EP-4735004-A2 - COMPOSITIONS COMPRISING STING AGONISTS AND METHODS OF USE FOR TREATING GLIOMA

Abstract

The present disclosure relates generally to the field of medicine, oncology, and immunology. More particularly, it comprises combination therapies including a STING agonist and dual specific antibodies with high affinity for PD-L1 and PD-L2 and further encompasses antibody drug conjugates including STING agonists linked to human dual specific antibodies with high affinity for PD-L1 and PD-L2 and their use in cancer therapies.

Inventors

• PERICLE, FEDERICA
• CURRAN, MICHAEL A.

Assignees

• Curran, Michael A.
• ImmunoGenesis, Inc.

Dates

Publication Date

20260506

Application Date

20240701

Claims (1)

1. CLAIMS What Is Claimed: 1. A method of treating glioma comprising administering to a subject in need thereof a composition comprising an effective amount of a STING agonist of Formula Ia: or a salt, ester, tautomer, or prodrug thereof, wherein: A 1 and A 2 are independently selected from CH and N; R 1a and R 1b are independently selected from H and NH 2 ; R 2 is selected from OH, F, Cl, N 3 , and NH 2 ; R 3 is selected from OH, F, Cl, N 3 , and NH 2 ; R 4a and R 4b are independently selected from NH 2 , OH, NHR 5 , and OR 5 ; and R 5 is independently selected from methyl, ethyl, and propyl. 2. The method of claim 1, wherein A 1 is CH and A 2 is N. 3. The method of claim 1, wherein A 1 is N and A 2 is CH. 4. The method of claim 1, wherein A 1 and A 2 are both CH. 5. The method of claim 1, wherein A 1 and A 2 are both N. 6. The method of claim 1, wherein A 1 is N and A 2 is CH, and R 2 is selected from F and Cl, and R 3 is -OH. 7 The method of claim 1, wherein A 1 and A 2 are both N, and R 2 is selected from F and Cl, and R 3 is OH. 8 The method of claim 1, wherein R 1a and R 1b are both H. 9. The method of claim 1, wherein R 4a and R 4b are independently selected from NH 2 and NHR 5 . 10. The method of claim 1, wherein R 4a and R 4b are independently selected from NH 2 and NHR 5 , R 1a and R 1b are both H, A 1 and A 2 are both N, R 2 is selected from F and Cl, and R 3 is OH. 11. The method of claim 1, wherein R 4a and R 4b are independently selected from NH 2 and NHR 5 , R 1a and R 1b are both H, A 1 is N and A 2 is CH, R 2 is selected from F and Cl, and R 3 is OH. 12. The method of claim 1, wherein R 4a and R 4b are both NH 2 . 13. The method of claim 1, wherein R 4a and R 4b are both NH 2 , and R 1a and R 1b are both H. 14. The method of claim 1, wherein the STING agonist is: or a pharmaceutically acceptable salt thereof. 15. The method of claim 1, wherein the STING agonist is: or a pharmaceutically acceptable salt thereof. 16. The method of claim 1, wherein the STING agonist is: or a pharmaceutically acceptable salt thereof. 17. The method of claim 1, wherein the glioma is astrocytomas, ependymomas, or oligodendrogliomas. 18. The method of claim 1, wherein the effective amount is from about 0.005 to about 50 mg/kg body weight. 19. The method of claim 1 wherein the composition is administered with a second therapeutic agent. 20 The method of claim 1 wherein the composition is administered in combination with a chemotherapeutic agent.

Description

COMPOSITIONS COMPRISING STING AGONISTS AND METHODS OF USE FOR TREATING GLIOMA CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. provisional patent application no. 63/524,349, which was filed on June 30, 2023 and is incorporated herein by reference in its entirety. STATEMENT REGARDING SEQUENCE LISTING [0002] The Sequence Listing XML associated with this application is provided in XML file format and is hereby incorporated by reference into the specification. The name of the XML file containing the Sequence Listing XML is IMGE_025_01WO_SeqList_ST26.xml. The XML file is 27.3 kilobytes, was created on July 1, 2024, and is being submitted electronically via USPTO Patent Center. FIELD [0003] The present disclosure relates generally to the field of medicine, oncology, and immunology. More particularly, the invention provides highly active cyclic-di-nucleotide (CDN) immune stimulators that are highly effective in treating gliomas that occur in the brain and in various locations in the nervous system, including the brain stem and spinal column. BACKGROUND [0004] Blockade of T cell co-inhibitory receptor PD-1 interaction with its ligand PD-L1 has become a pillar of modern oncology, which is now available even in the first line setting for subsets of melanoma and lung cancer patients (Boussiotis, 2016). Numerous antibodies targeting PD-1 or PD-L1 are currently FDA approved or in clinical trials; however, no agents targeting the second PD-1 ligand, PD-L2, are under development. PD-L2 binds PD-1 with an approximately 5-fold higher affinity than does PD-L1, and, like PD-L1, sends an inhibitory signal which attenuates T cell function (Cheng et al., 2013; Latchman et al., 2001; Lee et al., 2016; Li et al., 2017; Youngnak et al., 2003). If both ligands are present at similar expression levels, PD-L2 would be predicted to outcompete PD-L1 binding to PD-1 (Miao YR et al., BioRxiv -2020). Historically, PD-L2 was considered to be largely an inducible co-inhibitory molecule with expression limited to the tumor stroma; however, improved detection reagents for PD-L2 have revealed widespread PD-L2 expression both in the tumor microenvironment and on tumor cells themselves (Baptista et al., 2016; Danilova et al., 2016; Derks et al., 2015; Dong et al., 2016; Howitt et al., 2016; Kim et al., 2015; Kim et al., 2015; Nomi et al., 2007; Obeid et al., 2016; Ohigashi et al., 2005; Roemer et al., 2016; Shi et al., 2014; Shin et al., 2015; Xu et al., 2016). Recently, PD-L2 was shown to be an independent predictor of response to the PD-1 antibody pembrolizumab across multiple cancers (Yearley et al., 2017). The inventors have previously identified a dual specific antibody, which is disclosed in PCT International Application Publication No. WO 2019/182,867, which is incorporated herein by reference in its entirety. [0005] The inventors have identified administering a STING agonist of the invention and an antibody of the invention or an ADC comprised of a STING agonist of the invention and an antibody of the invention, wherein the antibody is a highly specific, antibody that selectively binds to PD-L1 and LD-L2 or a dual specific antibody that selectively binds to both PD-L1 and PD-L2 while also exhibiting little to no off-target binding is effective is reducing or ameliorating a tumor cell or treating various types of cancer. SUMMARY [0006] The invention generally encompasses methods of treating glioma and related disorders by administering a STING agonist of the invention to a subject in need thereof. [0007] In certain embodiments of the invention, the STING agonist compounds of the invention have a structure of Formula Ia: or a salt, ester, hydrate, or solvate thereof, wherein: A1 and A2 are independently selected from CH and N; R1a and R1b are independently selected from H and NH2; R2 is selected from OH, F, Cl, N3, and NH2; R3 is selected from OH, F, Cl, N3, and NH2; R4a and R4b are independently selected from NH2, OH, NHR5, and OR5; and R5 is independently selected from methyl, ethyl, and propyl. [0008] Also included are all stereoisomers, including enantiomers and diastereomers, of compounds of Formula Ia. [0009] In certain embodiments of the present invention, compounds have structural Formula IIa: or a salt, ester, tautomer, solvate, hydrate, or prodrug thereof, wherein: [0010] A1 and A2 are independently selected from CH and N; [0011] R1a and R1b are independently selected from H and NH2; [0012] R2 is selected from OH, F, and Cl; [0013] R3 is OH; and [0014] R4a and R4b are independently selected from NH2 and OH. [0015] Also provided are stereoisomeric forms of Formula IIa, including enantiomers and diastereomers for which the phosphorus indicated in Formula IIa has R absolute stereochemistry. [0016] In certain embodiments of any of Formulas Ia and IIa, A1 is CH and A2 is N. [0017] In certain embodiments of any of Formulas Ia and IIa, A1 is N and A2 is CH. [0018] In certain embodiments of