Hematopoietic growth factor proteins and analogs thereof and angiotensin converting enzyme inhibitors for treatment of radiation exposure
Inventors
Cox, George N. • Orschell, Christie M. • Medhora, Meetha Manek • Fish, Brian
Assignees
Medical College of Wisconsin • Indiana University Research and Technology Corp • Bolder Biotechnology Inc
Publication Number
US-12274736-B2
Publication Date
2025-04-15
Expiration Date
2036-09-19
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Abstract
Methods and compositions comprising hematopoietic growth factor proteins and/or protein analogs thereof and/or combinations thereof and angiotensin converting enzyme inhibitors to treat the acute and long term adverse effects of radiation exposure in subjects who have been or will be exposed to radiation are disclosed.
Core Innovation
The invention provides methods and compositions comprising hematopoietic growth factor proteins and/or protein analogs and angiotensin converting enzyme inhibitors (ACEIs) for treating subjects who have been or will be exposed to radiation. The approach involves administering an effective dose of an ACEI and at least one hematopoietic growth factor (HGF) or protein analog thereof, or combinations thereof, to improve survival and/or accelerate hematopoietic recovery following radiation exposure.
The background explains that acute, high dose radiation exposure leads to hematopoietic acute radiation syndrome (H-ARS) and results in significant reduction of blood cell counts and organ damage, particularly affecting the bone marrow, lung, heart, and kidney. Existing treatments, such as HGFs, often require rapid administration (within 24 hours) for efficacy. However, limitations exist in both timing and efficacy, and there is a need for combination therapies that improve survival when administered outside this window and address both early and late complications.
The core innovation solves these problems by combining ACEIs with HGFs or their analogs, particularly long-acting protein analogs, to optimize survival outcomes and prevent organ morbidity due to radiation exposure. This combination provides superior survival rates compared to either therapy alone, reduces lung, kidney, and heart complications, and enhances or accelerates the recovery of various blood cell lineages. The invention also identifies optimized dosages, timing, and specific analogs to maximize these benefits for subjects exposed to myelosuppressive or therapeutic radiation doses.
Claims Coverage
The patent contains one independent claim outlining a combination therapy involving specific ACE inhibitors and hematopoietic growth factor protein analogs for improving survival in subjects with radiation-induced hematopoietic acute radiation syndrome (H-ARS) and delayed effects of acute radiation exposure (DEARE).
Combination therapy of specified ACE inhibitors with selected hematopoietic growth factor protein analogs
A method for improving 90 day to 12 month survival from hematopoietic acute radiation syndrome (H-ARS) and delayed effects of acute radiation exposure (DEARE) in a subject who has been exposed to radiation, comprising: - Administering a combination therapy that includes: - An effective dose of an angiotensin-converting enzyme inhibitor (ACEI), selected from lisinopril, perindopril, captopril, enalapril, and ramipril. - An effective dose of at least one hematopoietic growth factor (HGF) or protein analog thereof, or combinations thereof, where the HGF or analog is selected from: - A granulocyte colony-stimulating factor (G-CSF) analog comprising a methionine at the N-terminus of SEQ ID NO:1; - A G-CSF analog comprising a cysteine residue substituted for A141 of G-CSF (SEQ ID NO:1) and a serine residue substituted for C17 of G-CSF (SEQ ID NO:1); - A granulocyte-macrophage colony-stimulating factor (GM-CSF) analog (SEQ ID NO:2); - A GM-CSF analog comprising a cysteine substitution at position 3 of SEQ ID NO:2; - An interleukin-11 (IL-11) analog comprising a cysteine residue added after the C-terminus of the protein having SEQ ID NO:3 or SEQ ID NO:7, with the P1 amino acid deleted; - Combinations of these analogs. - The combination therapy yields greater survival than treatment with any HGF analog or ACEI alone.
The claims broadly cover a method of using specific combinations of ACE inhibitors and particular HGF protein analogs to achieve superior survival outcomes in radiation-exposed subjects with H-ARS and DEARE, including defined structural variants of G-CSF, GM-CSF, and IL-11.
Stated Advantages
The combination therapy of ACE inhibitor and HGF or protein analog results in greater survival rates than use of either agent alone in radiation-exposed subjects.
Treatment correlates with accelerated hematopoietic recovery, evidenced by more rapid restoration of blood cell counts and stem/progenitor cells compared to controls.
The therapy reduces radiation-induced damage to organs, including decreased morbidity and injury to lung, kidney, and heart, in subjects exposed to radiation.
Using an ACE inhibitor in conjunction with HGF protein analogs mitigates increased organ morbidity (such as lung and kidney damage) that may be caused by HGFs alone.
Long-acting HGF analogs and their combinations provide a survival benefit with simplified dosing schedules compared to conventional HGFs.
Documented Applications
Improving survival and hematopoietic recovery in subjects who have been or will be exposed to high or myelosuppressive doses of radiation, including acute radiation syndrome (ARS) patients.
Reducing early and delayed adverse effects of radiation exposure in subjects, including organ-specific morbidity affecting lung, kidney, and heart.
Treatment of humans and other mammals (such as livestock and pets) for radiation exposure, including scenarios of nuclear accidents, bomb detonation, or therapeutic medical radiation (e.g., cancer patients).
Prevention or reduction of the severity of residual bone marrow damage and enhancement of immune reconstitution in radiation survivors.
Administration to subjects prior to radiation exposure (e.g., before planned therapeutic irradiation) to reduce severity of radiation-induced complications.
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