DIMERIZING AGENT REGULATED IMMUNORECEPTOR COMPLEXES
The present disclosure provides improved compositions for adoptive T cell therapies targeting BCMA for treating, preventing, or ameliorating at least one symptom of a B cell related condition. The present disclosure also relates to adoptive T cell therapies for dual targeting of BCMA and a B cell antigen for treating, preventing, or ameliorating at least one symptom of a B cell related condition.
1 . A non-natural cell comprising:
(a) a first polypeptide comprising: an FKBP-rapamycin binding (FRB) multimerization domain polypeptide or variant thereof; a CD8α transmembrane domain or a CD4 transmembrane domain; a CD137 co-stimulatory domain; and/or a CD3 ζ primary signaling domain; and
(b) a second polypeptide comprising: a binding domain that binds to B cell maturation antigen (BCMA); an FK506 binding protein (FKBP) multimerization domain polypeptide or variant thereof; and a CD4 transmembrane domain or an amnionless (AMN) transmembrane domain;
wherein a bridging factor promotes the formation of a polypeptide complex on the non-natural cell surface with the bridging factor associated with and disposed between the multimerization domains of the first and second polypeptides.
2 . The non-natural cell of claim 1 , wherein the FKBP multimerization domain is FKBP12.
3 . The non-natural cell of claim 1 , wherein the FRB polypeptide is FRB T2098L.
4 . The non-natural cell of claim 1 , wherein the bridging factor is selected from the group consisting of: AP21967, sirolimus, everolimus, novolimus, pimecrolimus, ridaforolimus, tacrolimus, temsirolimus, umirolimus, and zotarolimus.
5 . The non-natural cell of claim 1 , wherein the first polypeptide comprises a CD8α transmembrane domain; a CD137 co-stimulatory domain; and a CD3 ζ primary signaling domain.
6 . The non-natural cell of claim 1 , wherein the second polypeptide comprises a CD4 transmembrane domain.
7 . The non-natural cell of claim 1 , wherein the second polypeptide comprises an AMN transmembrane domain.
8 . The non-natural cell of claim 1 , wherein the binding domain comprises an antibody or antigen binding fragment thereof.
9 . The non-natural cell of claim 1 , wherein the binding domain comprises an antibody or antigen binding fragment thereof selected from the group consisting of: a Camel Ig, a Llama Ig, an Alpaca Ig, Ig NAR, a Fab′ fragment, a F(ab′) 2 fragment, a bispecific Fab dimer (Fab2), a trispecific Fab trimer (Fab3), an Fv, an single chain Fv protein (“scFv”), a bis-scFv, (scFv) 2 , a minibody, a diabody, a triabody, a tetrabody, a disulfide stabilized Fv protein (“dsFv”), and a single-domain antibody (sdAb, a camelid VHH, Nanobody).
10 . The non-natural cell of claim 1 , wherein the first polypeptide and/or the second polypeptide comprises a signal peptide.
11 . The non-natural cell of claim 1 , wherein the first polypeptide comprises a CD8α signal peptide.
12 . The non-natural cell of claim 1 , wherein the second polypeptide comprises an Igκ signal peptide.
13 . The non-natural cell of claim 1 , wherein the second polypeptide comprises a hinge or spacer domain between the binding domain and the multimerization domain.
14 . The non-natural cell of claim 1 , wherein the second polypeptide comprises a CD28 hinge domain between the binding domain and the multimerization domain.
15 . A non-natural cell comprising:
(a) a first polypeptide comprising: an FKBP-rapamycin binding (FRB) multimerization domain polypeptide or variant thereof; a CD8α transmembrane domain or a CD4 transmembrane domain; a CD137 co-stimulatory domain; and/or a CD3 ζ primary signaling domain;
(b) a second polypeptide comprising: a binding domain that binds to B cell maturation antigen (BCMA); an FK506 binding protein (FKBP) multimerization domain polypeptide or variant thereof; and a CD4 transmembrane domain or an amnionless (AMN) transmembrane domain; and
(c) a third polypeptide comprising: a binding domain that binds to a B cell antigen or a plasma cell antigen; an FK506 binding protein (FKBP) multimerization domain polypeptide or variant thereof; and a CD4 transmembrane domain or an amnionless (AMN) transmembrane domain;
wherein a bridging factor promotes the formation of a polypeptide complex on the non-natural cell surface with the bridging factor associated with and disposed between the multimerization domains of the first polypeptide and the second polypeptide and the multimerization domains of the first polypeptide and the third polypeptide.
16 - 142 . (canceled)
143 . A composition comprising the non-natural cell of claim 1 .
144 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the non-natural cell of claim 1 .
145 - 149 . (canceled)
150 . A method of treating a B cell related condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the composition of claim 144 .
151 . (canceled)
152 . The method of claim 150 , wherein the B cell related condition is a B cell malignancy.
153 . The method of claim 152 , wherein the B cell malignancy is multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL).
154 - 161 . (canceled)