Monomeric recombinant mhc molecules useful for manipulation of antigen-specific t-cells
AssigneesOregon Health & Science University, The United States Government as represented by the Department of Veterans Affairs
InventorsGregory G. Burrows, Arthur A. Vandenbark
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Abstract
The present invention provides, in particular embodiments, for modified recombinant T cell receptor (TCR) ligands (RTLs) comprising a MHC class I or MHC class II component. The modified RTLs have redesigned surface features that preclude or reduce aggregation, wherein the modified molecules retain the ability to bind Ag-peptides, target antigen-specific T cells, inhibit T cell proliferation in an Ag-specific manner and have utility to treat, inter alia, autoimmune disease and other conditions mediated by antigen-specific T cells in vivo.
Claims27
An isolated, modified recombinant T cell ligand (RTL) having a reduced potential for aggregation in solution, comprising:
- a major histocompatibility complex (MHC) component in the form of a single chain (sc) polypeptide comprising multiple, covalently-linked MHC domain elements selected from
- a) α1 and β1 domains of an MHC class II polypeptide, or portions thereof comprising an Ag-binding pocket/T cell receptor (TCR) interface;
- or
- b) α1 and α2 domains of an MHC class I polypeptide, or portions thereof comprising an Ag-binding pocket/TCR interface,
- wherein the MHC component is modified by one or more amino acid substitution(s), addition(s), deletion(s), or rearrangement(s) at a target site corresponding to a self-associating interface identified in a native MHC polypeptide or RTL comprising the native MHC polypeptide,
- whereby the modified RTL exhibits reduced aggregation in solution compared to aggregation exhibited by an unmodified, control RTL having the MHC component structure set forth in a) or b) but incorporating the native MHC polypeptide having an intact self-associating interface.
Dependencies are inferred from the claim text.