CHIMERIC TIM RECEPTORS AND USES THEREOF
The present disclosure relates to chimeric Tim receptors, host cells modified to include chimeric Tim receptor molecules, and methods of making and using such receptor molecules and modified cells.
1 . A chimeric engulfment receptor comprising a single chain chimeric protein, the single chain chimeric protein comprising from N-terminus to C-terminus:
(a) an extracellular domain comprising a binding domain comprising: a Tim4 IgV domain and a Tim4 mucin domain;
(b) a CD28 transmembrane domain;
(c) an intracellular signaling domain, wherein the intracellular signaling domain comprises: a CD28 signaling domain, a CD3ζ signaling domain, and a TLR2 signaling domain.
2 . The chimeric engulfment receptor of claim 23 , wherein the binding domain comprises the amino acid sequence of SEQ ID NO:2.
3 . The chimeric engulfment receptor of claim 23 , wherein the binding domain comprises the amino acid sequence of SEQ ID NO: 42.
4 . The chimeric engulfment receptor of claim 23 , wherein the CD28 transmembrane domain comprises the amino acid sequence of SEQ ID NO:7.
5 . The chimeric engulfment receptor of claim 23 , wherein the CD28 signaling domain comprises the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:26.
6 . The chimeric engulfment receptor of claim 23 , wherein the CD3ζ signaling domain comprises the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:27.
7 . The chimeric engulfment receptor of claim 23 , wherein the TLR2 signaling domain comprises the amino acid sequence of SEQ ID NO: 122.
8 . The chimeric engulfment receptor of claim 1 , wherein the chimeric engulfment receptor comprises from N-terminus to C-terminus: a Tim4 binding domain comprising the amino acid sequence of SEQ ID NO:42; a CD28 transmembrane domain comprising the amino acid sequence of SEQ ID NO:7; a CD28 signaling domain comprising the amino acid sequence of SEQ ID NO:4; a CD3ζ signaling domain comprising the amino acid sequence of SEQ ID NO:27; and a TLR2 signaling domain comprising the amino acid sequence of SEQ ID NO: 122.
9 . A polynucleotide encoding the chimeric engulfment receptor of claim 1 .
10 . A vector comprising the polynucleotide of claim 9 .
11 . The vector of claim 10 , wherein the vector is a viral vector.
12 . The vector of claim 11 , wherein the vector is a lentiviral vector.
13 . An engineered immune cell comprising the polynucleotide of claim 9 .
14 . An engineered immune cell comprising the vector of claim 10 .
15 . The engineered immune cell of claim 13 , wherein the immune cell is a T cell.
16 . The engineered immune cell of claim 14 , wherein the immune cell is a T cell.
17 . The engineered immune cell of claim 15 , wherein the T cell is a CD4+ T cell, a CD8+ T cell, or a CD4+/CD8+ T cell.
18 . The engineered immune cell of claim 16 , wherein the T cell is a CD4+ T cell, a CD8+ T cell, or a CD4+/CD8+ T cell.
19 . The engineered immune cell of claim 15 , wherein the T cell is a human T cell.
20 . The engineered immune cell of claim 16 , wherein the T cell is a human T cell.
21 . A pharmaceutical composition comprising the engineered immune cell of claim 15 and a pharmaceutically acceptable excipient.
22 . A pharmaceutical composition comprising the engineered immune cell of claim 16 and a pharmaceutically acceptable excipient.