REGULATABLE CHIMERIC ANTIGEN RECEPTOR

摘要

Compositions and methods relating to regulatable chimeric antigen receptors (RCARs), where the intracellular signaling or proliferation of the RCAR can be controlled to optimize the use of an RCAR-expressing cell to provide an immune response, are provided. For example, a RCAR can comprise a dimerization switch that, upon the presence of a dimerization molecule, can couple an intracellular signaling domain to an extracellular recognition element, e.g., an antigen binding domain, an inhibitory counter ligand binding domain, or costimulatory ECD domain. An RCAR can be engineered to include an appropriate antigen binding domain that is specific to a desired antigen target and used in the treatment of a disease.

主权项

1. A regulatable chimeric antigen receptor (RCAR), wherein the RCAR comprises:
a) an intracellular signaling member comprising:
an intracellular signaling domain domain, anda first switch domain; b) an antigen binding member comprising:
an antigen binding domain, anda second switch domain; and c) a transmembrane domain,wherein,
(i) the antigen binding member comprises more than one intracellular signaling domains; (ii) the first and second switch domains comprise a FKBP-FRB based switch, which comprises a switch domain comprising a FRB binding fragment or analog of FKBP and a switch domain comprising an FKBP binding fragment or analog of FRB, and the FKBP binding fragment or analog of FRB comprises one or more mutations; (iii) the RCAR comprises four intracellular signaling domain wherein,
(A) one of the first, second, third and fourth intracellular signaling domain is a primary intracellular signaling domain selected from the list in Table 1 and the other three are costimulatory signaling domains selected from the list in Table 2, or(B) two of the first, second, third, and fourth intracellular signaling domains are primary intracellular signaling domains selected from the list in Table 1, and the other two are costimulatory domain selected from the list in Table 2; (iv) the antigen binding domain does not comprise a transmembrane domain or membrane anchoring domain; (v) the RCAR further comprises c) an auxiliary antigen binding member comprising:
an antigen binding domain that binds a second antigen; anda transmembrane domain or membrane anchoring domain; (vi) the RCAR further comprises an inhibitory counter ligand binding member comprising,
an inhibitory counter ligand binding domain from Table 4, anda transmembrane domain or membrane anchoring domain; (vii) the RCAR further comprises an inhibitory CAR (iCAR) member, wherein the iCAR member comprises: an antigen binding domain (or other extracelluar domain) that recognizes an antigen on a non-target cell; a transmembrane domain; and, a domain from an inhibitory molecule listed in Table 12; (viii) the RCAR further comprising a second RCAR, or second antigen binding member, wherein the antigen binding domain of one of the RCARs or antigen binding members does not comprise a variable light domain and a variable heavy domain and the other is not an scFv; (ix) the antigen binding member comprises: an antigen binding domain; a transmembrane domain; a first intracellular switch domain; and a primary signaling domain, or a costimulatory signaling domain; (x) the first and second switch domains can form an extracellular dimerization switch; or (xi) the RCAR comprises an inhibitor of an inhibitory molecule chosen from Table 3.