Antibody drug conjugates comprising sting agonists

Abstract

The present disclosure provides scaffolds and antibody-drug conjugates (ADCs) comprising a stimulator of interferon genes (STING). The present disclosure also provides uses of the ADCs in treatment, e.g., treatment of cancer.

1 . An antibody-drug conjugate (ADC) of Formula (I):
   PBRM-[A 1 -(L C ) 0 or 1 -D] d15   (I)
   
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 PBRM denotes a protein-based recognition-molecule; 
 L C , when present, is a linker unit; 
 A 1  is a divalent linker moiety connecting the PBRM to L C  when L C  is present, or to D when L C  is absent; 
 D is a STING agonist drug moiety; and 
 d 15  is an integer from about 1 to about 20. 
 
     
     
         2 . A scaffold useful for conjugating with a PBRM, wherein the scaffold is of Formula (II):
   A 1′ -(L C ) 0 or 1 -D  (II)
   or a pharmaceutically acceptable salt or solvate thereof, wherein:   L C , when present, is a linker unit;   A 1′  is a monovalent linker moiety comprising a functional group capable of forming a covalent bond with a functional group of the PBRM; and   D is a STING agonist drug moiety.   
     
     
         3 . The conjugate of  claim 1 , wherein each L C , when present, independently is 
       
         
           
           
               
               
           
         
       
       wherein:
 # denotes attachment to A 1  and ## denotes attachment to D; 
 M A , when present, is a peptide moiety comprising at least two amino acids; 
 T 1 , when present, is a hydrophilic group; 
 L D  is a divalent linker moiety connecting D to M A  when M A  is present, or D to A 1  when M A  is absent; 
 wherein each L D  independently is 
 
       
         
           
           
               
               
           
         
          wherein: 
         L E , when present, is —NH—[(CH 2 CH 2 O) p —(CH 2 ) 0-2 ] q —C(O)—, —NH—(C 1 -C 6  alkyl)-O—C(O)—, or —NH—[(CH 2 CH 2 O) P —(CH 2 ) 0-2 ] q —C(O)—NH—(C 1 -C 6  alkyl)-O—C(O)—, wherein p is an integer ranging from about 1 to about 20, and q is an integer ranging from about 1 to about 10; 
         each W independently is a natural or unnatural amino acid unit; 
         w is an integer ranging from about 0 to about 12; 
         *** denotes attachment to M A  when M A  is present or to A 1  when M A  is absent; and 
         **** denotes attachment to D. 
       
     
     
         4 . (canceled) 
     
     
         5 . The conjugate of  claim 1 , wherein each A 1  independently is: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 7  is —O—, —NR 8 , —(C 1 -C 10  alkyl)-, —(C 1 -C 10  alkenyl)-, —(C 1 -C 10  alkynyl)-, —(C 3 -C 8  cycloalkyl)-, -aryl-, —O—(C 1 -C 8  alkyl)-, —O—(C 1 -C 10  alkenyl)-, —O—(C 1 -C 10  alkynyl)-, —(C 1 -C 10  alkyl)-(C 3 -C 8  cycloalkyl)-, —(C 1 -C 10  alkyl)-aryl-, —(C 2 -C 10  alkenyl)-(C 3 -C 8  cycloalkyl)-, —(C 2 -C 10  alkenyl)-aryl-, —(C 2 -C 10  alkynyl)-(C 3 -C 8  cycloalkyl)-, —(C 2 -C 10  alkynyl)-aryl-, —(C 3 -C 8  cycloalkyl)-(C 1 -C 10  alky)-, -aryl-(C 1 -C 10  alky)-, —(C 3 -C 8  cycloalkyl)-(C 2 -C 10  alkenyl)-, -aryl-(C 2 -C 10  alkenyl)-, —(C 3 -C 8  cycloalkyl)-(C 2 -C 10  alkynyl)-, -aryl-(C 2 -C 10  alkynyl)-, -(3- to 8-membered heterocycloalkyl)-, -(5- to 8-membered heteroaryl)-, —(C 1 -C 10  alkyl)-(3- to 8-membered heterocycloalkyl)-, —(C 1 -C 10  alkyl)-(5- to 8-membered heteroaryl)-, —(C 2 -C 10  alkenyl)-(3- to 8-membered heterocycloalkyl)-, —(C 2 -C 10  alkenyl)-(5- to 8-membered heteroaryl)-, —(C 2 -C 10  alkynyl)-(3- to 8-membered heterocycloalkyl)-, —(C 2 -C 10  alkynyl)-(5- to 8-membered heteroaryl)-, -(3- to 8-membered heterocycloalkyl)-(C 1 -C 10  alkyl)-, -(5- to 8-membered heteroaryl)-(C 1 -C 10  alkyl)-, -(3- to 8-membered heterocycloalkyl)-(C 2 -C 10  alkenyl)-, -(5- to 8-membered heteroaryl)-(C 2 -C 10  alkenyl)-, -(5- to 8-membered heteroaryl)-(C 2 -C 10  alknyl)-, -(5- to 8-membered heteroaryl)-(C 2 -C 10  alknyl)-, —O—C(O)—(CH 2 CH 2 O) r —(CH 2 ) 2 —, —(CH 2 CH 2 O) r —, or —(CH 2 CH 2 O) r —(CH 2 ) 2 —, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted; 
 R 8  is H, hydroxy, or C 1-4  alkyl; 
 r is an integer ranging from about 1 to about 12; and 
 * denotes attachment to PBRM and ** denotes attachment to L C  when L C  is present, or to D when L C  is absent. 
 
     
     
         6 . The conjugate of  claim 1 , wherein each A 1′  independently is: 
       
         
           
           
               
               
           
         
       
       wherein:
 r is an integer ranging from about 4 to about 6; and 
 ** denotes attachment to L C  when L C  is present, or to D when L C  is absent. 
 
     
     
         7 . The conjugate of  claim 3 , wherein each L D  independently is 
       
         
           
           
               
               
           
         
       
       wherein:
 L E , when present, is —NH—[(CH 2 CH 2 O) p —(CH 2 ) 0-2 ] q —C(O)—, —NH—(C 1 -C 6  alkyl)-O—C(O)—, or —NH—[(CH 2 CH 2 O) p —(CH 2 ) 0-2 ] q —C(O)—NH—(C 1 -C 6  alkyl)-O—C(O)—, wherein p is an integer ranging from about 1 to about 20, and q is an integer ranging from about 1 to about 10; 
 each W independently is a natural or unnatural amino acid unit; 
 w is an integer ranging from about 0 to about 12; 
 *** denotes attachment to M A  when M A  is present, or to A 1  when M A  is absent; and 
 **** denotes attachment to D. 
 
     
     
         8 . (canceled) 
     
     
         9 . The conjugate of  claim 7 , wherein L E , when present, is —NH—(CH 2 CH 2 O) 2 —(CH 2 ) 2 —C(O)—, —NH—CH 2 —CH(CH 3 )—O—C(O)—, or —NH—[(CH 2 CH 2 O) 1-4 —(CH 2 ) 2 —C(O)—NH—(CH 2 ) 2 —O—C(O)—; and w is 0, 1, 2, 3, 4, or 5. 
     
     
         10 . The conjugate of  claim 3 , wherein each L D , when present, independently is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein: *** denotes attachment to M A  when M A  is present, or to A 1  when M A  is absent; and **** denotes attachment to D. 
       
     
     
         11 . (canceled) 
     
     
         12 . The conjugate of  claim 3 , wherein L D  is 
       
         
           
           
               
               
           
         
       
       wherein:
 *** denotes attachment to M A  when M A  is present, or to A 1  when M A  is absent; and 
 **** denotes attachment to D; and 
 M A  is 
 
       
         
           
           
               
               
           
         
         wherein: * indicates attachment to A 1 ; ** indicates attachment to T 1 ; and *** indicates attachment to L D . 
       
     
     
         13 . (canceled) 
     
     
         14 . The conjugate of  claim 3 , wherein T 1  is —OH or 
       
         
           
           
               
               
           
         
       
       wherein:
 n 1  is an integer from 0 to about 6; 
 each R 58  is independently —H or C 1-8  alkyl; 
 R 60  is a bond, a C 1-6  alkyl linker, or —CHR 59 — wherein R 59  is —H, C 1-8  alkyl, cycloalkyl, or arylalkyl;
 R 61  is CH 2 OR 62 , COOR 62 , —(CH 2 ) n2 COOR 62 , or a heterocycloalkyl substituted with one or more hydroxyl; 
 R 62  is —H or C 1-8  alkyl; and 
 n 2  is an integer from 1 to about 5. 
 
 
     
     
         15 . The conjugate of  claim 14 , wherein T 1  is 
       
         
           
           
               
               
           
         
       
     
     
         16 . The conjugate of  claim 3 ,
 wherein T 1  is   
       
         
           
           
               
               
           
         
         wherein
 n 4  is an integer from 1 to about 25; 
 each R 63  is independently hydrogen or C 1-8  alkyl; 
 R 64  is a bond or a C 1-8  alkyl linker; 
 R 65  is H, C 1-8  alkyl, —(CH 2 ) n2 COOR 62  or —(CH 2 ) n2 COR 66 ; 
 R 62  is H or C 1-8  alkyl; 
 R 66  is H, 
 
       
       
         
           
           
               
               
           
         
         
            and 
           n 2  is an integer from 1 to about 5. 
         
       
     
     
         17 . The conjugate of  claim 3 ,
 wherein T 1  is:   
       
         
           
           
               
               
           
         
         wherein R 67  is —OH; 
       
       
         
           
           
               
               
           
         
         wherein n 4  is an integer from about 2 to about 20, from about 4 to about 16, from about 6 to about 12, from about 8 to about 12. 
       
     
     
         18 .- 20 . (canceled) 
     
     
         21 . The conjugate of  claim 1 ,
 wherein each D independently is of Formula (A):   
       
         
           
           
               
               
           
         
       
       or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein:
 Y 1 , Y 2 , Z 1  and Z 2  are each independently O, S, C or N; 
 X 1 , X 2 , W 1  and W 2  are each independently C or N; 
 X 3  and X 4  are each independently S or NR f ; 
 X 5  is N or CR A2 ; 
 X 6  is N or CR A1 ; 
 R 3  and R 5  are each independently —CON(R d )(R f ), —CH 2 N(R d )(R f ), —N(R d )(R f ), —N(R d )CO(R f ), —CH 2 N(R d )CO(R f ) or one of R 3  and R 5  is —CON(R d )(R f ), —CH 2 N(R d )(R f ), —N(R d )(R f ), —N(R d )CO(R f ) or —CH 2 N(R d )CO(R f ), and the other of R 3  and R 5  is H, —COOH, or —CO 2 (R C ); 
 R c  is C 1-4  alkyl; 
 R A2  and R A1  are each independently H, halogen, hydroxy, amino, amino(C 1-4  alkyl)-, optionally substituted (C 1-6  alkyl), or optionally substituted (C 1-6  alkyl)oxy-, wherein C 1-6  alkyl of said optionally substituted (C 1-6  alkyl), or optionally substituted (C 1-6  alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, C 1-4  alkoxyl, —N(R e )(R f ), —CO 2 (R f ), —CON(R e )(R f ), and —COOH; 
 each R d  is independently H, hydroxy, or C 1-4  alkyl; 
 R e  is selected from H, (C 1-4  alkyl), —CO(C 1-4  alkyl), —OCO(C 1-4  alkyl), and —CO 2 (C 1-4  alkyl); 
 each R f  is independently H, hydroxy, or (C 1-4  alkyl); 
 R 14  and R C2  are each independently absent or C 1-4  alkyl, wherein C 1-4  alkyl is optionally substituted by a substituent selected from halogen, —OR c , —NR c R d , —CO 2 R c , —CONR c R d , —SO 2 NR c R d , and —OCONR c R d ; 
 R 16  and R C1  are each independently absent, H or C 1-4  alkyl; and 
 R 15 , R 17 , R 18 , or R 19  are each independently absent, H, or C 1-4  alkyl, wherein C 1-4  alkyl is optionally substituted by a substituent selected from halogen, —OR c , —NR c R d , —CO 2 R c , —CONR c R d , —SO 2 NR c R d , and —OCONR c R d ; 
 wherein: (i) at least one of R A2  and R A1  is present, and wherein at least one of R A2  and R A1  is directly or indirectly connected to L C  when L C  is present, or to A 1  when L C  is absent, via at least one functional group of the R A2  and/or R A1 ; or (ii) at least one of R C2  and R C1  is present, and wherein at least one of R C2  and R C1  is directly or indirectly connected to L C  when L C  is present, or to A 1  when L C  is absent, via at least one functional group of the R C2  and/or R C1 . 
 
     
     
         22 . The conjugate of  claim 21 , wherein each D independently is of Formula (A-a), (A-b), (A-c), (A-d), (A-e), (A-f), (A-f1), (A-f2), (A-f)3, (A-f4), (A-f5), (A-g), (A-g1), (A-g2), (A-g3), (A-g4), (A-g5), (A-h), (A-h1), (A-h2), or (A-i): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof. 
     
     
         23 . The conjugate of  claim 21 , wherein each D independently is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 R 2  is absent, —O— or —NR 4 —; 
 R 4  is H or C 1-3  alkyl; and 
 
       
         
           
           
               
               
           
         
         denotes attachment to L C  when L C  is present, or to A 1  when L C  is absent. 
       
     
     
         24 . The conjugate of  claim 21 , wherein each D independently is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 R 2  is absent, —O— or —NR 4 —; 
 R 4  is H or C 1-4  alkyl; and 
 
       
         
           
           
               
               
           
         
         denotes attachment to L C  when L C  is present, or to A 1  when L C  is absent. 
       
     
     
         25 .- 28 . (canceled) 
     
     
         29 . The conjugate of  claim 1 , being 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         30 . The conjugate of  claim 29 , being 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         31 . (canceled) 
     
     
         32 . A pharmaceutical composition comprising the conjugate of  claim 1  and one or more pharmaceutically acceptable carriers or excipients. 
     
     
         33 . The pharmaceutical composition comprising the conjugate of  claim 1 , further comprising at least one immuno-modulator or at least one immunostimulatory agent. 
     
     
         34 . (canceled) 
     
     
         35 . A method of preventing or treating a cancer in a subject, comprising administering to the subject a therapeutically effective amount of the conjugate of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         36 - 41 . (canceled) 
     
     
         42 . The method of  claim 35 , wherein the disease or disorder is bladder cancer, breast cancer, colorectal cancer, colon cancer, endometrial cancer, gastric cancer, head and neck squamous carcinoma, melanoma, lung cancer, ovarian cancer, esophageal cancer, biliary cancer, urothelial cancer, cervical cancer, papillary thyroid cancer, papillary renal cell cancer, cholangiocarcinoma, salivary duct cancer, kidney cancer, or pancreatic cancer. 
     
     
         43 . A conjugate of Formula BB 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein the conjugate comprises the XMT-1519 antibody comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 20); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 21); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 22); and a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 27); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 28); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 29), and d 15  is about 8. 
       
     
     
         44 . A method of preventing or treating a cancer in a subject, comprising administering to the subject a therapeutically effective amount of the conjugate of  claim 43  or a pharmaceutically acceptable salt thereof. 
     
     
         45 . (canceled) 
     
     
         46 . The method of  claim 44 , wherein the cancer is breast cancer, gastric cancer, colorectal cancer, colon cancer, esophageal cancer, biliary cancer, endometrial cancer, urothelial cancer or non-small cell lung cancer.