Antibody adjuvant conjugates

Abstract

The invention provides an immunoconjugate comprising an antibody construct which includes an antigen binding domain and an Fc domain, an adjuvant moiety, and a linker, wherein each adjuvant moiety is covalently bonded to the antibody via the linker. Methods for treating cancer with the immunoconjugates of the invention are also described.

1 . A composition comprising a plurality of immunoconjugates and one or more pharmaceutically acceptable excipients, the immunoconjugates each independently comprising
 (a) an antibody construct comprising (i) an antigen binding domain and (ii) an Fc domain,   (b) an adjuvant moiety of formula:   
       
         
           
           
               
               
           
         
       
       wherein each J independently is hydrogen, OR 4 , or R 4 , each R 4  independently is hydrogen, or an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group comprising from 1 to 8 carbons, each U independently is CH or N wherein at least one U is N, each subscript t independently is an integer from 1 to 3, Q is optionally present and is an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group comprising from 1 to 8 carbons, and the dashed line (“ ”) represents the point of attachment of the adjuvant, and
 (c) a linker, 
 
       wherein the adjuvant moiety is covalently bonded to the antibody construct via the linker. 
     
     
         2 . The composition of  claim 1 , wherein the antigen binding domain binds to an antigen selected from the group consisting of CDH1, CD19, CD20, CD29, CD30, CD38, CD40, EpCAM, MUC1, MUC16, VEGF, SLAMF7, PDGFRa, gp75, CTLA4, CD47, EGFR, PD-L1, PD-1, PD-L2, LAG-3, B7-H4, KIR, TNFRSF4, OX40L, IDO-1, IDO-2, BTLA, TIM3, A2Ar, VISTA, CEACAM1, CLEC4C (BDCA-2, DLEC, CD303, CLECSF7), CLEC4D (MCL, CLECSF8), CLEC4E (Mincle), CLEC6A (Dectin-2), CLEC5A (MDL-1, CLECSF5), CLEC1B (CLEC-2), CLEC9A (DNGR-1), and CLEC7A (Dectin-1). 
     
     
         3 . The composition of  claim 1 , wherein the antigen binding domain binds to HER2. 
     
     
         4 . The composition of  claim 1 , wherein the antibody construct is an antibody. 
     
     
         5 . The composition of  claim 4 , wherein the antibody is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, avelumab, ipilimumab, obinutuzumab, cetuximab, rituximab, pertuzumab, bevacizumab, daratumumab, etanercept, olaratumab, elotuzumab, margetuximab, and biosimilars thereof. 
     
     
         6 . The composition of  claim 4 , wherein the antibody is trastuzumab or a biosimilar thereof. 
     
     
         7 . The composition of  claim 4 , wherein the antibody comprises a modified Fc domain, wherein (i) the modified Fc domain contains at least one amino acid insertion, deletion, or substitution and/or (ii) the modified Fc domain is deglycosylated or afucosylated. 
     
     
         8 . The composition of  claim 4 , wherein the immunoconjugates each independently have a structure according to Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         Ab is the antibody with 
       
       
         
           
           
               
               
           
         
          being an amino acid residue of the antibody, wherein A is a modified or unmodified sidechain of the amino acid residue, 
         Z is the linker, 
         Adj is the adjuvant moiety, and
 subscript r is an integer from 1 to 10. 
 
       
     
     
         9 . The composition of  claim 4 , wherein the immunoconjugates each independently have a structure according to Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         Ab is the antibody with 
       
       
         
           
           
               
               
           
         
          being an amino acid residue of the antibody, wherein A is a lysine sidechain, thiol-modified lysine sidechain, or cysteine sidechain of the amino acid residue, 
         Adj is the adjuvant moiety, 
         subscript r is an integer 1 to 10,
 Z 1  is selected from —C(O)—, —C(O)NH—, and —CH 2 —, 
 Z 2  and Z 4  are each independently selected from a bond, C 1-30  alkylene, and 3- to 30-membered heteroalkylene, wherein
 one or more groupings of adjacent atoms in the C 1-30  alkylene and 3- to 30-membered heteroalkylene are optionally and independently replaced by —C(O)—, —NR a C(O)—, or —C(O)NR a —, wherein each R a  is independently selected from H and C 1-6  alkyl, 
 one or more groupings of adjacent atoms in the C 1-30  alkylene and 3- to 30-membered heteroalkylene are optionally and independently replaced by a 4- to 8-membered divalent carbocycle, and 
 one or more groupings of adjacent atoms in the C 1-30  alkylene and 3- to 30-membered heteroalkylene are optionally and independently replaced by a 4- to 8-membered divalent heterocycle having one to four heteroatoms selected from O, S, and N, 
 
 Z 3  is a bond, a divalent peptide moiety, or a divalent polymer moiety, and 
 Z 5  is selected from an amine-bonded moiety and a thiol-bonded moiety. 
 
       
     
     
         10 . The composition of  claim 4 , wherein the immunoconjugates each independently have a structure according to Formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         Ab is the antibody with 
       
       
         
           
           
               
               
           
         
          being a lysine residue of the antibody, 
         Adj is the adjuvant moiety, 
         G is CH2, C═O, or a bond, 
         L is a linking moiety, and
 subscript r is an integer from 1 to 10. 
 
       
     
     
         11 . The composition of  claim 10 , wherein L is selected from: 
       
         
           
           
               
               
           
         
         wherein R is optionally present and is a linear or branched, cyclic or straight, saturated or unsaturated alkyl, heteroalkyl, aryl, or heteroaryl chain comprising from 1 to 8 carbons, a is an integer from 1 to 40, each A is independently selected from any amino acid, subscript c is an integer from 1 to 20, the dashed line (“ ”) represents the point of attachment to 
       
       
         
           
           
               
               
           
         
          and the wavy line (“ ”) represents the point of attachment to 
       
       
         
           
           
               
               
           
         
       
     
     
         12 . The composition of  claim 10 , wherein L is: 
       
         
           
           
               
               
           
         
       
       a is an integer from 1 to 40; the dashed line (“ ”) represents the point of attachment to 
       
         
           
           
               
               
           
         
       
       and the wavy line (“ ”) represents the point of attachment to 
       
         
           
           
               
               
           
         
       
       wherein each adjuvant moiety is covalently bonded to the antibody via the linker. 
     
     
         13 . The composition of  claim 12 , wherein G is a bond. 
     
     
         14 . The composition of  claim 13 , wherein a is an integer from 1 to 10. 
     
     
         15 . The composition of  claim 14 , wherein is r is an integer from 1 to 5. 
     
     
         16 . The composition of  claim 1 , wherein Q is not present. 
     
     
         17 . The composition of  claim 16 , wherein each U is N and each subscript t is 2. 
     
     
         18 . The composition of  claim 1 , wherein each U is N and each subscript t is 2. 
     
     
         19 . The composition of  claim 1 , wherein the adjuvant moiety is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The composition of  claim 6 , wherein Q is not present. 
     
     
         21 . The composition of  claim 20 , wherein each U is N and each subscript t is 2. 
     
     
         22 . The composition of  claim 6 , wherein each U is N and each subscript t is 2. 
     
     
         23 . The composition of  claim 6 , wherein the adjuvant moiety is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The composition of  claim 1 , wherein the immunoconjugates each independently have a structure according to Formula IIIb: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 Ab is an antibody construct comprising (i) an antigen binding domain and (ii) an Fc domain, Adj is an adjuvant moiety of formula: 
 
       
       
         
           
           
               
               
           
         
         wherein R 4  is an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group comprising from 1 to 8 carbons, each J is hydrogen, each U is N, each t is 2, Q is not present, the dashed line (“ ”) represents a point of the adjuvant to G, and G is a bond; subscript a is an integer from 1 to 20; and subscript r is an integer from 1 to 10. 
       
     
     
         25 . The composition of  claim 24 , wherein the antigen binding domain binds to an antigen selected from the group consisting of CDH1, CD19, CD20, CD29, CD30, CD38, CD40, EpCAM, MUC1, MUC16, VEGF, SLAMF7, PDGFRa, gp75, CTLA4, CD47, EGFR, PD-L1, PD-1, PD-L2, LAG-3, B7-H4, KIR, TNFRSF4, OX40L, IDO-1, IDO-2, BTLA, TIM3, A2Ar, VISTA, CEACAM1, CLEC4C (BDCA-2, DLEC, CD303, CLECSF7), CLEC4D (MCL, CLECSF8), CLEC4E (Mincle), CLEC6A (Dectin-2), CLEC5A (MDL-1, CLECSF5), CLEC1B (CLEC-2), CLEC9A (DNGR-1), and CLEC7A (Dectin-1). 
     
     
         26 . The composition of  claim 24 , wherein the antigen binding domain binds to HER2. 
     
     
         27 . The composition of  claim 24 , wherein the antibody construct is an antibody. 
     
     
         28 . The composition of  claim 27 , wherein the antibody is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, avelumab, ipilimumab, obinutuzumab, cetuximab, rituximab, pertuzumab, bevacizumab, daratumumab, etanercept, olaratumab, elotuzumab, margetuximab, and biosimilars thereof. 
     
     
         29 . The composition of  claim 27 , wherein the antibody is trastuzumab or a biosimilar thereof. 
     
     
         30 . The composition of  claim 27 , wherein the antibody comprises a modified Fc domain, wherein (i) the modified Fc domain contains at least one amino acid insertion, deletion, or substitution and/or (ii) the modified Fc domain is deglycosylated or afucosylated. 
     
     
         31 . The composition of  claim 24 , wherein a is an integer from 1 to 10. 
     
     
         32 . The composition of  claim 24 , wherein R 4  is a heteroalkyl group comprising from 1 to 8 carbons. 
     
     
         33 . The composition of  claim 24 , wherein R 4  is an alkyl group comprising from 1 to 8 carbons. 
     
     
         34 . The composition of  claim 24 , wherein R 4  is butyl. 
     
     
         35 . The composition of  claim 24 , wherein the adjuvant moiety is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         36 . The composition of  claim 29 , wherein a is an integer from 1 to 10. 
     
     
         37 . The composition of  claim 29 , wherein R 4  is a heteroalkyl group comprising from 1 to 8 carbons. 
     
     
         38 . The composition of  claim 29 , wherein R 4  is an alkyl group comprising from 1 to 8 carbons. 
     
     
         39 . The composition of  claim 29 , wherein R 4  is butyl. 
     
     
         40 . The composition of  claim 29 , wherein the adjuvant moiety is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         41 . The composition of  claim 1 , wherein the average number of adjuvant moieties per immunoconjugate ranges from about 1 to about 4. 
     
     
         42 . The composition of  claim 6 , wherein the average number of adjuvant moieties per immunoconjugate ranges from about 1 to about 4. 
     
     
         43 . The composition of  claim 23 , wherein the average number of adjuvant moieties per immunoconjugate ranges from about 1 to about 4. 
     
     
         44 . The composition of  claim 24 , wherein the average number of adjuvant moieties per immunoconjugate ranges from about 1 to about 4. 
     
     
         45 . The composition of  claim 29 , wherein the average number of adjuvant moieties per immunoconjugate ranges from about 1 to about 4. 
     
     
         46 . The composition of  claim 40 , wherein the average number of adjuvant moieties per immunoconjugate ranges from about 1 to about 4. 
     
     
         47 . A method for treating a HER2 expressing cancer comprising administering a therapeutically effective amount of a composition according to  claim 1  to a subject in need thereof. 
     
     
         48 . The method of  claim 47 , wherein the cancer is liver cancer, gall bladder cancer, bile duct cancer, cervical cancer, esophageal cancer, melanoma, breast cancer, gastric cancer, ovarian cancer, uterine cancer, bladder cancer, lung cancer, head and neck cancer, or colorectal cancer. 
     
     
         49 . A method for treating a HER2 expressing cancer comprising administering a therapeutically effective amount of a composition according to  claim 6  to a subject in need thereof. 
     
     
         50 . The method of  claim 49 , wherein the cancer is liver cancer, gall bladder cancer, bile duct cancer, cervical cancer, esophageal cancer, melanoma, breast cancer, gastric cancer, ovarian cancer, uterine cancer, bladder cancer, lung cancer, head and neck cancer, or colorectal cancer. 
     
     
         51 . A method for treating a HER2 expressing cancer comprising administering a therapeutically effective amount of a composition according to  claim 23  to a subject in need thereof. 
     
     
         52 . The method of  claim 51 , wherein the cancer is liver cancer, gall bladder cancer, bile duct cancer, cervical cancer, esophageal cancer, melanoma, breast cancer, gastric cancer, ovarian cancer, uterine cancer, bladder cancer, lung cancer, head and neck cancer, or colorectal cancer. 
     
     
         53 . A method for treating a HER2 expressing cancer comprising administering a therapeutically effective amount of a composition according to  claim 24  to a subject in need thereof. 
     
     
         54 . The method of  claim 53 , wherein the cancer is liver cancer, gall bladder cancer, bile duct cancer, cervical cancer, esophageal cancer, melanoma, breast cancer, gastric cancer, ovarian cancer, uterine cancer, bladder cancer, lung cancer, head and neck cancer, or colorectal cancer. 
     
     
         55 . A method for treating a HER2 expressing cancer comprising administering a therapeutically effective amount of a composition according to  claim 29  to a subject in need thereof. 
     
     
         56 . The method of  claim 55 , wherein the cancer is liver cancer, gall bladder cancer, bile duct cancer, cervical cancer, esophageal cancer, melanoma, breast cancer, gastric cancer, ovarian cancer, uterine cancer, bladder cancer, lung cancer, head and neck cancer, or colorectal cancer. 
     
     
         57 . A method for treating a HER2 expressing cancer comprising administering a therapeutically effective amount of a composition according to  claim 40  to a subject in need thereof. 
     
     
         58 . The method of  claim 57 , wherein the cancer is liver cancer, gall bladder cancer, bile duct cancer, cervical cancer, esophageal cancer, melanoma, breast cancer, gastric cancer, ovarian cancer, uterine cancer, bladder cancer, lung cancer, head and neck cancer, or colorectal cancer. 
     
     
         59 . A method for treating a HER2 expressing cancer comprising administering a therapeutically effective amount of a composition according to  claim 41  to a subject in need thereof. 
     
     
         60 . The method of  claim 59 , wherein the cancer is liver cancer, gall bladder cancer, bile duct cancer, cervical cancer, esophageal cancer, melanoma, breast cancer, gastric cancer, ovarian cancer, uterine cancer, bladder cancer, lung cancer, head and neck cancer, or colorectal cancer. 
     
     
         61 . A method for treating a HER2 expressing cancer comprising administering a therapeutically effective amount of a composition according to  claim 42  to a subject in need thereof. 
     
     
         62 . The method of  claim 61 , wherein the cancer is liver cancer, gall bladder cancer, bile duct cancer, cervical cancer, esophageal cancer, melanoma, breast cancer, gastric cancer, ovarian cancer, uterine cancer, bladder cancer, lung cancer, head and neck cancer, or colorectal cancer. 
     
     
         63 . A method for treating a HER2 expressing cancer comprising administering a therapeutically effective amount of a composition according to  claim 43  to a subject in need thereof. 
     
     
         64 . The method of  claim 63 , wherein the cancer is liver cancer, gall bladder cancer, bile duct cancer, cervical cancer, esophageal cancer, melanoma, breast cancer, gastric cancer, ovarian cancer, uterine cancer, bladder cancer, lung cancer, head and neck cancer, or colorectal cancer. 
     
     
         65 . A method for treating a HER2 expressing cancer comprising administering a therapeutically effective amount of a composition according to  claim 44  to a subject in need thereof. 
     
     
         66 . The method of  claim 65 , wherein the cancer is liver cancer, gall bladder cancer, bile duct cancer, cervical cancer, esophageal cancer, melanoma, breast cancer, gastric cancer, ovarian cancer, uterine cancer, bladder cancer, lung cancer, head and neck cancer, or colorectal cancer. 
     
     
         67 . A method for treating a HER2 expressing cancer comprising administering a therapeutically effective amount of a composition according to  claim 45  to a subject in need thereof. 
     
     
         68 . The method of  claim 67 , wherein the cancer is liver cancer, gall bladder cancer, bile duct cancer, cervical cancer, esophageal cancer, melanoma, breast cancer, gastric cancer, ovarian cancer, uterine cancer, bladder cancer, lung cancer, head and neck cancer, or colorectal cancer. 
     
     
         69 . A method for treating a HER2 expressing cancer comprising administering a therapeutically effective amount of a composition according to  claim 46  to a subject in need thereof. 
     
     
         70 . The method of  claim 69 , wherein the cancer is liver cancer, gall bladder cancer, bile duct cancer, cervical cancer, esophageal cancer, melanoma, breast cancer, gastric cancer, ovarian cancer, uterine cancer, bladder cancer, lung cancer, head and neck cancer, or colorectal cancer.