Dimerizing agent regulated immunoreceptor complexes comprising interleukin receptor signaling domains
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. A fusion polypeptide comprising:
(a) a first polypeptide comprising, in the following order:
(i) a first extracellular multimerization domain;
(ii) a first transmembrane domain; and
(iii) an IL-18R1 immune receptor intracellular signaling domain;
(b) a polypeptide cleavage signal; and
(c) a second polypeptide comprising, in the following order:
(i) a second extracellular multimerization domain;
(ii) a second transmembrane domain; and
(iii) an IL-18RAP immune receptor intracellular signaling domain;
wherein the first extracellular multimerization domain comprises an FKBP12-rapamycin binding (FRB) polypeptide and the second extracellular multimerization domain comprises an FK506 binding protein (FKBP12) polypeptide; or
wherein the first extracellular multimerization domain comprises an FKBP12 polypeptide and the second extracellular multimerization domain comprises an FRB polypeptide; and
wherein the fusion polypeptide has a sequence having at least 95% identity to SEQ ID NO: 5.
2. The fusion polypeptide of claim 1 , wherein the first multimerization domain and the second multimerization domain associate with a bridging factor, wherein the bridging factor is rapamycin or a rapalog thereof.
3. The fusion polypeptide of claim 1 , wherein the FRB polypeptide is FRB T2098L or FRB T89L.
4. The fusion polypeptide of claim 1 , wherein:
a) the first transmembrane domain and the second transmembrane domain are independently selected from the group consisting of: a CD4 transmembrane domain, a CD8α transmembrane domain, an amnionless (AMN) transmembrane domain, a CD28 transmembrane domain, a CD154 transmembrane domain, and a CD71 transmembrane domain; or
b) the first transmembrane domain and the second transmembrane domain are independently selected from the group consisting of: a CD4 transmembrane domain and a CD8α transmembrane domain.
5. The fusion polypeptide of claim 1 , wherein the polypeptide cleavage signal is a viral self-cleaving polypeptide selected from the group consisting of: a foot-and-mouth disease virus (FMDV) (F2A) peptide, an equine rhinitis A virus (ERAV) (E2A) peptide, a Thosea asigna virus (TaV) (T2A) peptide, a porcine teschovirus-1 (PTV-1) (P2A) peptide, a Theilovirus 2A peptide, and an encephalomyocarditis virus 2A peptide.
6. The fusion polypeptide of claim 1 , wherein the first multimerization domain localizes extracellularly when the first polypeptide is expressed and the second multimerization domain localizes extracellularly when the second polypeptide is expressed.
7. A fusion polypeptide comprising the amino acid sequence of SEQ ID NO: 5.