NON-NATURAL MIC PROTEINS

摘要

This invention describes soluble, monovalent, non-natural protein molecules that can activate NK cells and certain T-cells to attack specific cellular target cells by attaching the NKG2D-binding portions of monovalent MICA or MICB protein, i.e. their α1-α2 platform domain, to the intended target cell specifically. The α1-α2 domain is contiguous with a heterologous α3 domain that has been genetically modified to bind directly or indirectly to the extracellular aspect of the target cell, thereby serving as the targeting domain. The genetic modification to create a non-natural and non-terminal targeting motif within the α3 domain can include a portion of an antibody, another protein molecule or portion thereof, a peptide, or a non-natural, modified α3 domain of a MIC protein.

主权项

1. A method of treating a mammal suspected of having a malignancy or viral infection comprising,
administering an effective amount of a non-natural, monomeric, soluble, mammalian MHC class I chain-related (MIC) molecule to said mammal, wherein the MIC molecule comprises, an α1-α2 platform domain attached to a targeting motif, wherein the α1-α2 platform domain is at least 80% identical to a native α1-α2 platform domain of a MIC protein, and wherein the α1-α2 platform domain binds an NKG2D receptor, and wherein the targeting motif comprises a MIC α3 domain and one or more heterologous peptides, wherein the heterologous peptide or peptides are inserted into the MIC α3 domain within one or more sites in a solvent-exposed loop at a non-carboxy-terminal site, wherein the heterologous peptide or peptides direct binding of the targeting motif to the target molecule on a target cell, thereby delivering the attached α1-α2 platform domain to the target cell, and wherein the target cell is a malignant cell or a virus-infected cell.