WO2022211508A1 - 인간 cldn18.2에 대한 항체를 포함하는 항체 약물 접합체 및 이의 용도 - Google Patents

인간 cldn18.2에 대한 항체를 포함하는 항체 약물 접합체 및 이의 용도 Download PDF

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WO2022211508A1
WO2022211508A1 PCT/KR2022/004552 KR2022004552W WO2022211508A1 WO 2022211508 A1 WO2022211508 A1 WO 2022211508A1 KR 2022004552 W KR2022004552 W KR 2022004552W WO 2022211508 A1 WO2022211508 A1 WO 2022211508A1
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Prior art keywords
conjugate
acceptable salt
solvate
pharmaceutically acceptable
independently
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PCT/KR2022/004552
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English (en)
French (fr)
Korean (ko)
Inventor
박창식
송호영
장태익
정철웅
정명진
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Harbour Biomed Suzhou Co Ltd
Ligachem Biosciences Inc
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Harbour Biomed Suzhou Co Ltd
Legochem Biosciences Inc
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Application filed by Harbour Biomed Suzhou Co Ltd, Legochem Biosciences Inc filed Critical Harbour Biomed Suzhou Co Ltd
Priority to MX2023011507A priority Critical patent/MX2023011507A/es
Priority to CN202280026360.1A priority patent/CN117279663A/zh
Priority to BR112023020093A priority patent/BR112023020093A2/pt
Priority to IL307301A priority patent/IL307301A/en
Priority to CA3213985A priority patent/CA3213985A1/en
Priority to US18/285,194 priority patent/US20240131178A1/en
Priority to AU2022250810A priority patent/AU2022250810A1/en
Priority to JP2023555736A priority patent/JP2024515934A/ja
Priority to EP22781627.9A priority patent/EP4321180A1/en
Publication of WO2022211508A1 publication Critical patent/WO2022211508A1/ko
Anticipated expiration legal-status Critical
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
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    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Definitions

  • the present invention provides a novel antibody-drug conjugate (ADC) targeting claudin 18 isoform 2 (claudin 18 isoform 2, CLDN18.2), active metabolites of these ADCs, methods for preparing these ADCs, and disease to the use of these ADCs for treatment and/or prophylaxis, and also to the use of these ADCs for the production of medicaments for the treatment and/or prophylaxis of diseases, more particularly hyperproliferative and/or angiogenic diseases such as cancer diseases. and, more particularly, to an antibody-drug conjugate comprising a novel antibody or antigen-binding fragment thereof that binds to CLDN18.2, and a pharmaceutical composition comprising the same.
  • ADC antibody-drug conjugate
  • Cancer refers to a disease caused by an abnormally grown mass caused by the autonomous overgrowth of body tissues, and is the result of uncontrolled cell growth in various tissues. Early stage tumors can be removed by surgery and radiation therapy, and metastases are usually treated with chemotherapy for palliative care.
  • chemotherapeutic agents can induce serious effects of unwanted side effects and even toxicity as a result of systemic administration, thus enabling improved and selective application of these chemotherapeutic agents in tumor cells or immediately adjacent tissues.
  • the focus has been on the development of novel chemotherapeutic agents to simultaneously achieve increased efficacy and minimized toxicity/side effects.
  • Antibody-drug conjugates are target-directed new technologies that bind to an antigen-binding antibody with a toxin or drug and then release a toxic substance from the inside of the cell, leading to apoptosis of cancer cells, etc. It is a technology that delivers drugs accurately to target cancer cells with minimal effect on healthy cells and releases them only under specific conditions, so it is more effective than the antibody treatment itself and can significantly lower the risk of side effects compared to existing anticancer drugs.
  • the basic structure of such an antibody-drug conjugate is composed of "antibody-linker-small molecule drug (toxin)".
  • the linker not only plays a functional role of simply linking the antibody and the drug, but also stably reaches the target cell when circulating in the body, and then the antibody-drug conjugate enters the cell and dissociates between the antibody and the drug (e.g., for enzyme hydrolysis). result), the drug should fall off well and show the drug effect on the target cancer cells. That is, depending on the stability of the linker, the linker plays a very important role in terms of safety such as efficacy and systemic toxicity of the antibody-drug conjugate (Discovery Medicine 2010, 10(53): 329-39). 85-8 2018-08-14)
  • the inventors of the present invention have developed a linker containing an effective self-immolative group that is more stable in plasma, stable even when circulating in the body, and that the drug is easily released in cancer cells to show drug efficacy.
  • a patent has been secured (Korea Patent No. 1,628,872).
  • monoclonal antibodies for the treatment of cancer has achieved considerable success.
  • Monoclonal antibodies are suitable for target-directed addressing of tumor tissues and tumor cells.
  • Antibody drug conjugates have become a powerful and new therapeutic option for the treatment of lymphoma and solid cancers, and immunomodulatory antibodies have recently achieved considerable clinical success.
  • the development of therapeutic antibodies is based on a deep understanding of cancer serology, protein engineering techniques and their actions, mechanisms of resistance, and interactions between the immune system and cancer cells.
  • an antigen expressed on the cell surface of human cancer refers to a wide range of targets that are overexpressed or mutated and selectively expressed compared to normal tissues.
  • a key challenge is to identify antigens suitable for antibody-based therapies. These therapeutics mediate changes in antigen or receptor function (i.e., function as stimulants or antagonists), modulate the immune system through Fc and T cell activation, and deliver specific drugs that bind to specific antigen-targeting antibodies. exert its effectiveness.
  • Molecular technologies that can change antibody pharmacokinetics, function, size and immune stimulation are emerging as key factors in the development of novel antibody-based therapies.
  • Evidence obtained from clinical trials of therapeutic antibodies in cancer patients shows that the affinity and binding of the antibodies to the target antigen, the selection of antibody structures, and the optimization of antibodies, including therapeutic approaches (blocking signal transduction or immune function), Emphasizes the importance of approaches to choice.
  • Human claudin 18 subtype 2 (claudin 18 isoform 2, CLDN18.2) is a transmembrane type membrane protein consisting of 261 amino acids in full length, 2 extracellular loops and 4 transmembrane domains. It differs from CLDN18.1, which is expressed in some normal tissues, in part of the amino acid sequence up to the extracellular domain loop 1.
  • CLDN18.2 belongs to the claudin family, which is an important component of tight junctions.
  • the claudin protein is expressed in various cancer tissues and is known as a potential target for diagnostic and therapeutic modalities. It is also known to play an important role in tumorigenesis and inflammatory response, and changes in claudin protein expression cause dysfunction of tight junctions, affect signal transduction pathways, and are known to have a tumor-promoting action in some epithelial cancers. .
  • CLDN18.2 is specifically expressed in primary and metastatic gastric cancer, except for expression in the apical region of some gastric mucosa, and is known as a cancer-specific antigen that is also associated with malignant transformation, pancreatic cancer , ectopic activation has been reported in esophageal cancer, ovarian cancer, and lung cancer.
  • An object of the present invention is to provide a novel antibody-linker drug conjugate targeting claudin 18 isoform 2 (CLDN18.2) or a salt or solvate thereof.
  • An object of the present invention is to provide an antibody-drug conjugate comprising an antibody that specifically binds to CLDN18.2 and a drug that binds thereto, and a pharmaceutical composition comprising the same.
  • An object of the present invention is to provide an antibody-linker-drug (toxin) system that can stably reach cells and effectively exhibit drug effects while significantly lowering toxicity.
  • Ab is an antibody or antigen-binding fragment that specifically binds to claudin 18 isoform 2 (CLDN18.2) comprising a heavy chain variable region and a light chain variable region,
  • the heavy chain variable region comprises a heavy chain CDR1 consisting of the amino acid sequence shown in SEQ ID NO: 2, a heavy chain CDR2 consisting of the amino acid sequence shown in SEQ ID NO: 4, and a heavy chain CDR3 consisting of the amino acid sequence shown in SEQ ID NO: 6,
  • the light chain variable region includes a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 9, a light chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 11, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 13,
  • LINKER is a linker
  • l and m are each independently an integer selected from 1 to 20,
  • B may be the same as or different from each other.
  • the antibody or antigen-binding fragment that specifically binds to CLDN18.2 comprises a heavy chain variable region and a light chain variable region,
  • the heavy chain variable region comprises a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 2, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 6,
  • the light chain variable region includes a light chain CDR1 comprising the amino acid sequence shown in SEQ ID NO: 9, a light chain CDR2 comprising the amino acid sequence shown in SEQ ID NO: 11, and a light chain CDR3 comprising the amino acid sequence shown in SEQ ID NO: 13.
  • the heavy chain variable region may include the heavy chain FR of a human antibody, and the gene encoding the heavy chain FR may be derived from the germline V gene IGHV3-23.
  • the heavy chain FR is a heavy chain FR1 consisting of the amino acid sequence shown in SEQ ID NO: 1, heavy chain FR2 consisting of the amino acid sequence shown in SEQ ID NO: 3, heavy chain FR3 consisting of the amino acid sequence shown in SEQ ID NO: 5, SEQ ID NO: 7 and a heavy chain FR4 consisting of the indicated amino acid sequence.
  • the light chain variable region includes the light chain FR of a human antibody, and the gene encoding the light chain FR may be derived from the germline V gene IGKV3-11 or IGKV3-15.
  • the light chain FR is a light chain FR1 consisting of the amino acid sequence shown in SEQ ID NO: 8, light chain FR2 consisting of the amino acid sequence shown in SEQ ID NO: 10, light chain FR3 consisting of the amino acid sequence shown in SEQ ID NO: 12, SEQ ID NO: 14 and a light chain FR4 consisting of the indicated amino acid sequence.
  • the light chain FR4 may include a moiety consisting of the amino acid sequence shown in SEQ ID NO: 19 at the C-terminus for binding to the linker.
  • the antibody or antigen-binding fragment that specifically binds to CLDN18.2 comprises an amino acid sequence represented by SEQ ID NO: 15; Or a heavy chain variable region consisting of an amino acid sequence having at least 80% homology thereto and an amino acid sequence represented by SEQ ID NO: 16; or a light chain variable region consisting of an amino acid sequence having at least 80% homology thereto.
  • the antibody or antigen-binding fragment that specifically binds to CLDN18.2 includes an amino acid sequence represented by SEQ ID NO: 15; Or a heavy chain variable region consisting of an amino acid sequence having at least 80% or more, 85% or more, 90% or more, 95% or more homology thereto and the amino acid sequence represented by SEQ ID NO: 16; Or it includes a light chain variable region consisting of an amino acid sequence having at least 80% or more, 85% or more, 90% or more, 95% or more homology thereto, and specifically binds to CLDN18.2.
  • the antibody or antigen-binding fragment that specifically binds to CLDN18.2 includes an amino acid sequence represented by SEQ ID NO: 15; or at least 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more.
  • a heavy chain variable region and sequence comprising an amino acid sequence having at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% homology.
  • the antibody or antigen-binding fragment that specifically binds to CLDN18.2 comprises an amino acid sequence represented by SEQ ID NO: 17; or a heavy chain consisting of an amino acid sequence having at least 80% homology thereto and an amino acid sequence represented by SEQ ID NO: 18; or a light chain consisting of an amino acid sequence having at least 80% homology thereto.
  • the antibody or antigen-binding fragment that specifically binds to CLDN18.2 includes an amino acid sequence represented by SEQ ID NO: 17; or an amino acid sequence represented by SEQ ID NO: 18 and a heavy chain consisting of an amino acid sequence having at least 80% or more, 85% or more, 90% or more, 95% or more homology thereto; or a light chain consisting of an amino acid sequence having at least 80% or more, 85% or more, 90% or more, 95% or more homology thereto, and specifically binds to CLDN18.2.
  • the antibody or antigen-binding fragment that specifically binds to CLDN18.2 includes an amino acid sequence represented by SEQ ID NO: 17; or at least 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more.
  • a heavy chain consisting of an amino acid sequence having at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% homology and SEQ ID NO: 18 amino acid sequence represented by; or at least 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more. at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% homology, It binds specifically to CLDN18.2.
  • the heavy chain consisting of an amino acid sequence having at least 80% homology to the amino acid sequence represented by SEQ ID NO: 17 includes L237A and L238A mutations.
  • the antibody or antigen-binding fragment thereof is a monoclonal antibody, a domain antibody (dAb), a single chain antibody (scAb), a Fab fragment, a Fab' fragment, F(ab')2 fragment, scFab fragment, Fv fragment, dsFv fragment, single chain variable fragment (scFv), scFv-Fc fragment, single domain heavy chain antibody, single domain light chain
  • dAb domain antibody
  • scAb single chain antibody
  • Fab fragment fragment
  • Fab' fragment F(ab')2 fragment
  • scFab fragment Fv fragment
  • dsFv fragment single chain variable fragment
  • scFv-Fc fragment single domain heavy chain antibody
  • linker refers to a compound that covalently binds a cytotoxic compound to a ligand.
  • linkers described herein may be cleavable, non-cleavable, hydrophilic or hydrophobic.
  • the cleavable linker is cleavable under intracellular conditions such that cleavage of the linker releases the active agent from the antibody construct-activator conjugate in the intracellular environment.
  • a cleavable linker is cleavable by a cleaving agent present in the intracellular environment (eg, in a lysosome or endosome or caveolea).
  • the cleavable linker may be, for example, a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme including, but not limited to, a lysosomal or endosomal protease.
  • the peptidyl linker is at least 2 amino acids in length or at least 3 amino acids in length.
  • Cleavage agents may include cathepsins B and D and plasmin, all of which are known to hydrolyze dipeptide drug derivatives to release the active drug in target cells (eg, Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123).
  • Peptidyl linkers cleavable by enzymes present in antigen-expressing cells are most common.
  • a peptidyl linker cleavable by the thiol-dependent protease cathepsin-B which is highly expressed in cancer tissues, can be used (eg, a Phe-Leu or Gly-Phe-Leu-Gly linker).
  • Other such linkers are described, for example, in US Pat. No. 6,214,345.
  • peptidyl linker cleavable by an intracellular protease is described in, for example, a Val-Cit linker, a Phe-Lys linker (eg, U.S. Patent No. 6,214,345, which describes the synthesis of doxorubicin using a Val-Cit linker). see) or a Val-Ala linker.
  • the Val-Cit linker or Val-Ala linker may contain a pentafluorophenyl group and may contain a succinimide group or a maleimide group.
  • it may contain a PABA group and a pentafluorophenyl group, and may contain a 4-aminobenzoic acid (PABA) group and a maleimide group, and may contain a PABA group and a succinimide group.
  • PABA 4-aminobenzoic acid
  • intracellularly cleaved and intracellular cleavage refer to a metabolic process or response inside a cell to an antibody construct-activator conjugate, whereby an active agent ( B) and the covalent attachment between the antibody construct (Ab), eg the linker is disrupted, resulting in free drug or other metabolites of the conjugate separated from the intracellular antibody.
  • the cleavable linker is pH-sensitive, i.e., can be readily hydrolyzed at certain pH values.
  • the pH-sensitive linker can be hydrolyzed under acidic conditions.
  • acid-labile linkers capable of being hydrolyzed in lysosomes (e.g., hydrazone, semicarbazone, thiosemicarbazone, cis-aconic amide (cis) -aconitic amide), orthoesters, acetals, ketals, etc.) can be used (e.g., U.S. Patent Nos. 5,122,368; 5,824,805; 5,622,929; Dubowchik and Walker, 1999, Pharm. Therapeutics 83).
  • linkers are relatively stable at neutral pH conditions, such as blood, but are unstable below pH 5.5 or 5.0, the approximate pH of lysosomes.
  • hydrolysable linkers include thioether linkers (eg, thioethers attached to a therapeutic agent via an acylhydrazone bond (see, eg, US Pat. No. 5,622,929)).
  • the linker is cleavable under reducing conditions (eg, a disulfide linker).
  • a disulfide linker For example, SATA (N-succinimidyl-5-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N-succinimidyl- Formed using 3-(2-pyridyldithio)butyrate) and SMPT (N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-thio)toluene)-, SPDB and SMPT
  • SATA N-succinimidyl-5-acetylthioacetate
  • SPDP N-succinimidyl-3-(2-pyridyldithio)propionate
  • SPDB N-succinimidyl- Formed using 3-(2-pyrid
  • linkers include malonate linkers (Johnson et al., 1995, Anticancer Res. 15:1387-93), maleimidobenzoyl linkers (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1299- 1304), 3'-N-amide analogs (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1305-12), beta-glucuronide linker (Jeffery et al) ., 2006, Bioconjug Chem. 17(3):832-40), or beta-galactosidase linker (Kolodych et al., 2017, Eur J Med Chem. Dec 15;142:376- 382) may be.
  • the non-cleavable linker may be a maleimidocaproyl linker.
  • the maleimidocaproyl linker may comprise N-maleimidomethylcyclohexane-1-carboxylate.
  • the maleimidocaproyl linker may contain a succinimide group.
  • the maleimidocaproyl linker may contain a pentafluorophenyl group.
  • the linker may be a combination of a maleimide group and one or more polyethylene glycol molecules.
  • the linker may be a combination of a maleimidocaproyl group and one or more polyethylene glycol molecules.
  • the linker may be a maleimide-PEG4 linker.
  • the linker may be a combination of a maleimidocaproyl linker containing a succinimide group and one or more polyethylene glycol molecules.
  • the linker may be a combination of a maleimidocaproyl linker containing a pentafluorophenyl group and one or more polyethylene glycol molecules.
  • the linker may contain a maleimide linked to a polyethylene glycol molecule, wherein the polyethylene glycol allows for more linker flexibility or may use a longer linker.
  • the linker may be a (maleimidocaproyl)-(valine-citrulline)-(para-aminobenzyloxycarbonyl) linker.
  • the linker may be a cleavable linker.
  • the linker is a protease cleavable linker, an acid-cleavable linker, a disulfide linker, a self-immolative linker or a self-stabilizing linker, a malonate linker, maleimidobenzoyl linker, 3'-N-amide analog, beta-glucuronide linker, or beta-galactoside linker.
  • the protease cleavable linker may include a thiol-reactive spacer or a dipeptide, and more specifically, the protease cleavable linker is a thiol-reactive maleimidocaproyl spacer, valine -citrulline dipeptide or p-amino-benzyloxycarbonyl spacer.
  • the acid-cleavable linker may be a hydrazine linker or a quaternary ammonium linker.
  • the linker may have a structure of Formula II.
  • the tilde indicates a site linked to an antibody or antigen-binding fragment that specifically binds to CLDN18.2, * indicates a site linked to an active agent;
  • G is a glucuronic acid moiety or ego
  • R 3 is hydrogen or a carboxyl protecting group, and each R 4 is independently hydrogen or a hydroxyl protecting group;
  • R 1 and R 2 are each independently hydrogen, C 1-8 alkyl or C 3-8 cycloalkyl
  • W is -C(O)-, -C(O)NR'-, -C(O)O-, -SO 2 NR'-, -P(O)R''NR'-, -SONR'- or -PO 2 NR'-, wherein C, S or P is directly bonded to a phenyl ring, and R' and R'' are each independently hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di- C 1-8 alkylamino, C 3-20 heteroaryl or C 6-20 aryl;
  • Z is independently hydrogen, C 1-8 alkyl, halogen, cyano or nitro;
  • n is an integer from 0 to 3;
  • L is any one of the following A) or B):
  • L is 1 to 50 membered heteroalkylene
  • said alkylene is substituted with one or more C 1-20 alkyl
  • the conjugate may have a structure of the following general formula IIa.
  • Ab is an antibody or antigen-binding fragment that specifically binds to CLDN18.2 comprising a heavy chain variable region and a light chain variable region,
  • B' are each independently the same or different active agents
  • G is each independently a glucuronic acid moiety or ego;
  • R 3 is hydrogen or a carboxyl protecting group, and each R 4 is independently hydrogen or a hydroxyl protecting group;
  • R 1 and R 2 are each independently hydrogen, C 1-8 alkyl or C 3-8 cycloalkyl
  • W is each independently -C(O)-, -C(O)NR'-, -C(O)O-, -SO 2 NR'-, -P(O)R''NR'-, -SONR '- or -PO 2 NR'-, wherein C, S or P is directly bonded to a phenyl ring, wherein NR' is bonded to L, and R' and R'' are each independently hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl or C 6- 20 is aryl;
  • each Z is independently hydrogen, C 1-8 alkyl, halogen, cyano or nitro;
  • n is an integer from 0 to 3, and when n is an integer of 2 or more, each Z may be the same as or different from each other;
  • Each L is independently any one of the following A) or B):
  • L is 1 to 50 membered heteroalkylene
  • said alkylene is further substituted with one or more C 1-20 alkyl
  • n is an integer selected from 1 to 20.
  • the present invention relates to a conjugate represented by the following general formula IIa or a pharmaceutically acceptable salt or solvate thereof.
  • Ab is an antibody or antigen-binding fragment that specifically binds to claudin 18 isoform 2 (CLDN18.2),
  • G is each independently a glucuronic acid moiety or ego;
  • R 3 is hydrogen or a carboxyl protecting group, and each R 4 is independently hydrogen or a hydroxyl protecting group;
  • R 1 and R 2 are each independently hydrogen, C 1-8 alkyl or C 3-8 cycloalkyl
  • W is each independently -C(O)-, -C(O)NR'-, -C(O)O-, -SO 2 NR'-, -P(O)R''NR'-, -SONR '- or -PO 2 NR'-, wherein C, S or P is directly bonded to a phenyl ring, wherein NR' is bonded to L, and R' and R'' are each independently hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl or C 6- 20 is aryl;
  • each Z is independently hydrogen, C 1-8 alkyl, halogen, cyano or nitro;
  • n is an integer from 0 to 3;
  • Each L is independently any one of the following A) or B):
  • L is 1 to 50 membered heteroalkylene
  • said alkylene is substituted with one or more C 1-20 alkyl
  • B' is an active agent
  • l and m are each independently an integer selected from 1 to 20,
  • the active agents may each be the same or different.
  • G is a glucuronic acid moiety or a compound of formula (IIIa):
  • R 3 is hydrogen or a carboxyl protecting group
  • each R 4 is each independently hydrogen or a hydroxyl protecting group.
  • each G is independently ego
  • R 3 is hydrogen or a carboxyl protecting group
  • Each of said R 4 is independently hydrogen or a hydroxyl protecting group.
  • R 3 is hydrogen, and each R 4 is hydrogen.
  • R 1 and R 2 are each hydrogen.
  • each Z is independently hydrogen, C 1-8 alkyl, halogen, cyano or nitro.
  • W is -C(O)-, -C(O)NR'- or -C(O)O-, and more specifically, W is -C(O)NR'-, wherein C( O) is connected to a phenyl ring, and NR' is connected to L.
  • R' is hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di- C 1-8 alkylamino, C 3 20 heteroaryl or C 6-20 aryl.
  • n 0, 1, 2 or 3, more specifically 0, 1 or 2, and even more specifically 0.
  • G is a compound of formula (IIIa):
  • R 3 is hydrogen or a carboxyl protecting group
  • each R 4 is each independently hydrogen or a hydroxyl protecting group
  • W is -C(O)NR'-, wherein C(O) is connected to a phenyl ring and NR' is bonded to L, each Z is C 1-8 alkyl, halogen, cyano or nitro, n is 0, m is 1, and R 1 and R 2 are each hydrogen.
  • At least one L is alkylene having 1 to 100 carbon atoms, wherein the carbon atoms of the alkylene are one or more heteroatoms selected from the group consisting of N, O and S. may be substituted, and the alkylene may be further substituted with one or more alkyl having 1 to 20 carbon atoms.
  • At least one L is C 1-50 alkylene or 1-50 membered heteroalkylene, and may satisfy one or more of the following:
  • L is 1 to 50 membered heteroalkylene
  • said alkylene is substituted with one or more C 1-20 alkyl.
  • the at least one L is a nitrogen-containing 1-50 membered heteroalkylene
  • the linker includes two or more atoms of a hydrophilic amino acid
  • the nitrogen is capable of forming a peptide bond with a carbonyl of the hydrophilic amino acid.
  • L is C 2-50 alkylene, C 2-50 heteroalkylene, hydrophilic amino acid, -C(O)-, -C(O)NR''-, -C(O)O -, -(CH 2 ) s -NHC(O)-(CH 2 ) t -, -(CH 2 ) u -C(O)NH-(CH 2 ) v -, -(CH 2 ) s -NHC( O)-(CH 2 ) t -C(O)-, -(CH 2 ) u -C(O)NH-(CH 2 ) v -C(O)-, -S(O) 2 NR''- , -P(O)R'''NR''-, -S(O)NR''-, or -PO 2 NR''-,
  • R'' and R''' are each independently hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1 -8 alkylamino, C 3-20 heteroaryl or C 5-20 aryl, and s, t, u and v are each independently an integer from 0 to 10.
  • L is a nitrogen-containing 1-5 membered heteroalkylene
  • the linker includes two or more atoms of a hydrophilic amino acid, and the nitrogen forms a peptide bond with the carbonyl of the hydrophilic amino acid.
  • L is covalently bonded to the antibody through a thioether bond, and the thioether bond includes a sulfur atom of cysteine of the antibody.
  • At least one L is a hydrophilic amino acid.
  • the hydrophilic amino acid may be arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine, or threonine.
  • the hydrophilic amino acid may be an amino acid comprising a side chain having a residue having a charge at neutral pH in aqueous solution.
  • the hydrophilic amino acid is aspartate or glutamate.
  • the hydrophilic amino acid is ornithine or lysine.
  • the hydrophilic amino acid is arginine.
  • At least one L is -C(O)-, -C(O)NR''-, -C(O)O-, -S(O) 2 NR''-, -P (O)R'''NR''-, -S(O)NR''-, or -PO 2 NR''-, wherein R'' and R'' are each independently hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl, or C 6-20 aryl.
  • At least one L is -C(O)NR''-, -(CH 2 ) s -NHC(O)-(CH 2 ) t -, -(CH 2 ) u -C( O)NH-(CH 2 ) v -, -(CH 2 ) s -NHC(O)-(CH 2 ) t -C(O)-, or -(CH 2 ) u -C(O)NH-( CH 2 ) v —C(O)—, wherein R′′ is hydrogen, C 1-5 alkyl, C 3-8 cycloalkyl, C 1-5 alkoxy, C 3-20 heteroaryl, or C 6 -20 aryl, and s, tu and v are each independently an integer from 0 to 10.
  • At least one L is -C(O)NR''- and R'' is hydrogen.
  • At least one L is -(CH 2 ) s -NHCO-, and s is an integer from 1 to 5.
  • At least one L is -(CH 2 ) u -C(O)NH-(CH 2 ) v -C(O)-, u is an integer from 1 to 5, and v is 1 to an integer of 5.
  • L is,
  • L 1 is a direct bond or alkylene having 1 to 30 carbon atoms
  • R 11 is hydrogen or alkyl having 1 to 10 carbon atoms
  • L 2 is alkylene having 1 to 30 carbon atoms.
  • L further comprises a second unit represented by the general formula VIII or IX.
  • the at least one second unit is represented by the general formula VIII or IX:
  • V is a single bond, -O-, -S-, -NR 21 -, -C(O)NR 22 -, -NR 23 C(O)-, -NR 24 SO 2 - or -SO 2 NR 25 - ego;
  • X is —O—, C 1-8 alkylene or —NR 21 —;
  • R 21 to R 25 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkyl C 6-20 aryl or C 1-6 alkyl C 3-20 heteroaryl;
  • r is an integer from 0 to 10;
  • p is an integer from 0 to 10;
  • q is an integer from 1 to 20;
  • w is an integer from 1 to 20;
  • q may be 4 to 20, more specifically 5 to 20. Also, q may be 1 to 10, or 2 to 12, and more specifically 2, 4, 5, or 11. Also, r may be 1 or 2. Also, p may be 1 or 2. Also, V may be -O-.
  • r may be 2
  • p may be 2
  • q may be 2
  • 4 5 or 11
  • V may be -O-.
  • X may be -O-.
  • w may be an integer from 4 to 20.
  • X is -O-, and w may be 1 to 10, or 4 to 20.
  • the at least one second unit is at least one polyethylene glycol unit, or has the structure of
  • n 1 to 12.
  • the at least one second unit is 1 to 12 -OCH 2 CH 2 -units, or 3 to 12 -OCH 2 CH 2 -units, or 5 to 12 -OCH 2 CH 2 -units, or 6 to 12 -OCH 2 CH 2 -unit, or 3 -OCH 2 CH 2 -unit.
  • the at least one second unit is -(CH 2 CH 2 X) w -,
  • X is a single bond, —O—, C 1-8 alkylene, or —NR 21 —;
  • R 21 is hydrogen, C 1-6 alkyl, C 1-6 alkyl-C 6-20 aryl, or C 1-6 alkyl-C 3-20 heteroaryl, w is an integer from 1 to 20, specifically 1, 3, 6, or 12.
  • X is -O-, and w is an integer from 6 to 20.
  • L comprises an oxime, and at least one polyethylene glycol unit covalently bonds the oxime to the active agent.
  • the linker is 1,3-dipolar cycloaddition reactions, hetero-Diels-Alder reactions, nucleophilic substitutions formed by reactions, non-aldol type carbonyl reactions, addition to carbon-carbon multiple bond, oxidation reactions or click reactions a third unit.
  • the third unit is formed by a reaction between an alkyne and an azide, or between an aldehyde or ketone group and a hydrazine or alkoxyamine.
  • L further includes a third unit represented by the following general formula IVa, IVb, IVc, IVd, or IVe.
  • L 1 is a single bond or alkylene having 1 to 30 carbon atoms
  • R 11 is hydrogen or C 1-10 alkyl.
  • the third unit comprises:
  • L 1 is a single bond or alkylene having 1 to 30 carbon atoms, preferably alkylene having 10, 11, 12, 13, 14, 15 or 16 carbon atoms;
  • R 11 is hydrogen or alkyl having 1 to 10 carbon atoms, specifically methyl
  • L 2 is alkylene having 1 to 30 carbon atoms.
  • L 1 and L 2 are each independently a single bond or C 1-30 alkylene; R 11 is hydrogen or C 1-10 alkyl.
  • L 1 is a single bond, or alkylene having 11 carbon atoms, or alkylene having 12 carbon atoms.
  • the third unit or including,
  • V is a single bond , -O-, -S-, -NR 21 -, -C(O)NR 22 -, -NR 23 C(O)-, -NR 24 SO 2 -, or -SO 2 NR 25 - is;
  • R 21 to R 25 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkyl C 6-20 aryl, or C 1-6 alkyl C 3-20 heteroaryl;
  • r is an integer from 1 to 10;
  • p is an integer from 0 to 10;
  • q is an integer from 1 to 20;
  • L 1 is a single bond.
  • r may be 2 or 3. Also, p may be 1 or 2. Also, q may be 1 to 6.
  • r is 2 or 3; p is 1 or 2; q may be 1 to 6.
  • the linker comprising the third unit is
  • tilde indicates a site connected to the antibody construct
  • * indicates a site connected to the active agent
  • n is an integer from 0 to 20.
  • the third unit comprises: or includes
  • the linker is in a precursor state
  • the third unit may be formed by a reaction between an alkyne and an azide in the above structure, specifically, a click reaction.
  • the linker is in the precursor state.
  • Including, through the structure can form a third unit, the third unit
  • L is 3 to 50 heteroalkylene including oxime
  • the oxygen atom of the oxime is on the side of L linked to W and the carbon atom of the oxime is on the side of L linked with Ab;
  • the carbon atom of the oxime is on the side of L linked to W, and the oxygen atom of the oxime is on the side of L linked to Ab.
  • L comprises an oxime, and at least one isoprenyl unit is to covalently bond the oxime to Ab.
  • the linker is It may further contain at least one isoprenyl unit having the structure of , wherein n is at least 2 or more.
  • the at least one isoprenyl unit is a substrate of an isoprenoid transferase or a product of an isoprenoid transferase.
  • the isoprenyl unit of the linker is covalently bound to the antibody by a thioether bond, the thioether bond comprising the sulfur atom of the cysteine of the antibody construct.
  • the isoprenyl unit can covalently bond the oxime included in the linker to the antibody construct.
  • the antibody construct comprises an amino acid motif recognized by an isoprenoid transferase and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif.
  • the antibody construct comprises an amino acid motif recognized by an isoprenoid transferase and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif.
  • the amino acid motif is a sequence selected from the group consisting of CXX, CXC, XCXC, XXCC, and CYYX, wherein C represents cysteine; Y at each occurrence independently represents an aliphatic amino acid; X independently for each occurrence represents glutamine, glutamate, serine, cysteine, methionine, alanine, or leucine; The thioether linkage contains the sulfur atom of the cysteine of the amino acid motif.
  • the amino acid motif is the sequence CYYX, and Y for each occurrence is independently alanine, isoleucine, leucine, methionine or valine.
  • the amino acid motif is a CVIM or CVLL sequence.
  • At least one of 1 to 20 amino acids preceding the amino acid motif may be independently selected from glycine, arginine, aspartic acid and serine.
  • At least one of 1 to 20 amino acids preceding the amino acid motif is glycine.
  • one or more of the 1 to 10 amino acids preceding the amino acid motif may each be independently selected from glycine, arginine, aspartic acid and serine.
  • at least one of the seven amino acids preceding the amino acid motif is glycine.
  • at least three of the seven amino acids preceding the amino acid motif are each independently selected from glycine, arginine, aspartic acid and serine.
  • 1 to 10 amino acids preceding the amino acid motif are glycine, specifically, at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids preceding the amino acid motif are glycine.
  • the antibody may comprise the amino acid sequence of GGGGGGGCVIM.
  • L may include the amino acid sequence GGGGGGGCVIM at the C-terminus.
  • the second unit connects L and the third unit, L and the fourth unit, or the third unit and the fourth unit,
  • the one or more fourth units are capable of releasing one or more drugs or toxins
  • L is for connecting the second unit and the fourth unit, the second unit and the third unit, or the second unit with another second unit.
  • the fourth unit has the structure of formula (IIb):
  • G is a sugar, sugar acid, or sugar derivatives
  • W is -C(O)-, -C(O)NR'-, -C(O)O-, -S(O) 2 NR'-, -P(O)R''NR'-, -S (O)NR'-, or -PO 2 NR'-,
  • R' and R'' are each independently hydrogen, (C 1-8 )alkyl, (C 3-8 )cycloalkyl, (C 1 - 8 )alkoxy, (C 1-8 )alkylthio, mono- or di-(C 1-8 )alkylamino, (C 3-20 )heteroaryl, or (C 6-20 )aryl, W is L or connected to the second unit,
  • each Z is independently hydrogen, (C 1-8 )alkyl, halogen, cyano or nitro;
  • n is an integer from 1 to 3
  • n 0 or 1
  • R 1 and R 2 are each independently hydrogen, (C 1-8 )alkyl or (C 3-8 )cycloalkyl, or R 1 and R 2 together with the carbon atom to which they are attached are (C 3-8 )cycloalkyl. form an alkyl ring.
  • the sugar or sugar acid is a monosaccharide.
  • G is a compound of the structure (IIIa):
  • R 3 is hydrogen or a carboxyl protecting group
  • each R 4 is each independently hydrogen or a hydroxyl protecting group.
  • R 3 is hydrogen and each R 4 is hydrogen.
  • W is -C(O)NR'-, wherein C(O) is connected to a phenyl ring and NR' is connected to L or a second unit.
  • Z is hydrogen
  • R 1 and R 2 are each hydrogen.
  • the second unit is -(CH 2 ) r (V(CH 2 ) p ) q -, -((CH 2 ) p V) q -, -(CH 2 ) r (V(CH ) 2 ) p ) q Y-, -((CH 2 ) p V) q (CH 2 ) r -, -Y((CH 2 ) p V) q - or -(CH 2 ) r (V(CH 2 ) p ) represented by q YCH 2 -,
  • r is an integer from 0 to 10;
  • p is an integer from 1 to 10;
  • q is an integer from 1 to 20,
  • V and Y are each independently a single bond, -O-, -S-, -NR 21 -, -C(O)NR 22 -, -NR 23 C(O)-, -NR 24 SO 2 -, or - SO 2 NR 25 -,
  • R 21 to R 25 are each independently hydrogen, (C 1-6 )alkyl, (C 1-6 )alkyl(C 6-20 )aryl or (C 1-6 )alkyl(C 3-20 )heteroaryl .
  • r is 2.
  • p is 2.
  • q is an integer from 6 to 20.
  • q is 2, 5, or 11.
  • V and Y are each independently -O-.
  • L or the third unit is , , or including,
  • L 1 is a direct bond or alkylene having 1 to 30 carbon atoms
  • R 11 is hydrogen or alkyl having 1 to 10 carbon atoms, specifically methyl
  • L 2 is alkyl having 1 to 30 carbon atoms it's ren
  • L 1 is alkylene having 12 carbon atoms.
  • R 11 is methyl
  • L 2 is alkylene having 11 carbon atoms.
  • the Binding Unit is covalently bound to the antibody by a thioether bond, the thioether bond comprising the sulfur atom of a cysteine of the antibody.
  • the antibody comprises an amino acid motif recognized by an isoprenoid transferase, and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif.
  • the amino acid motif is a sequence selected from the group consisting of CXX, CXC, XCXC, XXCC, and CYYX, wherein C represents cysteine; Y at each occurrence independently represents an aliphatic amino acid; X independently for each occurrence represents glutamine, glutamate, serine, cysteine, methionine, alanine, or leucine; The thioether linkage contains the sulfur atom of the cysteine of the amino acid motif.
  • the amino acid motif is the sequence CYYX, and Y for each occurrence is independently alanine, isoleucine, leucine, methionine or valine.
  • the amino acid motif is a CVIM or CVLL sequence.
  • At least one of the 1 to 20 amino acids preceding the amino acid motif is glycine.
  • one or more of the 1 to 20 amino acids preceding the amino acid motif may each be independently selected from glycine, arginine, aspartic acid and serine.
  • 1 to 20 amino acids preceding the amino acid motif are glycine, in particular at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids are glycine.
  • the antibody may comprise the amino acid sequence of GGGGGGGCVIM.
  • the isoprenoid transferase is farnesyl protein transferase (FTase) or geranylgeranyl transferase (GGTase).
  • FTase farnesyl protein transferase
  • GTTase geranylgeranyl transferase
  • L comprises one or more branched linkers covalently bonded to Ab
  • each branched linker comprises a fifth unit covalently linked to the Ab by a first linker (PL);
  • each branched linker comprises a first branch (B1) wherein the first active agent is covalently linked to the fifth unit by a second linker (SL) and a cleavage group (CG); and
  • each branched linker comprises: a) a second branch (B2) wherein the second active agent is covalently linked to the fifth unit by a second linker (SL) and a cleavage group (CG); or b) a second branch (B2) wherein the polyethylene glycol moiety is covalently bound to the fifth unit,
  • Each of the cleavage groups may be hydrolyzed to release the active agent from the antibody construct-active agent conjugate.
  • the branched linker comprises a fifth unit (BR) covalently bonded to the reactive moiety by a first linker (PL);
  • the fifth unit comprises a first active agent covalently bonded to the first branch (B1) and covalently bonded to a second linker (SL) and a cleavage group (CG);
  • the fifth unit comprises a second active agent covalently linked to a second branch (B2) and covalently linked to a second linker (SL) and a cleavage group (CG) or b) a polyethylene glycol moiety, wherein Each cleavage group can be hydrolyzed to release the active agent.
  • the cleavage group is as shown in Formula II.
  • the second linker (eg, connecting the active agent to the fifth unit) is a 1,3-dipolar cycloaddition reaction, a hetero-Diels-Elder reaction (hetero) -Diels-Alder reaction, nucleophilic substitution reaction, non-aldol type carbonyl reaction, addition to a carbon-carbon multiple bond ), an oxidation reaction or a click reaction may include a third unit formed.
  • the third unit may be formed by a reaction of an alkyne with an azide as above, or a non-aldol-type carbonyl reaction, such as a reaction of an aldehyde or ketone group with a hydrazine or hydroxylamine, which is an active agent and/or to allow mild coupling of the cleavage group and L.
  • a non-aldol-type carbonyl reaction such as a reaction of an aldehyde or ketone group with a hydrazine or hydroxylamine, which is an active agent and/or to allow mild coupling of the cleavage group and L.
  • the fifth unit , , , , or ego the fifth unit , or ego,
  • the L 2 , L 3 , L 4 are each independently a direct bond or -C n H 2n -, wherein n is an integer from 1 to 30,
  • the G 1 , G 2 , G 3 are independently a direct bond, ,
  • R 30 is hydrogen or C 1-30 alkyl
  • R 40 is hydrogen, C 1-10 alkyl or -L 5 -COOR 50 , wherein L 5 is a direct bond or -C n H 2n -,
  • n is an integer from 1 to 10
  • R 50 is hydrogen or C 1-30 alkyl.
  • the fifth unit , , or ego the fifth unit , or ego
  • L 2 , L 3 , L 4 , G 1 , G 2 , G 3 , R 30 , R 40 , and L 5 may be the same as described above.
  • the cleavage group is cleavable in a target cell.
  • the cleavage group is capable of releasing one or more active agents.
  • the conjugate comprises Ab;
  • each branched linker is associated with one or two or more active agents
  • active agents are each the same or different.
  • each of said active agents is bound to a branched linker by a cleavable bond.
  • L is a linker comprising at least one fifth unit and a first linker (PL).
  • the first linker of the antibody-drug conjugate comprises an alkylene having 1 to 100, preferably 1 to 50 carbon atoms, or:
  • alkylene contains at least one unsaturated bond
  • alkylene includes at least one heteroarylene
  • a carbon atom of the alkylene is replaced by one or more heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S); or
  • Alkylene is further substituted with one or more alkyl having 1 to 20 carbon atoms.
  • each of said branched linkers comprises a fifth unit, each active agent binds to the fifth unit via a secondary linker, said fifth unit being an antibody by a primary linker is coupled to
  • the fifth unit is an amide and the primary linker comprises a carbonyl of the amide.
  • the fifth unit is a lysine unit.
  • At least one carbon atom of the alkylene is replaced with a nitrogen
  • the first linker comprises at least two atoms of a hydrophilic amino acid
  • the nitrogen forms a peptide bond with the backbone carbonyl of the hydrophilic amino acid.
  • the hydrophilic amino acid may be, for example, arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine or threonine.
  • the branched linker of the antibody-active agent comprises an amino acid having a side chain with a charged moiety at neutral pH in aqueous solution, preferably arginine, aspartate, glutamate, lysine or ornithine.
  • the amino acid may be located anywhere in the branched linker.
  • the oxime of the branched linker can be covalently bonded to the polyethylene glycol unit of the branched linker.
  • such amino acids may be present in a second linker, optionally in each second linker.
  • the linker-activator comprises a compound of the following structural formula.
  • B' and B'' represent active agents, which may be the same or different;
  • n1 to n3 each independently represent an integer of 0 to 30;
  • AA represents an amino acid group
  • AA represents an amino acid group
  • the amino acid group refers to a form in which one or more amino acids are bound.
  • the linker comprises a peptide sequence of a plurality of amino acids; ii) at least two active agents are covalently linked with the side chain of the amino acid.
  • the amino acid group is linked to a main chain of 1 to 20 amino acids; or a side chain bond.
  • the amino acid group comprises 1 to 20 main chain bonds of arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine or threonine; or a group by a side chain bond.
  • the amino acid group comprises 1 to 20 main chain bonds of arginine, aspartate, glutamate, lysine or ornithine; or a group by a side chain bond.
  • the amino acid group comprises at least one lysine of 1 to 20 amino acids.
  • amino acid group includes main chain and side chain bonds of lysine.
  • the branched linker comprising the fifth unit is
  • activator moiety refers to a compound covalently bonded to a linker or a portion of the linker, including an active agent.
  • an activator moiety may be directly bonded to the linker, and one or more, specifically, two or more, three or more, four or more, activator moieties to the linker may be directly bonded to the linker.
  • the active agent moiety in the present invention may include a compound unit for directly bonding the active agent to the linker.
  • a portion of the active agent moiety is cleavable and the portion can be cleaved to release the active agent in the intracellular environment.
  • the active moiety and the linker can determine the number of bonds in consideration of the DAR, pharmacological activity, etc. of the conjugate.
  • the active agent moiety may refer to the whole including the following structure and the active agent, through which the active agent and the linker may be directly bonded. However, this is illustrative and not limited thereto.
  • the active agents are each independently selected from a chemotherapeutic agent and a toxin.
  • the active agent may be an immunomodulatory compound, an anticancer agent, an antiviral agent, an antibacterial agent, an antifungal agent, an antiparasitic agent, or a combination thereof, and may optionally be used among the active agents listed below:
  • affinity ligand is a substrate, an inhibitor, an activator, a neurotransmitter, a radioactive isotope, or a combination thereof;
  • radioactive label 32P, 35S, fluorescent die, electron dense reagent, enzyme, biotin, streptavidin, dioxigenin, hapten, an immunogenic protein, a nucleic acid molecule with a sequence complementary to a target, or a combination thereof;
  • immunomodulatory compounds anticancer agents, anti-viral agents, anti-bacterial agents, anti-fungal agents , and an anti-parasitic agent, or a combination thereof;
  • the active agent is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-oxidedoxedoxedoxedoxethyl
  • y is an integer from 1 to 10.
  • the active agent is a pyrrolobenzodiazepine dimer
  • the linker and the antibody are connected through the N10 or N10' position of the pyrrolobenzodiazepine dimer.
  • -C(O)O-*, -S(O)O-*, -C(O)-*, -C(O)NR-*, - at the N10 and N10' positions of the pyrrolobenzodiazepine dimer each independently any one selected from the group consisting of S(O) 2 NR-*, -(P(O)R')NR-*, -S(O)NR-*, and -PO 2 NR-* groups is attached,
  • R and R' are each independently H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted substituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted C 1-8 alkylthio, substituted or unsubstituted C 3-20 heteroaryl, substituted or unsubstituted C 5-20 aryl or mono- or di-C 1-8 alkylamino;
  • C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl are substituted, H, OH, N substituted with a substituent selected from the group consisting of 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NNH 2 , halo, C 1-6 alkyl, C 1-6 alkoxy and C 6-12 aryl;
  • a pyrrolobenzodiazepine dimer prodrug, a pharmaceutically acceptable salt or solvate thereof may be used as the active agent.
  • the N10 position of the pyrrolobenzodiazepine dimer is substituted with X at the N'10 position or X' at the N'10 position, wherein X or X' connects the pyrrolobenzodiazepine dimer to the linker;
  • X and X' are each independently -C(O)O*, -S(O)O-*, -C(O)-*, -C(O)NR X -*, -S(O) 2 NR X -*, -P(O)R'NR X -*, -S(O)NR X -*, or -PO 2 NR X -*;
  • R X and R X ' are independently H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1 - 8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di(di)-C 1-8 alkylamino.
  • a pyrrolobenzodiazepine dimer precursor is provided as the active agent.
  • a pyrrolobenzodiazepine dimer precursor is provided as the active agent.
  • the antibody-drug conjugate prepared by the conventional method in the case of the antibody-drug conjugate prepared by the conventional method, the content of impurities is high and the exposed imine group is attacked by nucleophiles, which may result in the production of a drug having an unwanted structure.
  • the antibody-drug conjugate prepared by the method according to the present invention has the advantage of easy separation due to high purity, and it has been shown that the physical properties are more improved compared to the existing PBD or PBD dimer.
  • the pyrrolobenzodiazepine dimer precursor is a pyrrolobenzodiazepine dimer precursor, a pharmaceutically acceptable salt or solvate thereof, characterized in that it has the structure of Formula X or Formula XI:
  • the dotted line indicates the optional presence of a double bond between C1 and C2, between C2 and C3, between C'1 and C'2, or between C'2 and C'3;
  • R m ′ is selected from R m , CO 2 R m , COR m , CHO, CO 2 H, and halo;
  • each R m is independently C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 cycloalkyl, 3-7 - selected from the group consisting of -membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl;
  • R X2 , R X2 ' R X3 , R X3 ', R X5 , and R X5 ' are independently H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m 2 , NO 2 , and halo;
  • R X4 and R X4 ′ are independently H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m 2 , NO 2 , halo, C 1-6 alkyl C 1-6 alkoxy; C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-12 aryl, 5-7 membered heteroaryl, -CN, -NCO, -OR n , -OC(O)R n , -OC(O)NR n R n ', -OS(O)R n , -OS(O) 2 R n , -SR n , -S(O)R n , -S(O) 2 R n , -S(O)NR n R n ', -S(O) 2 NR n R n
  • X and X' are independently -C(O)O*, -S(O)O-*, -C(O)-*, -C(O)NR X -*, -S(O) 2 NR X -*, -P(O)R'NR X -*, -S(O)NR X -*, or -PO 2 NR X -*;
  • R X and R X ' are independently H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1 - 8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di(di)-C 1-8 alkylamino;
  • Y and Y' are independently selected from O, S, and N(H);
  • R X6 is independently selected from C 3-12 alkylene, C 3-12 alkenylene, or C 3-12 heteroalkylene;
  • R X7 and R X7 ' are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 6- 10 aryl, 5-7 membered heteroaryl, -OR r , -OC(O)R r , -OC(O)NR r R r ', -OS(O)R r , -OS(O) 2 R r , -SR r , -S(O)R r , -S(O) 2 R r , -S(O)NR r R r ', -S(O) 2 NR r R r ', -OS(O) NR r R r ', -OS(O) NR r R r ', -OS(O) 2 NR r R r ', -OS(O) NR r
  • each R r , R r ', R s , and R s ' is independently H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5-10 aryl, and 5 to 7-membered heteroaryl;
  • each R X8 and R X8 ′ is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 heteroalkyl, 3-7 membered heterocycloalkyl, C 5 -10 aryl, 5-7 membered heteroaryl, -S(O)R m , -S(O) 2 R m , -S(O)NR m R m ', -S(O) 2 NR m R m ', -NR m R m ', -NR m C(O)R m , -NR m C(O)OR n , -NR m C(O)NR n R n ', -NR m S(O)R n , -NR m S(O) 2 R n , -NR m S(O)NR n R n ', -NR m S(O) 2 NR n , -
  • Z a is selected from OR X12a , NR X12a R X12a , or SR X12a ;
  • Z b is selected from OR X13a , NR X13a R X13a , or SR X13a ;
  • Z a ' is selected from OR X12a ', NR X12a 'R X12a ', or SR X12a ';
  • Z b ' is selected from OR X13a ', NR X13 'R X13a ' or SR X13a ';
  • each R X12a , R X12a ', R X13a ' and R X13a ' is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 - membered heterocycloalkyl, C 5-10 aryl, 5-7 membered heteroaryl, -C(O)R X15a , -C(O)OR X15a and -C(O)NR X15a R X15a '; and
  • each R X15a and R X15a ′ is independently C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 cycloalkyl , 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl;
  • Z a and Z b are optionally taken together with the atoms to which they are attached to form a 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, or 3 to 7-membered heteroaryl, and Z a ' and Z b ' are optionally taken together with the atom to which they are attached to form a 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, or 3 to 7-membered heteroaryl; and
  • each of R n , R n ', R o , R o ', R p , and R p ' is independently H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5-10 aryl, and 5 to 7-membered heteroaryl.
  • R m is independently C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 selected from the group consisting of cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl,
  • R m is additionally C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 cycloalkyl , 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, or 5 to 7-membered heteroaryl.
  • R X4 and R X4 ' are independently H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m R m ', NO 2 , halo, C 1-6 alkyl C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-12 aryl, 5-7- membered heteroaryl, -CN, -NCO, -OR n , -OC(O)R n , -OC(O)NR n R n ', -OS(O)R n , -OS(O) 2 R n , -SR n , -S(O)R n , -S(O) 2 R n , -S(O)NR n R n ', -S
  • R X4 or R X4 ' is C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-12 aryl or 5-7 membered heteroaryl, additionally one or more C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl , 3-7-membered heterocycloalkyl, C 5-10 aryl, 5-7-membered heteroaryl, -OR p , -OC(O)R p , -OC(O)NR p R p ', -OS( O)R p , -OS(O) 2 R p , -SR p , -S(O)R p , -S(O) 2 R p , -S(O)NR p R
  • R X7 and R X7 ' are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7- membered heterocycloalkyl, C 6-10 aryl, 5-7 membered heteroaryl, -OR r , -OC(O)R r , -OC(O)NR r R R r ', -OS(O)R r , -OS(O) 2 R r , -SR r , -S(O)R r , -S(O) 2 R r , -S(O)NR r R r ', -S(O) 2 NR r R r ', -OS(O)NR r R r ', -OS(O) 2 NR r R r ', -OS(O)NR r R r ', -OS(O) 2 NR
  • R X7 or R X7 ' is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6-10 aryl, 5 to 7-membered heteroaryl, additionally C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6-10 aryl, 5-7 membered heteroaryl, -OR t , -OC(O)R t , -OC(O)NR t R t ', -OS(O)R t , -OS(O) 2 R t , -SR t , -S(O)R t , -S(O) 2 R t , -S(O)NR t R t ', -S(O) 2 NR
  • R r , R r ', R s , R s ', R t , R t ', R u and R u ' are independently H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-10 aryl, and 5-7 membered heteroaryl.
  • R X1 and R X1 ' are independently selected from R m ;
  • R m is selected from C 1-6 alkyl, C 2-6 alkenyl, C 5-7 aryl and C 3-6 heteroaryl.
  • R X2 , R X2 ′, R X3 , R X3 ′, R X5 , and R X5 ′ are independently selected from H or OH.
  • R X4 and R X4 ′ are independently selected from R m ;
  • R m is C 1-6 alkoxy.
  • R X4 and R X4 ' are independently any one selected from the group consisting of methoxy, ethoxy and butoxy.
  • Y and Y' are O.
  • R X6 is C 3-12 alkylene, C 3-12 alkenylene or C 3-12 heteroalkylene, and R X6 is -NH 2 , -NHR m , -NHC(O )R m , —NHC(O)CH 2 —[OCH 2 CH 2 ] n —R XX , or —[CH 2 CH 2 O] n —R XX substituted;
  • R XX is H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1 -8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkyl amino; and
  • n is an integer from 1 to 6.
  • the pyrrolobenzodiazepine dimer is represented by the following general formula X.
  • the dotted line indicates the optional presence of a double bond between C1 and C2, between C2 and C3, between C'1 and C'2, or between C'2 and C'3;
  • R X2 , R X2 ′ R X3 , and R X3 ′ are each independently selected from H, R m , OH, OR m , NR m 2 , NO 2 , and halo;
  • R X4 and R X4′ are each independently selected from H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m 2 , halo, and C 1-6 alkyl;
  • R X5 and R X5' are each independently H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m 2 , -NR m R m ', NO 2 , -NR m C( O)R m' , -NR m C(O)OR m' , -NR m C(O)NR m R m' , -S(O)R m , -S(O) 2 R m , -S( O)NR m R m ', -S(O) 2 NR m R m ', -NR m S(O)R m ', -NR m S(O) 2 R m ', -P(O)R m , -P(O)NR m R m ', -P(O) 2 NR m R m ', -P(O) 2
  • Y and Y' are each independently O, S, or N(H);
  • R X6 is independently C 3-12 alkylene, C 3-12 alkenylene, or C 3-12 heteroalkylene; R X6 is -NH 2 , -NHR m , -NHC(O)R m , -NHC(O)CH 2 -[OCH 2 CH 2 ] n -R XX , or -[CH 2 CH 2 O] n -R XX is substituted or unsubstituted;
  • R XX is H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1 -8 alkyl thio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkylamino, wherein n is an integer from 1 to 6;
  • R X7 and R X7 ' are each independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)R r , -C(O)OR s or -C (O)NR r R r ';
  • R r , R r ', and R s are each independently H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3-7 membered heterocyclo alkyl, C 5-10 aryl or 5 to 7 membered heteroaryl;
  • each R m' is independently selected from R m , CO 2 R m , COR m , CHO, CO 2 H, and halo;
  • R X2 , R X2 ′, R X3 , and R X3 ′ are each independently selected from H or OH.
  • the R X5 , and R X5 ' are each independently H, OH, -S(O)R m , S(O) 2 R m , -P(O)R m , and -P (O) 2 R m is selected from the group consisting of, wherein R m is H, OH, C 1-12 alkyl, C 1-12 alkoxy, C 2-12 alkenyl, or C 2-12 alkynyl.
  • R X4 and R X4 ' are each independently C 1-6 alkoxy.
  • R X4 and R X4 ' are independently any one selected from the group consisting of methoxy, ethoxy and butoxy.
  • Y and Y' are O.
  • R X6 is C 3-12 alkylene, C 3-12 alkenylene or C 3-12 heteroalkylene, and R X6 is -NH 2 , -NHR m , -NHC(O )R m , -NHC(O)CH 2 -[OCH 2 CH 2 ] n -R XX , or -[CH 2 CH 2 O] n -R XX ;
  • R XX is H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1 -8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkyl amino; and
  • n is an integer from 1 to 6.
  • the active agent is a pyrrolobenzodiazepine dimer represented by the general formula XII or XIII:
  • X a and X a ' are independently selected from a bond or C 1-6 alkylene;
  • Z X ' and Z X are independently hydrogen, C 1-8 alkyl, halogen, cyano, nitro, , or -(CH 2 ) m -OCH 3 ;
  • n is an integer from 0 to 12;
  • Z X ' and Z X are independently hydrogen, , And -(CH 2 ) m -OCH 3 Any one selected from the group consisting of,
  • R 80 , R 90 and R 100 is any one selected from the group consisting of hydrogen, C 1-3 alkyl and C 1-3 alkoxy,
  • n 1 to 6.
  • the [LINKER-(B) l ] precursor is
  • the [LINKER-(B) l ] precursor is
  • MMAE is monomethyl auristatin E
  • MMAF is monomethyl auristatin F.
  • the [LINKER-(B) l ] precursor comprises the following structure.
  • B' and B'' represent an active agent, which may be the same or different;
  • n and n each independently represent an integer of 0-30.
  • the present invention relates to a pharmaceutical composition for the prevention or treatment of hyperproliferative, cancer, or angiogenic diseases comprising the conjugate.
  • the pharmaceutical composition further comprises a pharmaceutically effective amount of a chemotherapeutic agent.
  • the cancer is lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, bowel cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi Any one selected from the group consisting of sarcoma and melanoma.
  • the present invention also relates to a pharmaceutical formulation comprising the conjugate.
  • parenteral means an administration route in a broad sense, for example, transdermal, intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, intranasal, sublingual, intrathecal (intrathecal), inhalation, ocular, rectal, vaginal, ventricular administration, and the like.
  • composition When formulating the composition, it is usually prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant.
  • a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant.
  • Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, and such solid preparations include at least one compound according to the present invention and at least one excipient, for example, starch, calcium carbonate, It is prepared by mixing sucrose or lactose or gelatin.
  • excipients for example, starch, calcium carbonate, It is prepared by mixing sucrose or lactose or gelatin.
  • lubricants such as magnesium stearate talc are also used.
  • Liquid formulations for oral administration include suspensions, solutions, emulsions, or syrups.
  • various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, injections, freeze-dried formulations, suppositories, and the like.
  • propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solutions and suspensions.
  • injectable esters such as ethyl oleate
  • witepsol, macrogol, tween 61, cacao butter, laurin fat, glycerol, gelatin, etc. may be used as the base of the suppository.
  • the conjugate according to the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type, severity, and drug activity of the patient. , sensitivity to the drug, administration time, administration route and excretion rate, duration of treatment, factors including concurrent drugs, and other factors well known in the medical field.
  • the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the conjugate according to the present invention may vary depending on the age, sex, and weight of the patient, and is generally 0.01 mg to 150 mg per kg body weight, more specifically 0.1 mg to 100 mg per kg body weight. It can be administered daily or every other day, or divided into 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, severity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.
  • the antibody-drug conjugate according to the present invention contains an anti-CLDN18.2 antibody that specifically binds to claudin 18 isoform 2 (CLDN18.2) expressing cells and is internalized into the cells, thereby effectively and specific for the drug. It can be delivered selectively and selectively, and the drug is stably bound to the antibody to exhibit the desired cytotoxicity while maintaining in vivo stability.
  • grafting linker technology that includes a self-immolative group that is more stable in plasma and is stable even in circulation in the body, and the drug is easily released within cancer cells to maximize drug efficacy, drugs and/or toxins are transferred to target cells. It has the effect of providing a drug-linker-ligand system that can stably reach and effectively exhibit drug effects while significantly lowering toxicity.
  • FIGS. 2 and 3 are diagrams showing the in vivo experimental results of ADC samples.
  • FIGS 4 to 7 are schematic diagrams of the manufacturing process of the ADC according to the present invention.
  • the present invention is an antibody or antigen-binding fragment, wherein the antibody specifically binds to claudin 18 isoform 2 (CLDN18.2) comprising a heavy chain variable region and a light chain variable region, and the heavy chain variable region is SEQ ID NO: 2 a heavy chain CDR1 consisting of the amino acid sequence shown in SEQ ID NO: 4, a heavy chain CDR2 consisting of the amino acid sequence shown in SEQ ID NO: 4, and a heavy chain CDR3 consisting of the amino acid sequence shown in SEQ ID NO: 6, wherein the light chain variable region has an amino acid sequence shown in SEQ ID NO: 9 It relates to a conjugate comprising a light chain CDR1 consisting of, a light chain CDR2 consisting of the amino acid sequence shown in SEQ ID NO: 11, and a light chain CDR3 consisting of the amino acid sequence shown in SEQ ID NO: 13.
  • PR002726-heavy chain SEQ ID NO: FR1 EVQLLESGGGLVQPGGSLRLSCAAS One CDR1 GFTFSSFVMS 2 FR2 WVRQAPGKGLEWVS 3 CDR2 TISGSGRSTYYADSVKG 4 FR3 RFTISRDNSKNTLHLQMNSLRAEDTAVYYCAK 5 CDR3 DAAAAGTKFDY 6 FR4 WGQGTLVTVSS 7 V H EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFVMSWVRQAPGKGLEWVSTISGSGRSTYYADSVKGRFTISRDNSKNTLHLQMNSLRAEDTAVYYCAKDAAAAGTKFDYWGQGTLVTVSS 15 HC EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFVMSWVRQAPGKGLEWVSTISGSGRSTYYADSVKGRFTISRDNSKNTLHLQMNSLRAEDTAVYYCAKDAAAAGTKFDYWGQGTLVTV
  • the light chain FR4 (SEQ ID NO: 14) C-terminus of the antibody of Table 1 (PR002726) was fused with a CaaX peptide moiety (GGGGGGGCVIM; SEQ ID NO: 19) to prepare an antibody clone PR301839, and CHO cell-based Antibodies were produced through transient expression.
  • the produced PR301839 antibody was used for the next ADC synthesis.
  • the compounds 1 and 2 were prepared by the method described in Korean Patent Application Laid-Open No. 10-2018-0110645.
  • the compound 3 was prepared by the method described in International Patent Publication No. WO2017-089895.
  • the compound 4 and compound 5 were prepared by the method described in patent WO2017-089890.
  • ADC was prepared through the following two steps, and LCB14-0606 and LCB14-0512, which were commonly used, were prepared by the method described in Korean Patent Application Laid-Open No. 10-2014-0035393.
  • the structural formulas of LCB14-0606 and LCB14-0512 are as follows:
  • a prenylation reaction mixture of the antibody prepared in Example 1 was prepared and reacted at 30° C. for 16 hours.
  • the reaction mixture was prepared in a buffer containing 24 ⁇ M antibody, 400 nM FTase (Calbiochem #344145) and 0.25 mM LCB14-0511 or LCB14-0606 (50 mM Tris-HCl (pH 7.4), 5 mM MgCl 2 , 10 ⁇ M ZnCl 2 ) , 0.25 mM DTT).
  • the prenylated antibody was decontaminated with a G25 Sepharose column (AKTA purifier, GE healthcare) equilibrated with PBS buffer.
  • Step 2 Drug-conjugation method
  • the oxime bond generation reaction mixture between the prenylated antibody and the linker-drug was prepared in 100 mM Na-acetate buffer pH 5.2, 10% DMSO, 20 ⁇ M antibody and 200 ⁇ M linker-drug (in house, the compounds of Examples 1 and 2) 1, 2, 3, 4, 5, 7, and 8) were mixed and stirred gently at 30°C. After 6 hours or 24 hours of reaction, excess low molecular weight compounds were removed through FPLC (AKTA purifier, GE healthcare) process, and protein fractions were collected and concentrated.
  • FPLC AKTA purifier, GE healthcare
  • ADC using a copper-free click binding reaction between prenylated antibody and linker-drug was performed in PBS buffer (pH 7.4), 1% DMSO, 10 ⁇ M prenylated antibody and 100 ⁇ M linker-drug (in house, carried out)
  • Compound No. 2 of Example 1 was mixed to prepare a reaction mixture, and after reaction at 25 ° C for 6 hours, FPLC (AKTA purifier, GE healthcare) or G25 Sepharose column process was performed to remove excess low molecular weight compounds. concentrated.
  • the cancer cell binding ability of the Anti-CLDN18.2 antibody (PR002726) and the antibody (PR301839) used to prepare the ADC in the form of a CaaX peptide fused to the light chain FR4 C-terminus was confirmed by a cell binding experiment using a flow cytometer (FACS).
  • gastric cancer cell lines SNU-601 and SNU-620 known to express CLDN18.2, and pancreatic cancer cell line PATU-8988s were used as cancer cells.
  • a group treated with human IgG as a control antibody and a group treated with only a secondary antibody were used. .
  • PR002726 and PR301839 in SNU-601 were 22.95 times and 17.5 times stronger than the IgG control group, respectively.
  • PR002726 and PR301839 were confirmed to bind 15.09 times and 11.21 times stronger than the control group.
  • PATU-8988s PR301839 was confirmed to bind 16.21 times stronger than the control.
  • the two antibodies PR002726 and PR301839 were capable of binding to cancer cells expressing CLDN18.2. (See Fig. 1)
  • the cell proliferation inhibitory activity of the drugs and ADCs shown in Table 4 below was measured against cancer cell lines.
  • cancer cell lines commercially available human gastric cancer cell lines NUGC-4, SNU-601 SNU-602 and pancreatic cancer cell line PATU-8988s were used, and normal cell lines HaCaT, Fa2N-4, HK-2, and HS738.st/Int were used.
  • drugs MMAE and SG2057 were used as ADCs, and the ADCs in Table 3 were used.
  • Each cancer cell line was inoculated in a 96-well plate for 144 hours in a 144-hour treatment group, and 2,500 to 10,000 per well were seeded and cultured for 24 hours.
  • the auristatin-based antibody-drug complex (ADC3) showed equivalent or higher cytotoxicity than the pyrrolobenzodiazepine-based antibody-drug complex (ADC1, ADC2) in the cytotoxicity test with the same time response.
  • the pyrrolobenzodiazepine-based antibody-drug complex (ADC3, ADC4, ADC5) was compared to the auristatin-based antibody-drug complex (ADC3, ADC4, ADC5) in the same time response cytotoxicity test. of the antibody-drug complex (ADC1, ADC2) was confirmed to show strong cytotoxicity.
  • both 0.2 and 0.4 mg/kg of the pyrrolobenzodiazepine-based antibody-drug complex ADC1 confirmed the tumor growth inhibitory efficacy compared to the control group.
  • the tumor growth inhibitory efficacy was confirmed in a dose-dependent manner compared to the control group.
  • the experimental results (primary) of the in vivo efficacy of the ADC samples are shown in FIG. 2.
  • the secondary experimental results it was confirmed that the tumor growth inhibitory efficacy of the ADC3 1 mg/kg group was similar to the results of the primary experiment.
  • all doses of ADC4 and ADC5 the tumor growth inhibitory efficacy was confirmed in a dose-dependent manner.
  • the in vivo efficacy comparison experiment results (secondary) of ADC samples are as shown in FIG. 3 .
  • Fc ⁇ RI and Fc ⁇ RII interact with distinct but overlapping sites on human
  • the present invention can be usefully used in the pharmaceutical field through novel antibody-drug conjugates targeting claudin 18 subtype 2, active metabolites thereof, methods for preparing the same, uses thereof, and pharmaceutical compositions comprising the same.

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KR20240101987A (ko) 2022-12-23 2024-07-03 주식회사 와이바이오로직스 클라우딘-18.2에 특이적으로 결합하는 단클론항체 및 이의 용도
JP2026510495A (ja) * 2023-03-10 2026-04-07 リガケム バイオサイエンシズ， インク． ヒトｌ１ｃａｍに対する抗体を含む抗体－薬物コンジュゲートおよびその使用

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US12398124B2 (en) 2017-03-29 2025-08-26 Ligachem Biosciences Inc. Pyrrolobenzodiazepine dimer prodrug and ligand-linker conjugate compound of the same
WO2023194800A1 (en) * 2022-04-06 2023-10-12 Legochem Biosciences, Inc. Antibody-drug conjugate comprising antibody against human trop2 and use thereof
WO2024140670A1 (en) * 2022-12-26 2024-07-04 Full-Life Technologies Hk Limited Conjugate and uses thereof
US12178876B2 (en) 2023-04-18 2024-12-31 Astrazeneca, Ab Conjugates comprising cleavable linkers
US12337038B2 (en) 2023-04-18 2025-06-24 Astrazeneca Ab Conjugates comprising cleavable beta-glucuronide-containing linkers
WO2025032556A1 (en) * 2023-08-10 2025-02-13 Beigene Switzerland Gmbh Bioactive conjugates, preparation method and use thereof
WO2025032555A1 (en) * 2023-08-10 2025-02-13 Beigene Switzerland Gmbh Bioactive conjugates, preparation method and use thereof
WO2025078881A3 (en) * 2023-10-13 2025-05-22 Ligachem Biosciences Inc. Anti-claudin 18.2 antibody drug conjugates comprising topoisomerase i inhibitor and uses thereof

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