Insulin-like growth factor-chemotherapeputic conjugate for treating myelodysplastic syndrome
Inventors
McTavish, Hugh • Dudek, Arkadiusz Z.
Assignees
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Publication Number
US-11324834-B2
Publication Date
2022-05-10
Expiration Date
Abstract
Provided are methods of treating myelodysplastic syndrome (MDS), oligoblastic acute myelogenous leukemia (O-AML), or chronic myelomonocytic leukemia (CMML) using 765IGF-MTX and other IGF-receptor-targeted agents, and formulations for delivering 765IGF-MTX and other IGF-receptor-targeted agents to patients. Also provided are pharmaceutical compositions for use in treating MDS, O-AML, and CMML.
Core Innovation
The invention describes treating a patient in recognized need of treatment for myelodysplastic syndrome (MDS), oligoblastic acute myelogenous leukemia (O-AML), or chronic myelomonocytic leukemia (CMML) by administering an agent comprising an insulin-like growth factor type 1 receptor (IGF-1R) ligand conjugated to methotrexate. The IGF-1R ligand is covalently attached to methotrexate, is not IGF-1, and is selected from 765IGF, IGF132, long-R3-IGF, R3-IGF, or des(1-3)-IGF, or a variant at least 90% identical to IGF-1. The described embodiment includes 765IGF-MTX administered by infusion.
The invention further describes treatment in which a hypomethylating agent is administered together with an agent comprising an IGF-1R ligand conjugated to methotrexate. In this combination, the IGF-1R ligand remains covalently attached to methotrexate, has reduced binding affinity for IGF-1 binding proteins as compared to IGF-1, and is not IGF-1, with the IGF-1R ligand selected from the specified IGF variants or variants at least 90% identical to IGF-1.
The provided content also reports biological and efficacy evidence supporting the IGF-1R ligand-MTX conjugate concept. It reports cytotoxicity against MDS/AML cell lines, high IGF-1R expression in MDS-L cells, stronger tumor growth inhibition versus free MTX at lower methotrexate molar doses in mouse xenograft results, and pharmacokinetics, pharmacodynamics, and correlative biomarker and antibody assessments.
Claims Coverage
The independent claims cover two inventive features sets: treatment with an IGF-1R ligand-methotrexate covalent conjugate using non-IGF-1 IGF variants, and combination therapy using a hypomethylating agent together with the same conjugate. The claims also recite infusion administration in a defined dextrose/water volume and dose range, and assert inhibition of cancer cell growth.
IGF-1R ligand covalently attached to methotrexate for MDS/O-AML/CMML treatment
A method of treating a patient for myelodysplastic syndrome (MDS), oligoblastic acute myelogenous leukemia (O-AML), or chronic myelomonocytic leukemia (CMML) by administering an agent comprising an insulin-like growth factor type 1 receptor (IGF-1R) ligand conjugated to methotrexate, wherein the IGF-1R ligand is covalently attached to methotrexate.
Reduced-binding IGF-1R ligand not IGF-1
The IGF-1R ligand is a variant of IGF-1 that has reduced binding affinity for IGF-1 binding proteins as compared to IGF-1, is not IGF-1 (SEQ ID NO:3), and is or comprises 765IGF (SEQ ID NO:2), IGF132 (SEQ ID NO:4), long-R3-IGF (SEQ ID NO:5), R3-IGF (SEQ ID NO:6), or des(1-3)-IGF (SEQ ID NO:7), or a variant at least 90% identical to IGF-1 (SEQ ID NO:3).
Infusion delivery in defined dextrose/water volume and dose
The agent is administered by infusion dissolved in a volume of 100 ml to 1 liter of 5% to 10% dextrose in water at a dose of 0.2 to 2.5 microEq/kg patient body weight.
Inhibiting growth of cancer cells
The treating inhibits growth of cancer cells.
Combination with a hypomethylating agent
A method of treating a patient for AML, CML, O-AML, CMML, or MDS by administering a hypomethylating agent together with an IGF-1R ligand conjugated to methotrexate, with the same covalent attachment and non-IGF-1 IGF variant selection.
The claims require a covalent IGF-1R ligand-methotrexate conjugate using specified non-IGF-1 IGF variants, delivered by infusion in a defined dextrose/water volume and dose range, and used to inhibit cancer cell growth either alone for MDS/O-AML/CMML or together with a hypomethylating agent for AML, CML, O-AML, CMML, and MDS.
Stated Advantages
Improved safety versus methotrexate in cytopenia-prone myeloid disorders, as supported by human Phase I/clinical findings noting no evidence of cytopenia in treated subjects.
Higher in vivo tumor growth inhibition efficacy than free methotrexate at lower molar methotrexate doses.
Inhibits growth of cancer cells.
Documented Applications
Treatment of myelodysplastic syndrome (MDS), including oligoblastic acute myelogenous leukemia (O-AML) and chronic myelomonocytic leukemia (CMML), using an IGF-1R ligand covalently attached to methotrexate delivered by infusion.
Combination therapy for cancers including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), O-AML, CMML, and MDS by administering a hypomethylating agent together with an IGF-1R ligand-methotrexate conjugate.
Adjunct combination concept with hypomethylating agents such as azacitidine or decitabine together with the IGF-1R ligand-methotrexate conjugate.
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