Linker, antibody-drug conjugate including same and use thereof
Provided are a linker represented by Formula I or I′, an antibody-drug conjugate containing the same, and use of thereof, a pharmaceutical composition comprising the antibody-drug conjugate, and use of the antibody-drug conjugate for treating and/or preventing a disease.
1 . A compound represented by Formula III, a salt or a solvate thereof,
wherein:
A is a targeting compound selected from antibody; A is coupled to the site # or ## through a S atom in the B targeting compound;
B is an active compound selected from the group consisting of auristatin, methyl-auristatin E (MMAE), maytansine, maytansinoid, DM1, DM3, DM4, paclitaxel, calicheamicin, duocarmycin, doxorubicin, camptothecin, and pyrrolobenzodiazepine, wherein DM1, DM3 and DM4 are defined as:
B is coupled to the site * through a N atom or O atom in the active compound; or B is coupled to L 3 through a N atom or O atom in the active compound;
n is a number between 0.5 and 8.5;
R 1 is a C 1-6 linear or branched alkyl, and R 1 is optionally mono- or multi-substituted by one or more substituents selected from the group consisting of: halogen and C 1-4 alkoxy;
L 1 is selected from the group consisting of: —(CH 2 ) m —, —(CH 2 ) t O—, —(CH 2 CH 2 O) r —, —O—, —NH—, —S—, —S(O)—, —S(O) 2 —, —NCH 3 —, —NH(CH 2 ) 2 NH—, —C(O)—, —(CH 2 ) e —C(O)NH—(CH 2 CH 2 O) f —(CH 2 ) g —, —(CH 2 ) h —C(O)NH—CH[(CH 2 ) i —NHC(O)—(CH 2 CH 2 O)—(CH 2 ) k —CH 3 ]—,
q′ is 1 and q″ is 0, or q′ is 0 and q″ is 1;
R 3 is selected from the group consisting of: hydrogen, halogen, methyl, ethyl, nitro, methoxy, and ethoxy;
q is 0 or 1;
m, r, t, e, f, g, h, i, j and k are each independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11;
each p is independently 0, 1, 2, 3 or 4;
Y is an amino acid residue formed by a dipeptide selected from the group consisting of: Val-Cit, Val-Ala, Val-Lys, Val-Gly, Val-Thr, Val-Val, Val-Leu, Val-Ile, Val-Asn and Phe-Lys, wherein the N-terminus is connected to the carbonyl and the C-terminus is connected to the N atom;
Z is —CH 2 —, —CH(CH 3 )— or —C(CH 3 ) 2 —.
2 . The compound represented by Formula III according to claim 1 , a salt or a solvate thereof, wherein
L 1 is selected from the group consisting of: —(CH 2 ) m —, —(CH 2 ) t O—, —(CH 2 CH 2 O) r —, —O—, —NH—, —S—, —S(O)—, —S(O) 2 —, —NCH 3 —, —NH(CH 2 ) 2 NH—, —C(O)—,
wherein m, t and r are each independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11, or
L 1 is —(CH 2 ) e —C(O)NH—(CH 2 CH 2 O) f —(CH 2 ) g —, or —(CH 2 ) h —C(O)NH—CH[(CH 2 ) i —NHC(O)—(CH 2 CH 2 O) j —(CH 2 ) k —CH 3 ]—, wherein e, f, g, h, i, j and k are each independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11.
3 . The compound according to claim 1 , a salt or a solvate thereof, wherein the compound is a compound represented by Formula VI,
wherein,
A is a targeting compound selected from antibody; A is coupled to the site # or ## through a S atom in the targeting compound;
q′ is 0 or 1;
B is an active compound selected from the group consisting of auristatin, methyl-auristatin E (MMAE), maytansine, maytansinoid, DM1, DM3, DM4, paclitaxel, calicheamicin, duocarmycin, doxorubicin, camptothecin, and pyrrolobenzodiazepine, wherein DM1, DM3 and DM4 are defined as:
B is coupled to the site * through a N atom or O atom in the active compound when q′ is 1; or B is coupled to the site ** through a N atom or O atom in the active compound when q′ is 0;
n is a number between 0.5 and 8.5;
R 1 is a C 1-6 linear or branched alkyl group, and R 1 is optionally mono- or multi-substituted by one or more substituents selected from the group consisting of: halogen and C 1-4 alkoxy;
L 1 is selected from the group consisting of: —(CH 2 ) m —, —(CH 2 ) t O—, —(CH 2 CH 2 O) r —, —O—, —NH—, —S—, —S(O)—, —S(O) 2 —, —NCH 3 —, —NH(CH 2 ) 2 NH—, —C(O)—, —(CH 2 ) e —C(O)NH—(CH 2 CH 2 O) f —(CH 2 ) g —, —(CH 2 ) h —C(O)NH—CH[(CH 2 ) i —NHC(O)—(CH 2 CH 2 O) j —(CH 2 )—CH 3 ]—,
R′ is a substituent side chain in the variable group (R) of the amino acid residue; R′ is —CH 3 , —(CH 2 ) 3 NHCONH 2 , —(CH 2 ) 4 —NH 2 , —H, —CH(CH 3 )—OH, —CH—(CH 3 ) 2 , —CH 2 —CH(CH 3 ) 2 , —CH(CH 3 )—CH 2 —CH 3 or —CH 2 —CONH 2 ;
R 3 is independently selected from the group consisting of: hydrogen, halogen, methyl, ethyl, nitro, methoxy and ethoxy;
m, r and t are each independently selected from the group consisting of 0, 1, 2, 3 and 4;
e, f, g, h, i, j and k are each independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each p is independently 0, 1, 2, 3 or 4.
4 . The compound according to claim 1 , a salt or a solvate thereof, wherein the compound is selected from the group consisting of:
wherein MAB is an antibody, and n is defined as described in claim 1 .
5 . A pharmaceutical composition, which comprises at least one compound according to claim 1 , a salt or a solvate thereof, and one or more pharmaceutically acceptable carriers or excipients.
6 . A method for preparing the compound represented by Formula III according to claim 1 , a salt or a solvate thereof, comprising the following steps:
reacting a compound represented by Formula II or a salt or a solvate thereof with A, wherein A is coupled to the site # through a S atom in the targeting compound to obtain the compound represented by Formula III,
wherein:
wherein the two carbonyl groups are located on the same side of the C═C double bond, which is a cis structure, R 1 is a C 1-6 linear or branched alkyl, and R 1 is optionally mono- or multi-substituted by one or more substituents selected from the group consisting of: halogen and C 1-4 alkoxy;
the definitions of L 1 , L 2 , L 3 , q, q′, q″, and B are same as described in claim 1 .
7 . A method for diagnosis or treatment of a disease or condition or reducing a severity of the disease or condition, the method comprising administering to a patient in need of such treatment an effective amount of the compound according to claim 1 , salt or a solvate thereof, wherein the disease or condition is selected from the group consisting of tumor, infectious disease, hematological disease, metabolic disease and inflammation.
8 . The compound according to claim 4 , a salt or a solvate thereof, wherein MAB is selected from the group consisting of: anti-HER2 humanized monoclonal antibody mil40, trastuzumab, pertuzumab, cetuximab, panitumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, ofatumumab, bevacizumab, ipilimumab, denosumab, pembrolizumab, nivolumab, Avelumab, Atezolizumab, durvalumab, sacituzumab, and rovalpituzumab.
9 . The method according to claim 7 , wherein the tumor is selected from the group consisting of cancer, lymphoma, lymphoid tumor, blastoma, sarcoma and leukemia.
10 . The method according to claim 9 , wherein the cancer is selected from the group consisting of: breast cancer; squamous cell carcinoma; lung cancer; peritoneal cancer; liver cancer; gastric cancer; gastrointestinal cancer; pancreatic cancer; glioblastoma; cervical cancer; ovarian cancer; liver cancer; bladder cancer; urethral cancer; hepatocellular tumor; breast cancer; intestinal cancer; colon cancer; rectal cancer; colorectal cancer; endometrial cancer; uterine cancer; salivary gland cancer; renal or kidney cancer; prostate cancer; vulvar cancer; thyroid cancer; liver cancer; anal cancer; penile cancer; melanoma; multiple myeloma and B-cell lymphoma; brain cancer; gallbladder cancer; esophageal cancer; cholangiocarcinoma; head and neck cancer and related metastatic tumor.
11 . The method according to claim 10 , wherein the breast cancer is HER2-positive breast cancer, the squamous cell carcinoma is epithelial squamous cell carcinoma, the lung cancer is small cell lung cancer, non-small cell lung cancer, adenocarcinoma of lung or squamous cell carcinoma of lung.