JP-2022511974-A5 -

Dates

Publication Date

20221219

Application Date

20191212

Description

[Invention 1001]Isolated regulatory T cells (Tregs) containing a T cell receptor (TCR), wherein the TCR is(i) an alloantigen that is a human leukocyte antigen (HLA) molecule and is not encoded by a nucleotide sequence present in the genome of the Treg, or a fragment thereof,(ii) Autoantigens or fragments thereof that contribute to autoimmune disordersThe Treg that specifically binds to the Treg.[Invention 1002]Treg according to the present invention 1001, wherein the TCR specifically binds to HLA molecules.[Invention 1003]Treg according to the present invention 1002, wherein the TCR specifically binds to the hypervariable region (HVR) of the HLA molecule.[Invention 1004]Treg according to the present invention 1003, wherein the TCR specifically binds to the β-chain HVR of the HLA molecule.[Invention 1005]Treg according to Invention 1002, wherein the HLA molecule is an HLA-DR, HLA-DQ, HLA-DP, HLA-A, HLA-B, or HLA-C molecule, or a fragment thereof.[Invention 1006]Treg according to Invention 1005, wherein the HLA molecule is an HLA-DR, HLA-DQ, or HLA-DP molecule, or a fragment thereof.[Invention 1007]Treg according to Invention 1006, wherein the HLA-DR molecule is HLA-DR1, HLA-DR2, HLA-DR3, HLA-DR4, HLA-DR5, HLA-DR6, HLA-DR7, HLA-DR8, HLA-DR9, HLA-DR10, HLA-DR11, HLA-DR12, HLA-DR13, HLA-DR14, HLA-DR15, HLA-DR16, HLA-DR17, HLA-DR18, HLA-DR51, HLA-DR52, or HLA-DR53 molecule, or a fragment thereof.[Invention 1008]A Treg according to the present invention 1001, which can suppress the effector T cell (Teff) response directed to an alloantigen or autoantigen.[Invention 1009]Treg according to the present invention 1008, which can suppress the Teff proliferation response to direct allo-recognition, semi-direct allo-recognition, and/or indirect allo-recognition.[Invention 1010]A Treg according to the present invention 1008 that can activate an adenosinergic signaling pathway.[Invention 1011]A Treg according to the present invention 1001, expressing one or more markers selected from the group consisting of CD4, CD25, CD39, CD73, FOXP3, GITR, CLTA4, ICOS, GARP, LAP, PD-1, CCR6, and CXCR3.[Invention 1012]Treg according to the present invention 1002, wherein the TCR specifically binds to an HLA molecule, or a fragment thereof, which is encoded by a nucleotide sequence present in the genome of an organ or tissue donor.[Invention 1013]An isolated Treg containing a TCR, wherein the TCR is(i) an alloantigen that is an HLA molecule and is not encoded by a nucleotide sequence present in the genome of the Treg, or a fragment thereof,(ii) Autoantigens or fragments thereof that contribute to autoimmune disordersBinds specifically to;The Treg,(a) The step of bringing an immune cell population, including T cells obtained from a recipient subject, into contact with fragments of HLA molecules or autoantigens, and autoantigen-presenting cells (APCs); and(b) A step of expanding the immune cell population of step (a) for a sufficient amount of time and under conditions to form an expanded T cell line containing multiple Tregs; and optionally,(c) The step of purifying Treg cells from the immune cell population.The isolated Treg is prepared by a method including the following.[Invention 1014]The Treg of Invention 1013, wherein the immune cell population of (a) further comprises natural killer (NK) cells, and if step (c) is carried out, step (c) comprises purifying Treg and NK cells from the immune cell population, thereby creating a mixed population of Treg and NK cells.[Invention 1015]A mixed population of cells comprising Treg and NK cells according to the present invention 1001.[Invention 1016]A composition comprising Treg of the present invention 1001.[Invention 1017]A composition comprising a mixed population of cells including Treg and NK cells according to the present invention 1001.[Invention 1018]A method for suppressing an immune response in a subject, comprising the step of administering a pharmaceutical composition of the present invention 1016 or 1017 to the subject.[Invention 1019]The method of the present invention 1018, wherein the immune response is a Teff response directed to an alloantigen or autoantigen.[Invention 1020]A method for treating or preventing transplant rejection, or for treating an autoimmune disorder, comprising the step of administering a composition of the present invention 1016 or 1017 to a subject.[Invention 1021]The method of the present invention 1018, wherein the subject has an autoimmune disorder.[Invention 1022]The method of the present invention 1018, wherein the subject is a recipient of organ transplantation or tissue transplantation.[Invention 1023]The method of the present invention 1018, wherein the HLA molecule or fragment thereof to which the TCR specifically binds is encoded by a nucleotide sequence present in the genome of an organ or tissue donor.[Invention 1024]The method of the present invention 1018, further comprising reducing the dose of an immunosuppressant administered to a subject