Profiling peptides and methods for sensitivity profiling
Inventors
Bearss, David J. • Siddiqui-Jain, Adam • Whatcott, Clifford J. • Peterson, Peter W. • Warner, Steven L. • Mouritsen, Lars
Assignees
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Publication Number
US-10422788-B2
Publication Date
2019-09-24
Expiration Date
Abstract
The present disclosure is generally directed to profiling peptides, compositions, and kits, as well as methods of use thereof. The profiling peptides comprise an Mcl-1 binding domain, and optionally a cellular uptake moiety. The methods of using such profiling peptides include predicting sensitivity of a cancer, selecting a treatment, treating a cancer, producing a sensitivity profile, and the like.
Core Innovation
The disclosure describes profiling peptides for determining Mcl-1 dependency/sensitivity in cells, including peptides comprising an Mcl-1 binding domain identified as SEQ ID NO: 14. The approach includes acquiring a plurality of bone marrow cells from a subject and profiling the plurality of bone marrow cells with the profiling peptide comprising SEQ ID NO: 14 to obtain an MCL-1 dependency percentage (MDP).
The disclosure further describes determining sensitivity by detecting a decrease in mitochondrial integrity, including mitochondrial depolarization and mitochondrial membrane potential changes, in connection with the profiling peptide. Mitochondrial integrity is indicated using potentiometric mitochondrial dyes such as JC-1 and DiOC6, with the disclosure also referencing rhodamine 123, Cytochrome c leakage, and mitochondrial depolarization as mitochondrial-related indicators.
The disclosure emphasizes profiling without cell permeabilization agents, including omitting permeabilization such as digitonin. Based on the determined MDP, the disclosure frames treatment selection by administering alvocidib when the MDP determined for the subject is at least 15%, with treatment-response framing using Mcl-1 dependency thresholds.
Claims Coverage
The provided portion contains three independent method claims. Across the independent claims, the inventive features focus on profiling bone marrow cells with a peptide comprising SEQ ID NO: 14, determining an MCL-1 dependency percentage (MDP), and administering alvocidib when the subject’s MDP meets a specified minimum threshold.
Profiling bone marrow cells with a peptide comprising SEQ ID NO: 14
A method comprising acquiring a plurality of bone marrow cells from the subject and profiling the plurality of bone marrow cells with a profiling peptide comprising SEQ ID NO: 14.
Determining an MCL-1 dependency percentage (MDP)
A method comprising determining a MCL-1 dependency percentage (MDP) of the subject.
Administering alvocidib when MDP is at least 15%
A method comprising administering alvocidib to a subject with an MDP determined to be at least 15%.
Treating a subject with an MCL-1 dependent hematological cancer using MDP-selected alvocidib
A method for treating a subject with an MCL-1 dependent hematological cancer, where the workflow includes acquiring bone marrow cells, profiling with a profiling peptide comprising SEQ ID NO: 14, determining MDP, and administering alvocidib when the MDP is at least 15%.
Treating acute myeloid leukemia (AML) with MDP-selected alvocidib
A method for treating a subject having acute myeloid leukemia (AML), including acquiring bone marrow cells, profiling with a profiling peptide comprising SEQ ID NO: 14, determining MDP, and administering alvocidib when the MDP is at least 15%.
Treating myelodysplastic syndrome (MDS) with MDP-selected alvocidib
A method for treating a subject having myelodysplastic syndrome (MDS), including acquiring bone marrow cells, profiling with a profiling peptide comprising SEQ ID NO: 14, determining MDP, and administering alvocidib when the MDP is at least 15%.
Across the independent claims, the core coverage is a treatment workflow that selects subjects for alvocidib based on an MCL-1 dependency percentage (MDP) determined by profiling acquired bone marrow cells with a profiling peptide comprising SEQ ID NO: 14, with the baseline MDP threshold specified as at least 15% in each independent claim.
Stated Advantages
Improved reliability of the assay is indicated by Z-factors in comparisons between SEQ ID NO: 14 and NOXA assays.
Assay concordance/accuracy metrics are reported for SEQ ID NO: 14 compared to NOXA assays.
The disclosure provides performance/concordance data supporting improved reliability and concordance for the MCL-1 profiling approach using SEQ ID NO: 14.
Documented Applications
Profiling peptides for Mcl-1 dependency/sensitivity testing in relation to downstream treatment selection using MDP thresholds.
Treating a subject with an MCL-1 dependent hematological cancer using MDP-determined eligibility and administering alvocidib when MDP is at least 15%.
Treating acute myeloid leukemia (AML) using MDP-determined eligibility and administering alvocidib when MDP is at least 15%.
Treating myelodysplastic syndrome (MDS) using MDP-determined eligibility and administering alvocidib when MDP is at least 15%.
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