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-10267787-B2
Publication Date
2019-04-23
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 provides Mcl-1 binding profiling peptides, including peptides comprising SEQ ID NO: 1-11 and a profiling peptide comprising SEQ ID NO: 14. The peptides can be fused to a cellular uptake moiety, such as a TAT translocation domain or an ANT translocation domain, to generate Mcl-1 sensitivity profiles.
The disclosure uses the profiling to determine a Mcl-1 dependency percentage (MDP) for a subject. The disclosed profiling is tied to detecting changes in mitochondrial integrity, including mitochondrial membrane potential, and computing Mcl-1 dependency percentage from control and negative measurements.
A key theme is performing the profiling without a cell permeabilization agent such as digitonin. The Mcl-1 dependency results are used to select subjects and treat them by administering a CDK9 inhibitor, particularly alvocidib, when the MDP meets predetermined threshold criteria.
Claims Coverage
The independent claims are clm-00001, clm-00008, clm-00012, and clm-00013. The claim set centers on profiling bone marrow cells with a specified peptide sequence, determining a Mcl-1 dependency percentage, and administering alvocidib based on an MDP threshold, with additional constraints on cancer type and the absence of a permeabilizing agent.
Profiling bone marrow cells with a profiling peptide comprising SEQ ID NO: 14 to determine Mcl-1 dependency percentage (MDP)
Acquiring bone marrow cells from the subject; profiling a plurality of bone marrow cells with a profiling peptide comprising SEQ ID NO: 14; and determining a Mcl-1 dependency percentage (MDP) of the subject.
Administering alvocidib when MDP is at least 40%
Administering alvocidib to a subject with an MDP determined to be at least 40%.
Treating an MCL-1 dependent hematological cancer using SEQ ID NO: 14 profiling and alvocidib thresholding
Profiling a plurality of bone marrow cells with a profiling peptide comprising SEQ ID NO: 14, determining a Mcl-1 dependency percentage (MDP) of the subject, and administering alvocidib to a subject with an MDP determined to be at least 40% in a method for treating a subject with an MCL-1 dependent hematological cancer.
Profiling without a permeabilizing agent in AML treatment
Profiling a plurality of bone marrow cells with a profiling peptide comprising SEQ ID NO: 14 wherein the profiling is performed in the absence of a permeabilizing agent, determining a MCL-1 dependency percentage (MDP) of the subject, and administering alvocidib to a subject with an MDP determined to be at least 40%.
Profiling without a permeabilizing agent in MDS treatment
Profiling a plurality of bone marrow cells with a profiling peptide comprising SEQ ID NO: 14 wherein the profiling is performed in the absence of a permeabilizing agent, determining a MCL-1 dependency percentage (MDP) of the subject, and administering alvocidib to a subject with an MDP determined to be at least 40%.
Across the independent claims, the main inventive coverage is the use of a profiling peptide comprising SEQ ID NO: 14 to profile acquired bone marrow cells, the determination of a Mcl-1 dependency percentage (MDP), and administering alvocidib when MDP is at least 40%. Additional independent-claim scope limits treatment to AML or MDS and, in those claims, constrains profiling to be performed in the absence of a permeabilizing agent.
Stated Advantages
Improved assay reliability, including Z-factors, relative to comparison peptides (e.g., BCL2 family profiling comparison).
Provide concordance metrics and clinical response data for subjects, including a complete response rate in AML with MCL-1 dependence ≥40%.
Documented Applications
Treating a subject with an MCL-1 dependent hematological cancer by acquiring bone marrow cells, profiling with a profiling peptide comprising SEQ ID NO: 14, determining Mcl-1 dependency percentage (MDP), and administering alvocidib when MDP is at least 40%.
Treating a subject with acute myeloid leukemia (AML) by profiling bone marrow cells with SEQ ID NO: 14 in the absence of a permeabilizing agent, determining MCL-1 dependency percentage (MDP), and administering alvocidib when MDP is at least 40%.
Treating a subject with myelodysplastic syndrome (MDS) by profiling bone marrow cells with SEQ ID NO: 14 in the absence of a permeabilizing agent, determining MCL-1 dependency percentage (MDP), and administering alvocidib when MDP is at least 40%.
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