ANTIGEN-SPECIFIC T CELL REDIRECTORS

摘要

This disclosure describes compositions and methods for selectively recruiting antigen-specific T cells and re-direct them to kill targeted cells, particularly tumor cells. This approach permits selective engagement of specific effector cell populations and, by using nanoparticles, overcomes the geometric limitations associated with previous approaches.

主权项

1. A nanoparticle which comprises on its surface:
(A) an antibody that specifically binds to a target cell antigen or epitope thereof; and (B) a moiety that binds to an antigen-specific T cell, wherein the moiety is selected from the group consisting of:
(a) an anti-clonotypic TCR-specific antibody;(b) an MHC class I-immunoglobulin complex comprising:
(i) an immunoglobulin molecule comprising two immunoglobulin heavy chains and two immunoglobulin light chains; and(ii) two MHC class I molecules, each comprising an α chain and a β2 microglobulin, wherein each α chain comprises α1, α2, and α3 domains and wherein the α1 and α2 domains of each α chain form a peptide binding cleft, wherein the N terminus of each immunoglobulin heavy chain is linked to the N terminus of each α3 domain, and wherein the peptide binding cleft comprises a peptide antigen recognized by the antigen-specific T cell;(c) a monomeric MHC class I molecule comprising the peptide antigen recognized by the antigen-specific T cell;(d) a multimeric MHC class I molecule comprising the peptide antigen recognized by the antigen-specific T cell;(e) a monomeric MHC class II molecule comprising the peptide antigen recognized by the antigen-specific T cell;(f) a multimeric MHC class II molecule comprising the peptide antigen recognized by the antigen-specific T cell; and(g) an MHC class II-immunoglobulin complex comprising four fusion proteins, wherein:
(i) two first fusion proteins comprise (1) an immunoglobulin heavy chain, and (2) an extracellular domain of an MHC class IIβ chain; and(ii) two second fusion proteins comprise (1) an immunoglobulin light chain and (2) an extracellular domain of an MHC class II α chain, wherein the fusion proteins associate to form the molecular complex, wherein the MHC class II-immunoglobulin complex comprises two ligand binding sites, each ligand binding site formed by the extracellular domains of the α and β chains, and wherein the ligand binding sites comprise the peptide antigen recognized by the antigen-specific T cell.