TGFBETA SIGNAL CONVERTOR
The present disclosure provides improved compositions for adoptive T cell therapies for treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith.
1 .- 135 . (canceled)
136 . A polynucleotide encoding a signal converter comprising:
(a) a TGFβR2 polypeptide comprising:
(i) an extracellular TGFβ1-binding domain of TGFβR2;
(ii) an IL-12Rβ2 transmembrane domain; and
(iii) an IL-12Rβ2 intracellular signaling domain; and
(b) a TGFβR1 polypeptide comprising:
(i) an extracellular TGFβ1-binding domain of TGFβR1;
(ii) an IL-12Rβ1 transmembrane domain; and
(iii) an IL-12Rβ1 intracellular signaling domain.
137 . The polynucleotide of claim 136 , further encoding an engineered antigen receptor.
138 . The polynucleotide of claim 136 , wherein the IL-12Rβ2 transmembrane domain comprises the transmembrane domain within SEQ ID NO: 4.
139 . The polynucleotide of claim 136 , wherein the IL-12Rβ2 intracellular signaling domain comprises the intracellular signaling domain within SEQ ID NO: 4.
140 . The polynucleotide of claim 136 , wherein the IL-12Rβ1 transmembrane domain comprises the transmembrane domain within SEQ ID NO: 3.
141 . The polynucleotide of claim 136 , wherein the IL-12Rβ1 intracellular signaling domain comprises the intracellular signaling domain within SEQ ID NO: 3.
142 . A lentiviral vector comprising the polynucleotide of claim 136 .
143 . A cell comprising the polynucleotide of claim 136 .
144 . The cell of claim 139 , wherein the cell is:
(a) a hematopoietic cell;
(b) a T cell;
(c) a CD3+, CD4+, and/or CD8+ cell;
(d) an immune effector cell;
(e) a cytotoxic T lymphocyte (CTL), a tumor infiltrating lymphocyte (TIL), or a helper T cell; or
(f) a natural killer (NK) cell or natural killer T (NKT) cell.
145 . The cell of claim 144 , wherein the cell is a T cell.
146 . The cell of claim 144 , wherein the cell is an immune effector cell.
147 . The cell of claim 144 , wherein the cell is a cytotoxic T lymphocyte (CTL).
148 . A composition comprising the cell of claim 144 .
149 . A polynucleotide encoding a signal converter comprising:
(a) a TGFβR2 polypeptide comprising:
(i) an extracellular TGFβ1-binding domain of TGFβ2;
(ii) an IL-12Rβ1 transmembrane domain; and
(iii) an IL-12Rβ1 intracellular signaling domain; and
(b) a TGFβR1 polypeptide comprising:
(i) an extracellular TGFβ1-binding domain of TGFβR1;
(ii) an IL-12Rβ2 transmembrane domain; and
(iii) an IL-12Rβ2 intracellular signaling domain.
150 . The polynucleotide of claim 149 , further encoding an engineered antigen receptor.
151 . The polynucleotide of claim 149 , wherein the IL-12Rβ2 transmembrane domain comprises the transmembrane domain within SEQ ID NO: 4.
152 . The polynucleotide of claim 149 , wherein the IL-12Rβ2 intracellular signaling domain comprises the intracellular signaling domain within SEQ ID NO: 4.
153 . The polynucleotide of claim 149 , wherein the IL-12Rβ1 transmembrane domain comprises the transmembrane domain within SEQ ID NO: 3.
154 . The polynucleotide of claim 149 , wherein the IL-12Rβ1 intracellular signaling domain comprises the intracellular signaling domain within SEQ ID NO: 3.
155 . A lentiviral vector comprising the polynucleotide of claim 149 .
156 . A cell comprising the polynucleotide of claim 149 .
157 . The cell of claim 156 , wherein the cell is:
(a) a hematopoietic cell;
(b) a T cell;
(c) a CD3+, CD4+, and/or CD8+ cell;
(d) an immune effector cell;
(e) a cytotoxic T lymphocyte (CTL), a tumor infiltrating lymphocyte (TIL), or a helper T cell; or
(f) a natural killer (NK) cell or natural killer T (NKT) cell.
158 . The cell of claim 157 , wherein the cell is a T cell.
159 . The cell of claim 157 , wherein the cell is an immune effector cell.
160 . The cell of claim 157 , wherein the cell is a cytotoxic T lymphocyte (CTL).
161 . A composition comprising the cell of claim 157 .