Combination therapies comprising targeted therapeutics

Inventors

Ying, Weiwen • Chimmanamada, Dinesh U. • Proia, David

Assignees

Madrigal Pharmaceuticals Inc

Abstract

The present invention provides pharmacological compounds including an effector moiety conjugated to a binding moiety that directs the effector moiety to a biological target of interest. Likewise, the present invention provides compositions, kits, and methods (e.g., therapeutic, diagnostic, and imaging) including the compounds. The compounds can be described as a protein interacting binding moiety-drug conjugate (SDC-TRAP) compounds, which include a protein interacting binding moiety and an effector moiety. For example, in certain embodiments directed to treating cancer, the SDC-TRAP can include an Hsp90 inhibitor conjugated to a cytotoxic agent as the effector moiety.

Core Innovation

The invention relates to SDC-TRAP conjugates, including SDC-TRAP-0063, its tautomer, or its salt, and to small molecule drug conjugates trapped intracellularly. The conjugates include a protein-interacting binding moiety conjugated to an effector moiety, where the binding moiety enables selective accumulation intracellularly and the effector moiety provides therapeutic or imaging function.

The effector moiety is coupled via a linker that enables intracellular release, including discussion of cleavable linkers. The disclosure frames the constructs as enabling selective accumulation and intracellular release, with properties such as small molecular weight, passive/active cellular transport, binding affinity and target residence, effector release kinetics, and intracellular target-to-plasma ratios.

The disclosure includes Hsp90-targeted SDC-TRAPs as an example treatment context, including an Hsp90 inhibitor as the effector moiety and protein-interacting binding moieties that interact with Hsp90. It also describes treatment of cancer by administering SDC-TRAP-0063 together with at least one PARP inhibitor, where the cancer is BRCA1 and/or BRCA2 mutant.

Claims Coverage

The independent claim covers two related inventive features: SDC-TRAP design with a protein-interacting binding moiety and effector moiety coupled through a linker, and a method of treating BRCA1 and/or BRCA2 mutant cancer by administering SDC-TRAP-0063, or its tautomer or salt, together with at least one PARP inhibitor. Dependent claims refine the treatment method by specifying talazoparib and constraining administration and cancer types.

Overall, the claim set covers SDC-TRAP conjugates with a protein-interacting binding moiety, an effector moiety, and a linker enabling intracellular release, and also covers BRCA1 and/or BRCA2 mutant cancer treatment using SDC-TRAP-0063 with a PARP inhibitor. The treatment claims are further narrowed to talazoparib, once-weekly intravenous administration, an about 25 to about 200 mg/kg range, and non-small cell lung, breast, and ovarian cancer.

Stated Advantages

Documented Applications