Targeting the cofilin pathway
Inventors
Assignees
Publication Number
US-11377499-B2
Publication Date
2022-07-05
Expiration Date
2038-11-27
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Abstract
The present disclosure provides a method of restoring immune reconstitution, immune control of viremia, and one or more T cell functions in a subject infected with HIV. The method includes administering to the subject infected with HIV an agent that targets the cofilin pathway.
Core Innovation
The invention provides methods for restoring immune reconstitution, immune control of viremia, and one or more T cell functions in a subject infected with HIV by administering an agent that targets the cofilin pathway. The core mechanism involves addressing cofilin hyperactivation, which impairs T cell motility, tissue repopulation, migration, and homing to both lymphoid and non-lymphoid tissues. These methods include using proteins such as antibodies, specifically α4β7 integrin antibodies, to modulate the cofilin pathway.
The problem addressed is that antiretroviral therapy (ART), while successful in suppressing HIV viremia and prolonging patient lifespan, does not fully restore immune functions such as T cell migration and tissue repopulation. HIV infection leads to cofilin hyperactivation in CD4 T cells, causing a systemic migratory defect that is not reversed by ART, thereby preventing full immune restoration and immune control of viremia.
The present disclosure further includes methods of screening drugs for treating AIDS or alleviating symptoms of HIV infection, by evaluating the regulation of the cofilin pathway in HIV-infected T cells. The scope of the invention also encompasses pharmaceutical compositions containing agents that target the cofilin pathway, including α4β7 integrin antibodies and their fragments, for treating AIDS and promoting immune reconstitution in patients.
Claims Coverage
There are three independent claims covering methods for identifying and treating cofilin hyperactivation in patients using agents comprising anti-α4β7 integrin antibodies and chemokines.
Method for treating cofilin hyperactivation and loss of T-cell chemotaxis with anti-α4β7 integrin antibody and SDF-1
This method involves: 1. Identifying cofilin hyperactivation by performing an assay on a biological sample from a patient to profile cofilin phosphorylation. 2. Identifying loss of chemotaxis of T-cells in the sample. 3. Obtaining an agent comprising an anti-α4β7 integrin antibody and a chemokine comprising stromal cell-derived factor 1 (SDF-1). 4. Administering the agent to the patient.
Method for treating cofilin hyperactivation and loss of chemotaxis with anti-α4β7 integrin antibody and a chemokine targeting CCR5 and/or CXCR4
This method consists of: 1. Identifying cofilin hyperactivation in a patient sample by profiling cofilin phosphorylation. 2. Identifying loss of chemotaxis of T-cells in the sample. 3. Obtaining an agent comprising an anti-α4β7 integrin antibody and a chemokine comprising a molecule able to bind at a chemokine receptor (CCR5 and/or CXCR4) and possessing chemotactic property. 4. Administering the agent to the patient.
Method for treating cofilin hyperactivation and loss of chemotaxis with anti-α4β7 integrin antibody and chemokine with SDF-1-like chemotactic property
This method comprises: 1. Identifying cofilin hyperactivation in a patient sample by profiling cofilin phosphorylation. 2. Identifying loss of T-cell chemotaxis in the sample. 3. Obtaining an agent comprising an anti-α4β7 integrin antibody and a chemokine having chemotactic property of SDF-1. 4. Administering the agent to the patient.
The inventive features focus on detecting and treating cofilin hyperactivation and T cell chemotactic loss in patients by administering agents comprising anti-α4β7 integrin antibodies and chemokines to restore immune functions.
Stated Advantages
Targeting the cofilin pathway can restore T cell motility, tissue repopulation, migration, and homing to lymphoid and non-lymphoid tissues impaired as a result of HIV infection.
The methods promote immune reconstitution and immune control of viremia in subjects infected with HIV, addressing deficiencies not corrected by ART.
Administration of α4β7 integrin antibodies can reverse hyperactivation of cofilin in T cells, potentially leading to the functional cure of HIV infection.
Therapeutic targeting of cofilin may reduce latent viral reservoirs in peripheral blood by promoting homing of latent HIV+ cells to lymphoid tissues for reactivation and immune containment.
Documented Applications
Treating subjects infected with HIV to achieve immune reconstitution and immune control of viremia.
Restoring and/or promoting T cell motility, migration, homing, tissue repopulation, and/or CD4 T cell repopulation in HIV-infected subjects.
Reversing cofilin hyperactivation and associated T cell dysfunction in patients with HIV infection.
Alleviating symptoms caused by HIV infection or AIDS.
Screening for drugs that target the cofilin pathway in HIV-infected T cells.
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