Conjoint therapies for immunomodulation
Inventors
Sasikumar, Pottayil Govindan N. • Ramachandra, Muralidhara • Ramachandra, Raghuveer K. • Lazorchak, Adam S. • Wyant, Timothy L.
Assignees
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Publication Number
US-11497735-B2
Publication Date
2022-11-15
Expiration Date
Abstract
The present disclosure relates to methods comprising administering compounds that inhibit VISTA and PD-1 (e.g., PD-1, PD-L1, or PD-L2) pathways with a compound that inhibits TIM-3 and PD-1 (e.g., PD-1, PD-L1, or PD-L2) pathways. The disclosure also relates to treatment of disorders by inhibiting an immunosuppressive signal induced by VISTA, TIM-3, PD-1, PD-L1, and/or PD-L2.
Core Innovation
The invention relates to a method of modulating an immune response in a subject by administering an inhibitor of the VISTA pathway together with an inhibitor of the TIM-3 pathway. The VISTA pathway inhibitor is defined as a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the TIM-3 pathway inhibitor is defined as a compound of formula (II) or a pharmaceutically acceptable salt thereof.
The chemical scope of formula (I) and formula (II) is defined through substituent variables, including G, Ra, Ra', Rb, Rc, Rd, Re, and R_x/R_y for formula (I), and Z, G', Y, and the corresponding substituent variables for formula (II). The described embodiments include ring formation, 5- to 6-membered rings, and heteroatom-containing ring structures with 1 to 3 heteroatoms selected from O, N or S.
The disclosure also presents exemplary chemical structures and tables for concrete embodiments of the inhibitor compounds. The embodiments include stereochemical configurations (D/L), isotopically labeled variants, and amino-acid side chain stereochemical depictions such as L-threonine residue and D-threonine residue.
Claims Coverage
The provided content identifies one independent claim centered on immune modulation by conjoint administration of a VISTA pathway inhibitor and a TIM-3 pathway inhibitor, with formula-based chemical definitions and multiple dependent refinements.
Conjoint administration of VISTA and TIM-3 pathway inhibitors
A method of modulating an immune response in a subject by administering an effective amount of an inhibitor of the VISTA pathway and an effective amount of an inhibitor of the TIM-3 pathway.
VISTA pathway inhibitor defined as formula (I) compound or salt
The inhibitor of the VISTA pathway is a compound of formula (I) or a pharmaceutically acceptable salt thereof, with substituent definitions including G, Ra, Ra', Rb, Rc, Rd, Re, and R_x/R_y, including ring formation and heteroatom-containing ring constraints.
TIM-3 pathway inhibitor defined as formula (II) compound or salt
The inhibitor of the TIM-3 pathway is a compound of formula (II) or a pharmaceutically acceptable salt thereof, with substituent definitions including Z, G', Y, and the corresponding substituent variables, including ring formation and heteroatom-containing ring constraints.
Dependent refinements to chemical scope
Further limiting the method by specifying particular substituent values and ring/heteroatom patterns within the VISTA inhibitor definition and the TIM-3 inhibitor definition.
Overall, the claim coverage centers on one independent method claim requiring co-administration of a VISTA pathway inhibitor defined by formula (I) and a TIM-3 pathway inhibitor defined by formula (II). The inventive coverage is defined by the dual-pathway immune modulation and the specific formula-based inhibitor substitution scopes, with dependent claims narrowing particular structural configurations.
Stated Advantages
Provides beneficial effects beyond single combinations by simultaneous inhibition of VISTA, TIM-3, and PD-1/PD-L1/PD-L2.
Shows additive efficacy with conjoint administration in tumor-volume and immunophenotyping comparisons.
Documented Applications
Modulating an immune response in a subject by administering VISTA pathway and TIM-3 pathway inhibitors, including embodiments combined with PD-1/PD-L1/PD-L2 pathway blockade.
Treating cancer and other disease or disorder categories including immune disorders, immunodeficiency disorders, inflammatory disorders, infectious diseases, and transplant rejection.
Treating cancer selected from an enumerated list including small cell lung cancer, multiple myeloma, bladder carcinoma, primary ductal carcinoma, ovarian carcinoma, Hodgkin's lymphoma, gastric carcinoma, acute myeloid leukemia, and pancreatic cancer.
Cancer indications.
Infectious disease indications.
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