Methods and compositions for treating autoimmune disease
OwnerJeffrey Greve, Lih-Yun Hsuinventors
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Abstract
This disclosure provides for chimeric receptor polypeptides where upon binding of a first antigen to the antigen binding domain triggers a proteolytic cleavage and upregulation of a chimeric antigen receptor, wherein the chimeric antigen receptor binds to a second antigen. The first and second antigens are present on a population of B cells known as Autoimmune- or Age-related B cells or CD11c+T-bet+ B cells. The present disclosure includes methods and compositions for reducing or eliminating ABCs through the binding of the chimeric antigen receptor, and thus controlling or eliminating autoimmune disease.
Claims58
A method for modulating signaling in a cell, said method comprising transforming the cell with
- a nucleic acid sequence encoding a chimeric receptor polypeptide, wherein the chimeric receptor polypeptide comprises an extracellular domain, a transmembrane domain, and an intracellular domain, wherein the extracellular domain comprises a first antigen binding domain capable of binding to a first antigen on a CD11c+Tbet+ B cell, and wherein the intracellular domain comprises a transcriptional control unit and a proteolytic site;
- and
- a nucleic acid sequence encoding a chimeric antigen receptor polypeptide, wherein the chimeric antigen receptor comprises a second antigen binding domain capable of binding to a second antigen present on the CD11c+T-bet+ B cell, wherein the nucleic acid sequence encoding the chimeric antigen receptor polypeptide is operably linked to a transcriptional control element to which the transcriptional control unit can bind;
- and
- contacting the cell with a CD11c+T-bet+ B cell expressing the first antigen on its surface, wherein the contacting induces cleavage at the proteolytic site, thereby releasing the intracellular domain;
- and
- wherein the transcriptional control unit activates the transcriptional control element operably linked to the nucleic acid sequence encoding the chimeric antigen receptor polypeptide, thereby activating expression of the chimeric antigen receptor polypeptide.
A chimeric receptor polypeptide comprising an extracellular domain, a transmembrane domain, and an intracellular domain, wherein the extracellular domain comprises an antigen binding domain that binds antigens present on CD11c+Tbet+B cells, wherein the intracellular domain comprises a transcriptional control unit and a proteolytic site, and wherein the transcriptional control unit comprises a domain capable of activating a transcriptional control element.
A chimeric antigen receptor polypeptide comprising (i) a single-chain variable fragment (scFv) having binding specificity for a CD11c+T-Bet+ B cell antigen, (ii) a transmembrane domain, (iii) at least one co-stimulatory domain, and (iv) an activating domain.
Dependencies are inferred from the claim text.