IL-15 and IL-15Rα heterodimer dose escalation regimens for treating conditions
Inventors
Felber, Barbara K. • Finkielsztein, Sergio • Pavlakis, George N. • Vournakis, John N.
Assignees
Novartis AG • US Department of Health and Human Services
Publication Number
US-10335460-B2
Publication Date
2019-07-02
Expiration Date
2035-07-28
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Abstract
Described herein are dose escalation regimens for the administration of complexes comprising interleukin-15 (“IL-15”) covalently or noncovalently bound to IL-15 receptor alpha (“IL-15Rα”) to patients in order to enhance IL-15-mediated immune function. In a specific aspect, the dose escalation regimens are useful in the prevention, treatment, and/or management of disorders in which enhancing IL-15-mediated function is beneficial, such as cancer, infectious diseases, immunodeficiencies and lymphopenia. In another specific aspect, the dose escalation regimens are useful for eradicating or reducing HIV in HIV-infected patients.
Core Innovation
Described herein are dose escalation regimens for the administration of complexes comprising interleukin-15 ("IL-15") covalently or noncovalently bound to IL-15 receptor alpha ("IL-15Rα") to patients in order to enhance IL-15-mediated immune function. These dose escalation regimens are useful in the prevention, treatment, and/or management of disorders in which enhancing IL-15-mediated function is beneficial, such as cancer, infectious diseases, immunodeficiencies, and lymphopenia. The regimens are also useful for eradicating or reducing HIV in HIV-infected patients.
The patent addresses the issue that the amount of IL-15/IL-15Rα complex administered to a subject needs to be escalated over time to achieve an effective ratio of IL-15 to lymphocyte cell number, ensuring lymphocytes remain activated and survive. IL-15/IL-15Rα complex administration causes lymphocyte increase, necessitating increased IL-15/IL-15Rα dosage for further proliferation and survival. The methods achieve this ratio while avoiding the toxicity associated with high IL-15 doses and minimizing side effects such as blood pressure changes or increased body temperature.
Further, the methods are based on the discovery that high doses of IL-15/IL-15Rα activate lymphocytes, including HIV or SIV-infected lymphocytes, which can be eliminated if activated without causing systemic viral load increase. In chronically infected macaques, IL-15/IL-15Rα complex administration did not lead to systemic virus increase, indicating safety of the approach.
Claims Coverage
The independent claims describe methods for treating lymphocytopenia, cancer, or infectious diseases in human subjects using dosing regimens of IL-15/IL-15Rα complexes.
Method for treating diseases using IL-15/IL-15Rα complexes in a dose escalation regimen
A method comprising administering an initial low dose of a human IL-15/IL-15Rα complex (0.1 to 1 μg/kg based on single chain IL-15 mass) to a human subject, obtaining a plasma sample, detecting free IL-15 concentration of 1 pg/ml to 50 pg/ml post-administration, and administering successively higher doses from two to three times the previous dose.
Monitoring and controlling dosing based on IL-15 plasma levels
Administering the initial low dose one to six times over 7 to 14 days, administering each dose at least once to thrice over 7 to 14 days, measuring free IL-15 levels 24 to 72 hours after dosing, and not increasing dose if free IL-15 exceeds 50 pg/ml.
Maintenance dosing to maintain effective IL-15 levels
Administering a maintenance dose that maintains free IL-15 levels approximately 1 pg/ml to 50 pg/ml in plasma after dose escalation.
Cancer and infectious disease treatment specifics
The method applies to cancers such as melanoma, colon cancer, lung cancer, prostate cancer, renal cell carcinoma (including metastatic cases), and infectious diseases including HIV, pneumonia, and tuberculosis.
Modes of IL-15/IL-15Rα administration
Administration can be subcutaneous, intravenous, intramuscular, or intratumoral.
Molecular composition of the IL-15/IL-15Rα complex
The human IL-15 comprises amino acid residues 49 to 162 of SEQ ID NO:1, and human IL-15Rα comprises the amino acid sequence of SEQ ID NO:33.
Combination therapy with other agents
Methods further comprise administering one or more other therapies, including antibodies binding Her2, PD-1, PD-1 ligand, or CD19, as well as histone deacetylase inhibitors, TLR7 agonists, or cytokines such as IL-7, before or after IL-15/IL-15Rα administration.
The claims cover methods for treating lymphocytopenia, cancer, and infectious diseases in humans by administering IL-15/IL-15Rα complexes in escalating doses starting from a low initial dose, monitoring free IL-15 plasma levels to guide dose escalation, applying maintenance dosing, utilizing specific cancer and infectious disease targets, various administration routes, defined molecular forms, and optionally combined with other therapies.
Stated Advantages
The dose escalation regimens achieve an effective ratio of IL-15 to lymphocyte cell number while avoiding toxicity associated with high doses of IL-15.
The regimens decrease or do not cause side effects like decreases in blood pressure or increases in body temperature.
Administration of IL-15/IL-15Rα complexes activates lymphocytes, including HIV-infected cells, without inducing systemic increases in viral load, indicating safety in HIV-infected patients.
Documented Applications
Prevention, treatment and/or management of cancer including melanoma, colon cancer, lung cancer, prostate cancer, renal cell carcinoma, and metastatic cancers.
Prevention, treatment and/or management of infectious diseases including HIV/AIDS, pneumonia, and tuberculosis.
Prevention, treatment and/or management of lymphopenia and immunodeficiencies.
Eradication or reduction of HIV in HIV-infected patients.
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