WO2019034177A1 - Conjugué anticorps-médicaments présentant deux médicaments différents - Google Patents

Conjugué anticorps-médicaments présentant deux médicaments différents Download PDF

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WO2019034177A1
WO2019034177A1 PCT/CN2018/101215 CN2018101215W WO2019034177A1 WO 2019034177 A1 WO2019034177 A1 WO 2019034177A1 CN 2018101215 W CN2018101215 W CN 2018101215W WO 2019034177 A1 WO2019034177 A1 WO 2019034177A1
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antibody
drug
pharmaceutically acceptable
acceptable salt
drug conjugate
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PCT/CN2018/101215
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Chinese (zh)
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朱义
李�杰
卓识
万维李
余永国
李刚锐
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四川百利药业有限责任公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an antibody drug conjugate having two different drugs.
  • antibody-conjugated drugs generally consist of three parts: antibody or antibody ligands, small molecule drugs, and linkers that couple ligands to drugs.
  • the antibody-conjugated drug utilizes the specific recognition of the antigen by the antibody, transports the drug molecule to the vicinity of the target cell and effectively releases the drug molecule for therapeutic purposes.
  • FDA US Food and Drug Administration
  • Adecteis TM developed by Seattle Genes for the treatment of Hodgkin's lymphoma and relapsed large cell lymphoma (ALCL). The safety and efficacy of such drugs.
  • the ADC drug antibody mainly functions as a targeted delivery function, and finally the drug effect is the coupled drug molecule.
  • the drug molecules currently used in the field of ADC are classified according to different mechanisms of action: microtubule inhibitors, DNA damaging agents, topoisomerase inhibitors, RNA polymerase inhibitors, protein translation inhibitors, and the like.
  • ADC drugs In ADC drugs, antibodies carry drug molecules to the vicinity of tumor cells, releasing drug molecules around or within the tumor cells. At the same time, however, tumors have developed different mechanisms against drug molecules during this treatment, including pumping toxin molecules out of the cell with a PgP protein pump to escape killing.
  • ADC drug development mainly focuses on single antibody linking single-acting mechanism drugs. Modern medicine has proved that the combination of different drugs in the chemotherapy process can significantly enhance the efficacy. However, as the number and type of drugs in the ADC increase, the lipid solubility of the molecule increases, the stability in plasma is significantly reduced, and the efficacy is not improved, but also causes side effects.
  • the C-LOCK technique often results in a DAR of 2-4, and the K-LOCK technique also has obvious limitations: when the lysine-linked drug antibody coupling ratio (DAR) is >2 Since a single antibody molecule contains about 88 lysines, such a large amount of lysine results in poor amino coupling selectivity, and the number of couplings and the coupling position are difficult to determine, although a certain degree of control can be achieved by coupling conditions.
  • DAR lysine-linked drug antibody coupling ratio
  • the patent CN106132431 does not report the pharmacodynamic data and plasma stability in animals.
  • ADC drugs an innovative coupling method is needed to achieve plasma stabilization, antibody-conjugated drugs coupled to two different drugs, and a more convenient combination of drugs is achieved.
  • the present invention surprisingly meets the above needs.
  • the present invention aims to provide an antibody-drug conjugate having two different drugs. Two different drug molecules are linked to the same antibody by designing the conjugate. Due to the combined use of different mechanisms of action, the conjugate can effectively improve the efficacy.
  • the present invention provides an antibody drug conjugate comprising a different drug, or a pharmaceutically acceptable salt thereof, of Formula I
  • L1, L2 are optional linking units connectable to the drug
  • D1 and D2 are drug units
  • n and n are integers of 2-8.
  • the drugs D1 and D2 are antitumor drugs having different mechanisms of action.
  • the drugs D1, D2 are preferably selected from the group consisting of tubulin binding agents, DNA alkylating agents, DNA intercalating agents, enzyme inhibitors, immunomodulators, peptides and nucleotides, respectively.
  • the m is preferably 2, 4.
  • the drug D1 is preferably attached to the antibody in a site-directed coupling manner, and the D2 is coupled to the antibody in a non-targeted manner.
  • the preferred site-directed coupling of drug D1 is a half-pointed mutant antibody original amino acid to cysteine or by insertion of a cysteine or a cysteine-containing polypeptide, which is introduced by the above method.
  • the cystine thiol is coupled to the linker-toxin.
  • a preferred non-targeted coupling of D2 is the coupling of the original interchain disulfide bond of the antibody to the linker-toxin.
  • L1 and L2 have the following formula 2:
  • C is an optional extendable unit at the end
  • E is an optional cleavable unit
  • F is a spacer unit
  • subscript e, f is 0 or 1.
  • the wavy line indicates the attachment site to the succinimide and the drug unit.
  • the cleavable unit described by E is achieved by a tumor-associated protease or an acidic pH with a drug unit D or a spacer unit F
  • F is selected from the group consisting of p-aminobenzyl alcohol or with ethylenediamine units and derivatives thereof.
  • the drug-ligand conjugate compound of any of the present invention comprises a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of a pharmaceutically acceptable diluent carrier or excipient.
  • the invention comprises administering to the patient the drug-ligand conjugate of any of the preceding claims, wherein the patient has a tumor, an autoimmune disease or an infectious disease, and
  • the antibody-ligand conjugate antibody specifically binds to the target cell of the cancer, autoimmune disease
  • Figure 1 shows the results of the Payload S MS-TOF test.
  • FIG. 2 shows the results of the Payload E MS-TOF test.
  • Figure 3 shows a graph of the results of the ADC and control ADCs with different drugs.
  • the antibody drug conjugate represented by the following formula is provided by the present invention.
  • the trade name includes the product formulation, generic drug, and active pharmaceutical ingredient of the trade name product.
  • a “derivative" of a compound as used herein refers to a chemical structure that is similar to a compound but also contains at least one chemical group that is not present in the compound and/or lacks the chemical group present in at least one of the compounds.
  • the substance of the regiment. The compounds to which the derivatives are compared are referred to as "parent” compounds.
  • a “derivative" can be produced from a parent compound in one or more chemical reaction steps.
  • antibody or “antibody unit” is within the scope of its disclosure, including any portion of the antibody structure.
  • This unit can bind, reactively associate, or complex a receptor, antigen, or other receptor unit that the cell population has.
  • the antibody can be any protein or proteinaceous molecule that can bind, complex, or react with a portion of the cell population to be treated or bioengineered.
  • the linker is covalently attached to the sulfur atom of the antibody.
  • the sulfur atom is a sulfur atom of a cysteine residue that forms an interchain disulfide bond of the antibody.
  • the sulfur atom is a sulfur atom that has been introduced into the cysteine residue of the ligand unit, which forms an interchain disulfide bond of the antibody.
  • the sulfur atom is a sulfur atom that has been introduced into the cysteine residue of the ligand unit (eg, by site-directed mutagenesis or chemical reaction).
  • the linker-bonded sulfur atom is selected from a cysteine residue that forms an interchain disulfide bond of the antibody or a cysteine residue that has been introduced into the ligand unit (eg, by site-directed mutagenesis or chemical reaction).
  • the EU index in Kabat Kabat (Kabat EA et al, (1991)) "Sequences of proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242" Numbering system.
  • the antibody constituting the antibody drug conjugate of the present invention preferably retains the antigen binding ability in its original wild state. Therefore, the antibody of the present invention can, preferably, specifically bind to an antigen.
  • Antigens involved include, for example, tumor associated antigens (TAAs), cell surface receptor proteins and other cell surface molecules, cell survival regulators, cell proliferation regulators, molecules associated with tissue growth and differentiation (as known or predicted) Functional), lymphokines, cytokines, molecules involved in cell cycle regulation, molecules involved in angiogenesis, and molecules involved in angiogenesis (as known or predicted to be functional).
  • TAAs tumor associated antigens
  • cell survival regulators e.g., cell survival regulators, cell proliferation regulators, molecules associated with tissue growth and differentiation (as known or predicted) Functional)
  • lymphokines cytokines
  • molecules involved in cell cycle regulation e.g., cytokines, molecules involved in cell cycle regulation, molecules involved in angiogenesis, and molecules involved in angiogenesis (as known or predicted to be functional).
  • Antibodies for use in antibody drug conjugates described herein include, but are not limited to, antibodies directed against cell surface receptors and tumor associated antigens. Such tumor associated antigens are well known in the art and can be prepared by antibody preparation methods and information well known in the art.
  • tumor associated antigens are well known in the art and can be prepared by antibody preparation methods and information well known in the art.
  • transmembrane or other tumor-associated polypeptides are capable of being specifically expressed on the surface of one or more cancer cells with little or no expression on the surface of one or more non-cancer cells.
  • tumor-associated polypeptides are more overexpressed on the surface of cancer cells relative to the surface of non-cancer cells. Confirmation of such tumor-associated factors can greatly enhance the specific targeting characteristics of cancer-based treatment of cancer.
  • Tumor-associated antigens include, but are not limited to, tumor-associated antigens well known in the art. Nucleic acid and protein sequences corresponding to tumor associated antigens can be found in public databases such as Genbank. Antibody-targeting corresponding tumor-associated antigens include all amino acid sequence variants and isoforms, having at least 70%, 80%, 85%, 90%, or 95% homology to the sequences identified in the references, or The tumor-associated antigen sequences cited in the literature have completely identical biological properties and characteristics.
  • inhibiting means reducing the detectable amount or completely preventing it.
  • cancer refers to a physiological condition or disease characterized by dysregulated cell growth.
  • Tumors include cancer cells.
  • autoimmune disease is a disease or disorder that results from tissue or protein directed against the individual's own body.
  • site-directed coupling is preferably a cysteine introduced by the above method, either by the original amino acid of the site-directed mutant antibody to cysteine or by the insertion of a cysteine or a cysteine-containing polypeptide into the antibody.
  • the thiol group is coupled to the succinimide in the linker.
  • the "non-site-coupled” mode is coupled to the linker-toxin by utilizing the original interchain disulfide bond of the antibody.
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt of a compound (eg, a drug, a drug-linker or a ligand-linker-drug conjugate).
  • the compound may contain at least one amino or carboxyl group and thus may form an addition salt with the corresponding acid or base.
  • Exemplary salts include, but are not limited to, sulfates, trifluoroacetates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acids Phosphate, isonicotinic acid, lactate, salicylate, acidic citrate, tartrate, oleate, tannic acid, pantothenate, hydrogen tartrate, ascorbate, salicylate, Formate, orthoformate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, potassium salt, sodium salt, and the like.
  • pharmaceutically acceptable salts have more than one dotted atom in the structure.
  • An example in which a plurality of charged atoms are part of a pharmaceutically acceptable salt can have multiple counterexamples.
  • a pharmaceutically acceptable salt has one or more charged atoms and/or one or more counter atoms.
  • Drugs refer to: a cytotoxic drug used in the treatment of cancer, including but not limited to maytansine or maytansinoid, doxatin 10 (Dolastatin 10) analogs, calicheamicin drugs Pyrrolo[2,1-c][1,4]benzodi-azepines (PBDs) or PBD dimers (PBD dimmers) and derivatives amanita or derivatives thereof
  • PBDs Pyrrolo[2,1-c][1,4]benzodi-azepines
  • PBD dimers PBD dimers
  • Medium active drugs include, but are not limited to, benzopyrrolidone (duocarmycins, CC-1065, etc.) camptothecin compounds including camptothecin, hydroxycamptothecin, SN-38, ezetidine, irinotecan Wait.
  • the drug is not limited to the above-mentioned categories, but also includes all drugs that can be used for antibody drug conjugates.
  • linking unit or “linking unit of antibody drug conjugate” can be divided into two categories: non-cleavable linking unit and cleavable linking unit.
  • the drug release mechanism is: after the conjugate is bound to the antigen and endocytosed by the cell, the antibody is hydrolyzed in the lysosome, and the drug is released by the small molecule drug.
  • An active molecule composed of an amino acid residue of an antibody. The resulting change in the molecular structure of the drug does not diminish its cytotoxicity, but since the active molecule is charged (amino acid residues), it cannot penetrate into adjacent cells. Therefore, such active drugs cannot kill tumor cells (bystander effect) adjacent to the non-expressing target antigen (antigen-negative cells) (Ducry et al, 2010, Bioconjugate Chem. 21: 5-13).
  • a cleavable linker unit can cleave in the target cell and release the active drug (small molecule drug itself).
  • Breakable linkers can be divided into two main classes: chemically labile linkers and enzyme labile linkers.
  • Chemically labile linkers can be selectively cleaved due to differences in plasma and cytoplasmic properties. Such properties include pH, glutathione concentration, and the like.
  • pH sensitive linkers are often referred to as acid cleavage linkers. Such a linker is relatively stable in the neutral environment of blood (pH 7.3-7.5), but will be in the weakly acidic endosomes (pH 5.0-6.5) and lysosomes (pH 4.5-5.0). hydrolysis. Most of the first generation of antibody drug conjugates use such linkers, such as hydrazine, carbonate, acetal, ketal. Antibody drug conjugates based on such linkers typically have a shorter half-life (2-3 days) due to the limited plasma stability of the acid-cleaved linker. This shorter half-life limits the use of pH-sensitive linkers in a new generation of antibody drug conjugates to some extent.
  • disulfide bond For glutathione-sensitive linkers, it is also called disulfide bond. Drug release is based on a difference between the high concentration (in millimolar range) of intracellular glutathione and the relatively low concentration of glutathione (micromolar range) in the blood. This is especially true for tumor cells, where low oxygen levels result in enhanced reductase activity, resulting in higher glutathione concentrations. Disulfide bonds are thermodynamically stable and therefore have better stability in plasma.
  • Enzyme-labile linkers such as peptide linkers, provide better control of drug release.
  • Peptide linkers are capable of being efficiently cleaved by lysosome in vivo proteases such as cathepsin B or plasmin (an increase in the amount of such enzymes in some tumor tissues). This peptide linkage is believed to be very stable in the plasma circulation because the extracellular pH is inappropriate and the serum protease inhibitors cause the protease to be generally inactive.
  • enzyme-labile linkers are widely used as cleavable linkers for antibody drug conjugates.
  • Typical enzyme-labile linkers include Val-Cit (vc), Phe-Lys, and the like.
  • Suicide linkers are typically chimeric between the cleavable linker and the active drug, or are themselves part of a cleavable linker.
  • the mechanism of action of the suicide linker is that when the cleavable linker is broken under suitable conditions, the suicide linker can spontaneously rearrange the structure and release the active drug attached thereto.
  • Common suicide linkers include p-aminobenzyl alcohols (PAB) and beta-glucuronides.
  • This patent may use the following abbreviations and have the specified definitions: Boc, tert-butoxycarbonyl; DCC, cyclohexylcarbodiimide; DCM: dichloromethane; DIPEA: diisopropylcarbodiimide; DMF: N , N-dimethylformamide; DMAP: 4-(N,N-dimethylamino)pyridine; HATU: 2-(7-oxobenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate; HPLC: high performance liquid chromatography; PEG: polyethylene glycol; TFA: trifluoroacetic acid; THF: tetrahydrofuran; PBS: phosphate buffer solution (pH 7.0-7.5).
  • the pharmaceutically acceptable excipients include any carrier, diluent, adjuvant or excipient such as preservatives and antioxidants, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, solvents, dispersion media. , coating agents, antibacterial and antifungal agents and absorption delaying agents, and the like.
  • the use of such media and agents for the use of pharmaceutically active substances is well known in the art.
  • any conventional media or agents that are incompatible with the active ingredients their use in therapeutic compositions is also contemplated.
  • the additional active ingredient can also be incorporated into the compositions.
  • the antibody drug conjugate provided by the invention with two different drugs can effectively enhance the drug effect and obtain better therapeutic effect because of different action mechanism of the drug.
  • the method of the present invention provides a combination of site-directed coupling and non-spotting coupling, and the antibody drug conjugate containing two different drugs can be obtained by simple coupling.
  • the PCR reaction system (50 ⁇ L) was prepared in the following proportions, mixed thoroughly and then centrifuged instantaneously.
  • the antibody molecules having a monomeric ratio of more than 95% after preliminary purification were exchanged into a phosphate buffer solution containing EDTA using an ultrafiltration centrifuge tube at a concentration of 10 mg/ml.
  • TCEP was added 10 times the number of molecules of the antibody, and reacted at room temperature for 2 h.
  • the solution was changed to a phosphate buffer of pH 6.5 using an ultrafiltration centrifuge tube, and DHAA was added 10 times the number of molecules of the antibody, and reacted at room temperature for 2 hours. Then, a payload 1 of 3 times the number of molecules of the antibody was added, and the reaction was carried out for 4 hours at room temperature.
  • the solution was exchanged into a phosphate buffer containing EDTA using an ultrafiltration centrifuge tube having a molecular weight cut off of 30 KDa, and the unconjugated payload 1 was removed.
  • TCEP was added 10 times the number of molecules of the antibody, and reacted at room temperature for 8 hours.
  • the interchain disulfide bond was opened, and the number of free thiol groups was determined by the Ellman method to determine whether the disulfide bonds were all open. Then, add 2 times the antibody molar number of payload 2, and react at room temperature for 8 hours.
  • the solution was exchanged into PBS using an ultrafiltration centrifuge tube having a molecular weight cut off of 30 KDa, and unconjugated payload 2 was removed.
  • ADC hydrophobic interaction chromatography
  • MPB mobile phase B
  • MPB consisting of 1.5 M ammonium sulfate and .025 M sodium phosphate
  • MPB consisting of 0.025 M sodium phosphate, 25% isopropanol.
  • the sample loading was approximately 20 ⁇ g and the gradient elution was completed in 15 minutes.
  • UV 280 nm was used for detection, the stronger the water-transfer sample, the later the peak.
  • ADC sample Take a certain amount of ADC sample, add it to human plasma from which human IgG has been removed, repeat three tubes of each ADC, incubate in a 37 °C water bath, incubate for 0h, 72h, and then take out the ADC sample, and add ProteinA (MabSelect SuReTM) to each tube.
  • LX Lot: #10221479GE washed with PBS 100 ul, shaking with a vertical mixer for 2 h, after washing and eluting steps to obtain the ADC after incubation.
  • RP-HPLC detection of ADC samples for specific time of incubation. Plasma stability.
  • the colloid is formed in the reaction solution and attached to the bottom of the bottle; the colloid and the reaction solution are taken, dissolved in DCM, and the plate is washed with water, and the reaction is complete after 008, and the post-treatment is carried out.
  • reaction mixture was poured into 100 ml of water, and a large amount of solid was precipitated, which was extracted with DCM (60 ml ⁇ 3), and the organic phase was washed three times with brine, dried over anhydrous sodium sulfate and evaporated.
  • the VC-PABA obtained in the above step was dissolved in dry DMF, added with McOSu, DIEA, stirred at room temperature for 2 h, and the reaction was monitored by HPLC. After adding isopropyl ether at room temperature, stirring and crystallization for 2 h, then cooling to 0 ° C, stirring for 1 h, filtering, filter cake Wash twice with isopropyl ether and dry under reduced pressure
  • Mc-VC-PABA 8 g, 14 mmol was dissolved in 120 mL dry DMF, and bis(4-nitrophenyl) carbonate (8.5 g, 28 mmol, 2 eq), DIEA (3.66 ml) , 21.0 mmol, 1.5 eq).
  • the reaction mixture was stirred at room temperature for 1 h, then the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
  • a single-mutation cetux antibody was prepared by the general method A, and then the general procedure A was repeated to obtain a double-mutation cetux antibody.
  • a single-mutation cetux antibody was prepared by the general method A, and then the general procedure A was repeated to obtain a double-mutation cetux antibody.
  • the Cetuximab antibody having a monomeric ratio of more than 95% after preliminary purification was exchanged into a phosphate buffer solution containing EDTA at a concentration of 10 mg/ml using an ultrafiltration centrifuge tube.
  • TCEP was added 10 times the number of molecules of the antibody, and reacted at room temperature for 8 hours.
  • the interchain disulfide bond was opened, and the number of free thiol groups was determined by the Ellman method to determine whether the disulfide bonds were all open. Then, a payload 10 times the number of molecules of the antibody was added, and the reaction was carried out for 8 hours at room temperature.
  • the SEC assay was performed on the ADC described in the present invention according to the general method.
  • the data is summarized in the following table. From the results, it can be seen that the ADC ratio of the ADC drug with different toxins is slightly lower than that of the single toxin.
  • Human pharyngeal squamous cell carcinoma Fadu was cultured in vitro and inoculated subcutaneously in the back of nude mice according to the number of cells 5 ⁇ 10 6 . After the tumor grew to 70-90 mm 3 , the mice were given a single dose of ADC drug 5 mg/kg (tail vein injection). The vehicle control group was weighed regularly, the tumor volume was measured, and the drug efficacy against the Fadu model was evaluated by investigating the antitumor efficacy of the ADC drug. The results show that ADC drugs with different toxins have better in vivo efficacy than single toxin ADC drugs.

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Abstract

L'invention concerne un conjugué anticorps-médicaments présentant deux médicaments différents. Un des médicaments selon l'invention se lie sur le résidu cystéine de l'anticorps par couplage en un point fixe alors que le second médicament présentant une cytotoxicité à système fonctionnel différent se lie sur un résidu cystéine de l'anticorps par couplage sans point fixe.
PCT/CN2018/101215 2017-08-18 2018-08-18 Conjugué anticorps-médicaments présentant deux médicaments différents WO2019034177A1 (fr)

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CN111362926B (zh) * 2018-12-26 2021-04-30 联宁（苏州）生物制药有限公司 一种用于抗体偶联药物的中间体cla-sn38的合成方法及其中间体
CN111363005B (zh) * 2018-12-26 2021-08-17 联宁（苏州）生物制药有限公司 一种用于抗体偶联药物中间体clb-sn38的合成方法
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