherein the AChR autoantigen or a fragment thereof is encoded by a nucleic acid sequence comprising a nucleic acid sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with a nucleic acid sequence selected from the group consisting of SEQ ID NO: 3, 5, 7, 22, 23, 29, 33, and 42. [Invention 1005] The polynucleotide of the present invention 1001, wherein the AChR autoantigen or a fragment thereof comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 13, 15, 17, 26, 27, 31, 35, and 44. [Invention 1006] The polynucleotide of the present invention 1001, wherein the AChR autoantigen or a fragment thereof contains an amino acid sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 13, 15, 17, 26, 27, 31, 35, and 44. [Invention 1007] A polynucleotide according to any of invention 1001 to 1006, wherein the transmembrane domain includes a CD8α transmembrane domain. [Invention 1008] The polynucleotide of the present invention 1007, wherein the CD8α transmembrane domain is encoded by a nucleic acid sequence containing SEQ ID NO: 9. [Invention 1009] The polynucleotide of the present invention 1007, wherein the CD8α transmembrane domain contains the amino acid sequence of SEQ ID NO: 19. [Invention 1010] A polynucleotide according to any of the invention 1001 to 1009, wherein the intracellular domain of the co-stimulatory molecule includes a 4-1BB intracellular domain. [Invention 1011] The polynucleotide of the present invention 1010, wherein the 4-1BB intracellular domain is encoded by a nucleic acid sequence containing SEQ ID NO: 10 or 16. [Invention 1012] The 4-1BB intracellular domain contains the amino acid sequence of SEQ ID NO: 20, a polynucleotide of the present invention 1010. [Invention 1013] A polynucleotide according to any one of the invention 1001 to 1012, wherein the signal transduction domain includes a CD3ζ signal transduction domain. [Invention 1014] The polynucleotide of the present invention 1013, wherein the CD3ζ signaling domain is encoded by a nucleic acid sequence containing SEQ ID NO: 24 or SEQ ID NO: 53. [Invention 1015] The polynucleotide of the present invention 1013, wherein the CD3ζ signaling domain contains the amino acid sequence of SEQ ID NO: 38. [Invention 1016] The polynucleotide according to any of the inventions 1001 to 1015, wherein the CAAR is encoded by a nucleic acid sequence comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1, 6, 21, 28, 32, 36, 41, 45, 47, 48, 49, 50, 51, and 52. [Invention 1017] The CAAR is a polynucleotide according to any one of the inventions 1001 to 1015, wherein the CAAR contains an amino acid sequence selected from the group consisting of SEQ ID NO: 11, 25, 30, 34, 39, 43, and 46. [Invention 1018] The CAAR is a polynucleotide according to any one of the present invention 1001 to 1017, further comprising a hinge. [Invention 1019] The polynucleotide of the present invention 1018, wherein the hinge is encoded by a nucleic acid sequence con