CYTOTOXICITY TARGETING CHIMERAS FOR CXCR3-EXPRESSING CELLS
The present disclosure relates to heterobifunctional molecules, referred to as cytotoxicity targeting chimeras (CyTaCs) or antibody recruiting molecules (ARMs) that are able to simultaneously bind a target cell-surface protein as well as an exogenous antibody protein. The present disclosure also relates to agents capable of binding to a receptor on a surface of a pathogenic cell and inducing the depletion of the pathogenic cell in a subject for use in the treatment of cancer, inflammatory diseases, or autoimmune diseases.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is C 1-4 alkyl or C 3-6 cycloalkyl;
L is a divalent linker of Formula (L-a) or (L-e):
or a stereoisomer thereof,
wherein:
Ring A and Ring B are each independently C 4-6 cycloalkylene;
L 1a is C 3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with —O— or —NR a —;
each R a is independently hydrogen or C 1-3 alkyl; and
L 2a is —O—, —NHC(O)—, or —CH 2 —O—; or
wherein n is an integer of 3 to 50;
wherein each represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and each represents a covalent bond to the methylene group of Formula (I); and
Y is a bond or a divalent spacer moiety of one to twelve atoms in length.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 3 .
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-a-i):
or a stereoisomer thereof,
wherein Ring A, L 1a , L 2a , , and are as defined for Formula (L-a).
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-a-ii):
or a stereoisomer thereof,
wherein L 1a , L 2a , , and are as defined for Formula (L-a); p is 1 or 2; and m is 1 or 2.
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-a-iii):
or a stereoisomer thereof,
wherein p is 1 or 2; m is 1 or 2; n is 1, 2, or 3; and and are as defined for Formula (L-a).
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-a) selected from the group consisting of:
7 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein Y is a bond.
8 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
9 . A method of treating and/or preventing a disease or disorder in a patient in need thereof, the method comprising: administering to the patient a therapeutically effective amount of the compound of claim 1 and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the disease or disorder is selected from a cancer, an inflammatory disease, or an autoimmune disease.
10 . The method of claim 9 , wherein the disease or disorder is mediated by C—X—C motif chemokine receptor 3 (CXCR3) and/or is associated with CXCR3-positive pathogenic cells.
11 . The method of claim 9 , wherein the disease is a cancer that is a solid tumor.
12 . The method of claim 9 , wherein the disease or disorder is a cancer i-s-selected from leukemia, lymphoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), cervical squamous cell carcinoma (CESC), head and neck squamous cell carcinoma (HNSC), pancreatic cancer, metastatic castration-resistant prostate cancer (mCRPC), ovarian cancer, bladder cancer, melanoma cancer, or breast cancer.
13 . (canceled)
14 . (canceled)
15 . (canceled)
16 . A method of increasing antibody-dependent cell cytotoxicity (ADCC) of C—X—C motif chemokine receptor 3 (CXCR3)-expressing cells, the method comprising: contacting the cells with an effective amount of claim 1 and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the CXCR3-binding moiety of the compound binds the CXCR3 expressed on the cells.
17 . A method of depleting C—X—C motif chemokine receptor 3 (CXCR3)-expressing cells, the method comprising: contacting the cells with an effective amount of the compound of claim 1 and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the CXCR3-binding moiety of the compound binds the CXCR3 expressed on the cells.
18 . (canceled)
19 . The method of claim 12 , wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6.
20 . The method of claim 12 , wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO: 8.
21 . The method of claim 20 , wherein the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase ADCC activity.
22 . (canceled)
23 . The method of claim 12 , wherein the anti-cotinine antibody has a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.
24 . A combination comprising the compound of claim 1 and an anti-cotinine antibody, or antigen-binding fragment thereof.
25 . The combination of claim 24 , wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6.
26 . The combination of claim 25 , wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO: 8.
27 . (canceled)
28 . (canceled)
29 . The combination of claim 24 , wherein the anti-cotinine antibody has a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.