Recombinant T-cell receptor ligand for the treatment of cognitive and neuropsychiatric impairment induced by substance addiction

Inventors

Vandenbark, Arthur A. • Burrows, Gregory G.

Assignees

Oregon Health and Science University • US Department of Veterans Affairs

Abstract

Methods are provided for the treatment of subjects with cognitive or neuropsychiatric impairment induced by substance addiction and for increasing cognitive function in a subject with substance addiction. In some embodiments, the methods include administering to the subject a therapeutically effective amount of a major histocompatibility complex (MHC) molecule including covalently linked first, second, and third domains; wherein the first domain is an MHC class II β1 domain and the second domain is an MHC class II α1 domain; or wherein the first domain is an MHC class I α1 domain and the second domain is an MHC class I α2 domain; and wherein the third domain is covalently linked to the first domain and comprises an antigen of the central or peripheral nervous system.

Core Innovation

Methods are provided for treating subjects with cognitive or neuropsychiatric impairment induced by substance addiction and for increasing cognitive function in such subjects. The disclosed methods include administering to the subject a therapeutically effective amount of a major histocompatibility complex (MHC) molecule comprising covalently linked first, second, and third domains. The first and second domains can be either an MHC class II β1 domain covalently linked to an α1 domain or an MHC class I α1 domain covalently linked to an α2 domain. The third domain is covalently linked to the first domain and includes an antigen of the central or peripheral nervous system.

The invention addresses the significant problem that substance addiction, including to methamphetamine, opioids, and alcohol, induces cognitive and neuropsychiatric impairment, and that current treatments lack FDA-approved pharmacotherapies for methamphetamine addiction. High relapse rates of about 40-60% are observed with current treatments, and cognitive impairments and neuropsychiatric effects persisting during recovery likely contribute to these outcomes. New interventions are needed to help adults regain lost cognitive function, reintegrate socially, and avoid relapse.

The methods involve therapeutic administration of recombinant T cell receptor ligands (RTLs) which are MHC molecules engineered to include only the antigen-binding domains (β1α1 for class II or α1α2 for class I) optionally covalently linked to nervous system antigens such as myelin proteins (e.g., myelin oligodendrocyte glycoprotein, myelin basic protein, or proteolipid protein). These RTLs modulate immune responses and are designed to treat or improve cognitive or neuropsychiatric impairments specifically induced by substance addiction without including other MHC domains that are typically involved in anchoring or membrane integration.

Claims Coverage

The patent includes two independent claims concerning recombinant T cell receptor ligands (RTLs). The claims cover the isolated recombinant T cell receptor ligand and its composition with pharmaceutically acceptable carriers.

The claims cover the isolated recombinant T cell receptor ligand having a defined amino acid sequence and pharmaceutical compositions containing this ligand and acceptable carriers, thus encompassing both the therapeutic agent itself and its formulation.

Stated Advantages

Documented Applications