Recombinant T-cell receptor ligand for the treatment of cognitive and neuropsychiatric impairment induced by substance addiction
Inventors
Loftis, Jennifer • Huckans, Marilyn • Vandenbark, Arthur A.
Assignees
Oregon Health and Science University • US Department of Veterans Affairs
Publication Number
US-8685404-B2
Publication Date
2014-04-01
Expiration Date
2032-01-30
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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
The invention provides methods for treating cognitive or neuropsychiatric impairment induced by substance addiction and for increasing cognitive function in subjects with substance addiction. The methods involve administering a therapeutically effective amount of a major histocompatibility complex (MHC) molecule comprising covalently linked first, second, and third domains. Specifically, the first domain is an MHC class II β1 domain and the second domain is an MHC class II α1 domain, covalently linked such that the amino terminus of the α1 domain is linked to the carboxy terminus of the β1 domain, or the first domain is an MHC class I α1 domain and the second domain is an MHC class I α2 domain, linked in a corresponding covalent orientation. The third domain is covalently linked to the first domain and includes an antigen of the central or peripheral nervous system, such as a myelin protein.
The problem addressed by the invention is the lack of effective pharmacotherapies for substance addiction-induced cognitive and neuropsychiatric impairments, particularly those caused by highly addictive substances such as methamphetamine, opioids, and alcohol. Such substances cause long-term structural brain damage leading to impairments that contribute to high relapse rates seen with current substance abuse treatments. Existing treatment options poorly address the cognitive and neuropsychiatric deficits incurred, which impairs recovery success. Hence, there is a critical need for new interventions that can help affected adults recover lost functions, reduce relapse, and improve treatment retention.
The invention employs recombinant T cell receptor ligands (RTLs), which are monomeric recombinant polypeptides mimicking MHC functions. These RTLs include only the MHC domains defining the antigen binding cleft, such as the β1 and α1 domains in MHC class II or α1 and α2 domains in MHC class I molecules. RTLs can be covalently linked to selected nervous system antigens, like myelin oligodendrocyte glycoprotein (MOG) peptides. The methods disclosed include administering these RTLs, with or without linked antigen, to subjects with substance addiction to effect improvements in cognitive function or treat neuropsychiatric or cognitive impairments related to the addiction.
Claims Coverage
The patent contains two independent claims directed to methods of treating cognitive or neuropsychiatric impairment and methods of increasing cognitive function by administration of specific MHC molecules linked to particular antigenic peptides.
MHC molecule composition for treatment
Administration of an MHC molecule comprising covalently linked first (MHC class II β1 domain), second (MHC class II α1 domain), and third domains, wherein the α1 domain is covalently linked to the β1 domain with no inclusion of α2 or β2 domains, and the third domain comprising the MOG 35-55 antigenic determinant, to treat cognitive or neuropsychiatric impairment induced by substance addiction in a subject without multiple sclerosis or stroke.
Substance addiction and impairment scope
Treatment methods cover cognitive or neuropsychiatric impairments including cognitive impairment, anxiety, depression, fatigue, agitation, pain, sleep disturbance, drug craving, or combinations thereof, induced by substance addictions such as methamphetamine, other sympathomimetics, opioids, alcohol, or combinations thereof, in subjects without primary neurological disorders.
MHC molecule modifications to reduce aggregation
The MHC molecules may be modified by substitution of hydrophobic amino acids within a β-sheet platform (such as V102, I104, A106, F108, L110) with non-hydrophobic amino acids (polar or charged like serine or aspartic acid) to reduce aggregation in solution compared to unmodified molecules.
Covalent linkage features
The covalent linkage between the first and second domains is provided by a polypeptide linker; the linkage between the first and third domains is provided by a polypeptide linker or a disulfide bond.
Method for increasing cognitive function
Administration of the above defined MHC molecule comprising the MOG 35-55 antigen is also claimed to increase cognitive function in subjects with substance addiction who do not have multiple sclerosis or stroke.
The independent claims focus on therapeutic and cognitive enhancement methods using recombinant MHC class II β1α1 molecules covalently linked to nervous system antigens (particularly MOG 35-55), including specific structural features and modifications to reduce aggregation, targeting subjects with substance addiction-induced impairments and excluding certain neurological disorders.
Stated Advantages
The methods can help treat cognitive and neuropsychiatric impairments induced by substance addiction, potentially reducing relapse rates and improving recovery success.
Treatment with RTLs may improve cognitive function including memory, attention, information processing, executive functions, and other neuropsychological domains affected by substance addiction.
Certain modified MHC molecules show reduced aggregation in solution, enabling better pharmaceutical formulation and consistent therapeutic activity.
RTL treatment may modulate neuroinflammatory responses by increasing anti-inflammatory cytokines (e.g., IL-10 and IL-4) in peripheral blood, supporting immunoregulatory mechanisms favorable to cognitive improvement.
Documented Applications
Treatment of cognitive or neuropsychiatric impairment induced by substance addiction including methamphetamine, opioid, and alcohol addictions.
Increasing cognitive function in subjects with substance addiction, especially impairments related to drugs like methamphetamine.
Use of recombinant MHC class II β1α1 molecules linked to myelin protein antigens (e.g., MOG 35-55) for therapeutic intervention in substance addiction-related brain impairments.
Assessment and potential treatment of peripheral immune system alterations associated with substance addiction using these MHC molecules.
Pharmaceutical compositions and dosing regimens for administering RTLs to subjects with cognitive or neuropsychiatric impairments induced by substance addiction.
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