Combination therapy method of treating myeloproliferative neoplasms with a diphtheria toxin-human interleukin-3 conjugate in combination with other agents
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Publication Number
US-12357700-B2
Publication Date
2025-07-15
Expiration Date
Abstract
The present invention provides methods for treating or inhibiting a myeloproliferative neoplasm (MPN) in a subject in need thereof, comprising administering to the subject a diphtheria toxin-human interleukin-3 conjugate (DT-IL3) and one or more Jak inhibitors and/or one or more hypomethylating agents.
Core Innovation
The invention relates to methods for treating or inhibiting a myeloproliferative neoplasm (MPN) in a human subject in need thereof by administering a diphtheria toxin-human interleukin-3 conjugate (DT-IL3). The method includes administering DT-IL3 together with one or more Jak inhibitors and/or one or more hypomethylating agents.
The described combination approach addresses MPNs including myelofibrosis, including primary MF, post-PV MF, and post-ET MF, and includes patient populations characterized by refractory/intolerant disease, low platelet counts, ineligibility for ruxolitinib, and/or blast phase disease. Eligibility and subject characterization include molecular features such as mutations in JAK2, MPL, ASXL1, TET2, and CALR, including JAK2V617F.
The invention is supported by preclinical evidence described as in vitro and colony forming assay results in CMML cell models, where the combination of azacitidine (AZA) and DT-IL3 (SL-401) reduces viability and colony formation versus monotherapy. The documented clinical trial designs describe treatment-naïve and refractory patients and expected efficacy measures including spleen/liver reductions using response criteria referenced in the document.
Claims Coverage
The independent claim is clm-00001. It defines a method of treating or inhibiting an MPN by administering DT-IL3 together with one or more Jak inhibitors and/or one or more hypomethylating agents, with dependent claims refining the DT-IL3 composition, dosing schedules, eligibility criteria, and example agent selections.
DT-IL3 combined with Jak inhibition and/or hypomethylation for MPN treatment
A method for treating or inhibiting a myeloproliferative neoplasm (MPN) in a human subject in need thereof, comprising administering a diphtheria toxin-human interleukin-3 conjugate (DT-IL3) and one or more Jak inhibitors and/or one or more hypomethylating agents.
DT-IL3 dosing threshold and maximum tolerated dose
DT-IL3 is administered at a dose of at least 1 μg/kg, within one of several listed μg/kg ranges or discrete values, or at the maximum tolerated dose.
Treatment-cycle spacing and DT-IL3 administration across cycles
Treatment cycles are spaced by at least 1–5+ weeks, with DT-IL3 given at specified day schedules such as at least 3 consecutive days every 21 days for four cycles, then every 28 days for 3 cycles, then every 42 days.
DT-IL3 defined as diphtheria toxin linked to human IL-3
DT-IL3 comprises amino acid residues 1 to 388 of diphtheria toxin linked via a peptide bond to human IL-3.
Subject eligibility based on prior response/tolerance, platelets, mutations, and blast phase
The human subject is characterized by specified clinical and molecular features, including prior refractoriness or intolerance to Jak inhibitors/hypomethylating agents, low platelet counts/ineligibility for Jak inhibitors, prior response, mutations in JAK2/MPL/ASXL1/TET2/CALR, and/or MPN in blast phase.
Hypomethylating agent selection including azacitidine, decitabine, and/or SGI-110
The one or more hypomethylating agents comprise azacitidine, decitabine, and/or SGI-110.
Across the independent claim and its refinements, the core coverage is combination therapy using DT-IL3 with one or more Jak inhibitors and/or one or more hypomethylating agents for MPN treatment, with dependent features specifying DT-IL3 dosing levels, cycle schedules, a defined DT-IL3 construct/linkage format, and subject eligibility defined by prior treatment tolerance/response, low platelet counts, specific gene mutations, and blast phase.
Stated Advantages
The combination of azacitidine and DT-IL3 reduces viability and colony formation in CMML cell models versus monotherapy.
Documented Applications
Treating or inhibiting myeloproliferative neoplasms (MPNs) including myelofibrosis (primary MF, post-PV MF, and post-ET MF) in human subjects.
Use in human subjects characterized by refractory/intolerant disease, low platelet counts, and/or ineligibility for Jak inhibitors such as ruxolitinib.
Use in patient populations including MPN in blast phase.
Preclinical application described for CMML cell models using colony forming assay and in vitro viability assessment to compare AZA + DT-IL3 versus monotherapy.
Clinical-trial use described for treatment-naïve and refractory patients with expected efficacy measures including spleen/liver reduction.
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