Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11730836-B2
Publication Date
2023-08-22
Expiration Date
Abstract
Conjugates of topoisomerase I inhibitors linked to a macromolecule through a linkage that undergo beta elimination in situ in combination with one or more of an assessed defect in DNA damage response (DDR) in a subject bearing cancer, a cell cycle checkpoint inhibitor and/or a DDR inhibitor provides improved outcomes for cancer-bearing subjects.
Core Innovation
The invention relates to treating cancer by administering an effective amount of a conjugate of the topoisomerase I inhibitor SN-38 coupled to a macromolecule through a linker, together with an effective amount of a poly(ADP-ribose) polymerase (PARP) inhibitor. The conjugate has a defined formula in which m is 1-6 and n is 200-250. The described approach is positioned as a synergistic cancer treatment strategy combining the SN-38 macromolecule conjugate with PARP inhibition.
The described concept also addresses cancer treatment in subjects having defects in the DNA damage response (DDR) and/or treatment combinations involving DDR inhibitors and/or cell-cycle checkpoint pathway inhibitors. The conjugate linker is described as being cleaving by in situ beta elimination, including a beta elimination decoupling linker. This is presented together with an emphasis on improved pharmacokinetics for the conjugate.
The partial disclosure provides a preferred conjugate, referred to as PLX038 (and PLX038A), with m=1 and n approximately 225. Preclinical xenograft examples are described to support synergy between PLX038A and the PARP inhibitor talazoparib (BMN673/Talazoparib), including reduced tumor growth and improved event-free survival in BRCA-deficient tumor models.
Claims Coverage
The independent claim recites 2 main inventive elements: (1) administering a specific SN-38 macromolecule conjugate with defined linker parameters (m=1-6 and n=200-250), and (2) administering the conjugate in combination with a PARP inhibitor. Dependent claims further refine the conjugate parameters, the treated subject population, coadministration timing, and subject type.
SN-38 macromolecule conjugate with defined parameters
Administering to the subject an effective amount of a conjugate of the topoisomerase I inhibitor SN-38 coupled to a macromolecule through a linker, wherein the conjugate has a formula with m=1-6 and n=200-250.
Combination with a PARP inhibitor
Administering the SN-38 macromolecule conjugate in combination with an effective amount of a poly(ADP-ribose) polymerase (PARP) inhibitor.
Conjugate parameter refinement to m=1 and n approximately 225
The method where the conjugate is defined with m=1 and n=about 225.
Treatment of subjects with genetic defects in DNA damage response (DDR)
The method performed on a subject who has a genetic defect in the DNA damage response (DDR).
Simultaneous coadministration of the conjugate and PARP inhibitor
The method wherein the conjugate and the PARP inhibitor are administered simultaneously.
Sequential coadministration of the conjugate and PARP inhibitor
The method wherein the conjugate and the PARP inhibitor are administered sequentially.
Human subject limitation
The method wherein the subject is a human.
Across the independent claim and its dependencies, coverage centers on use of an SN-38 topoisomerase I inhibitor macromolecule conjugate with defined linker parameters (m and n) administered together with a PARP inhibitor, with additional narrowing to specific conjugate parameters (m=1 and n≈225), DDR-defective subjects, simultaneous or sequential administration, and human subjects.
Stated Advantages
Improved pharmacokinetics for the conjugate.
Synergistic cancer treatment when combining PLX038A with a PARP inhibitor (talazoparib/BMN673/Talazoparib).
Enhanced efficacy in BRCA-deficient tumor models, including reduced tumor growth and improved event-free survival.
Documented Applications
Treating cancer in a subject using an effective amount of an SN-38 macromolecule conjugate (with defined linker parameters) in combination with a PARP inhibitor.
Single-agent use of the approach in subjects with DDR defects [procedural detail omitted for safety].
Combination therapy in subjects involving PARP inhibition (including talazoparib/BMN673) with an SN-38 macromolecule conjugate.
Synergy evaluation using PLX038A with the PARP inhibitor talazoparib (BMN673/Talazoparib) in preclinical xenograft examples, including BRCA-deficient tumor models.
Interested in licensing this patent?