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WO2024225838A1 - Procédé de préparation d'un conjugué anticorps-médicament présentant un dar uniforme et comprenant un lieur contenant du maléimide - Google Patents

Procédé de préparation d'un conjugué anticorps-médicament présentant un dar uniforme et comprenant un lieur contenant du maléimide Download PDF

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WO2024225838A1
WO2024225838A1 PCT/KR2024/005739 KR2024005739W WO2024225838A1 WO 2024225838 A1 WO2024225838 A1 WO 2024225838A1 KR 2024005739 W KR2024005739 W KR 2024005739W WO 2024225838 A1 WO2024225838 A1 WO 2024225838A1
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Prior art keywords
antibody
drug
linker
producing
drug polymer
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Pending
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English (en)
Korean (ko)
Inventor
정진현
진승하
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Abchembio Co Ltd
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Abchembio Co Ltd
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Priority claimed from KR1020230161296A external-priority patent/KR20250074353A/ko
Application filed by Abchembio Co Ltd filed Critical Abchembio Co Ltd
Publication of WO2024225838A1 publication Critical patent/WO2024225838A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes

Definitions

  • the present invention relates to a method for producing an antibody-drug polymer comprising a linker including a maleimide unit, and provides a method for producing an antibody-drug polymer having a uniform DAR.
  • Antibody-Drug Conjugate is a new drug that combines the specificity of antibodies and the cytotoxicity of drugs to increase TI. About 10 types of ADC have been approved by the FDA so far, but the number is not large. Early ADCs used a method of binding to the amine group of lysine exposed on the surface of antibodies or a bond using cysteine obtained by reducing the inter-chain disulfide bond of native antibodies.
  • ADCs antibody-drug conjugates
  • metastatic breast cancer accounts for 15-20% of breast cancers, occurs frequently in young people under 50 years of age, and is a disease with a poor prognosis that exhibits rapid cancer cell growth, high recurrence rate, and metastasis.
  • breast cancer The most basic treatment for breast cancer is surgical resection of the lesion, and for metastatic breast cancer treatment, endocrine therapy, chemotherapy, and targeted therapy are mainly used.
  • Many breast cancer patients receive endocrine therapy as a first-line treatment, but they experience disease progression due to resistance during treatment, and in the case of patients who must receive chemotherapy, there is a problem that their quality of life inevitably worsens due to side effects such as vomiting, general weakness, and hair loss.
  • breast cancer targeted anticancer drugs include Herceptin (trastuzumab), Perjeta (pertuzumab), and Avastin (bevacizumab).
  • Antibody-Drug Conjugate (ADC) applied to anticancer drugs is a technology that conjugates chemicals, toxins, radioactive substances, enzymes, etc. that are effective in treating diseases to antibodies as a way to maximize the resistance and efficacy of existing antibody-targeted anticancer drugs.
  • the antibody and drug are always combined at a constant ratio.
  • the number of drugs combined also affects the in vivo pharmacokinetic properties of the ADC.
  • T-DM1 Kadcyla
  • Enhertu a linker terminal functional group that binds to the inter-chain disulfide bond of the antibody.
  • Enhertu uses deruxtecan as the drug and has a DAR of approximately 7.7, which is relatively homogeneous, but is still heterogeneous.
  • Kadcyla is an early-stage ADC in which the tubulin inhibitor drug DM1 is conjugated to the SMCC linker, a non-cleavable linker, via the lysine residue of trastuzumab. It is a heterogeneous ADC with a DAR of approximately 3.5.
  • Kadcyla® the first ADC approved for solid tumors (breast cancer), has grown into a blockbuster drug in the past few years.
  • the payload of Kadcyla®, DM1 has a narrow therapeutic index (TI) range, making it difficult to use it alone in patients.
  • TI therapeutic index
  • DM1 a drug with relatively good solubility, high stability, and excellent efficacy, is also a drug very suitable for ADC development.
  • trastuzumab the antibody of Kadcyla®
  • HER2 protein The target of trastuzumab, HER2 protein, is overexpressed in various cancer types, including breast cancer, stomach cancer, colon cancer, ovarian cancer, lung cancer, and head and neck cancer. Since Kadcyla®, many HER2-targeting ADCs have been developed, and HER2 currently accounts for a significant portion of ADC targets.
  • ADC synthesized by reducing inter-chain disulfide bonds was known to have an optimal DAR value of 2 to 4. This is because a higher DAR may show weakness in PK properties even though the efficacy is better.
  • the high DAR of the ADC can be maintained while controlling toxicity and stability, the higher and more uniform the DAR, the better the ADC can be evaluated.
  • DAR 8.0
  • SMCC Succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate
  • SMCC is a linker with considerable efficiency and simplicity, characterized by the presence of maleimide and succinimide ester functionalities on both sides.
  • SMCC forms a linkage with the maleimide functionality via 1, 4-addition. Consequently, SMCC-DM1 is expected to bind to antibodies by attacking the succinimide ester with the free amine of antibody surface lysines.
  • IgG1 displays a surface distributed with approximately 70–80 lysine residues, thereby exhibiting inherent heterogeneity even without antibody engineering.
  • Heterologous ADCs are known to have several vulnerabilities during clinical pharmacokinetic evaluation. Therefore, SMCC-DM1 offers a simple and convenient synthetic approach, but has clear limitations.
  • the inventors of the present invention have endeavored to generate a linker similar to SMCC through simple synthesis, and have developed a homogeneous ADC utilizing an improved linker compared to SMCC linker using the antibody-drug (trastuzumab-DM1) combination validated in Kadcyla®.
  • DM1 antibody-drug
  • DM1 as a payload
  • the facile combination of free thiol and maleimide functionalities of DM1 was considered.
  • a dimaleimide linker featuring maleimide functionalities at both ends was designed.
  • experiments were conducted to determine whether the stability and efficacy of the ADC differ depending on the length of the dimaleimide linker.
  • Patent Document 0001 Republic of Korea Registered Patent No. 10-2442906
  • Patent Document 0002 Republic of Korea Publication Patent No. 10-2023-0008723
  • Patent Document 0003 Republic of Korea Publication Patent No. 10-2019-0038579
  • the present invention relates to a method for producing an antibody-drug polymer comprising a linker-payload conjugate comprising a maleimide unit, and aims to provide a method for producing an antibody-drug polymer having a uniform DAR.
  • One aspect of the present invention comprises: 1) a step of preparing a linker including a di-maleimide group, comprising the steps of dissolving diamine and maleic anhydride in a solvent, reacting them, removing the solvent, and purifying the remaining mixture;
  • step 2) a step of preparing a linker-drug conjugate by contacting the drug with the linker prepared in step 1) at room temperature and optionally isolating the linker-drug conjugate;
  • a method for producing an antibody-drug polymer comprising the step of reacting an antibody or an antigen-binding fragment thereof with the linker-drug conjugate prepared in step 2) and purifying the same.
  • Another aspect of the present invention comprises the steps of: a) preparing a linker-drug conjugate by contacting a drug with a linker comprising any one structure selected from the following chemical formulae II to IV at room temperature and optionally isolating the linker-drug conjugate; and
  • step b) a step of reacting an antibody or an antigen-binding fragment thereof with a linker-drug conjugate prepared in step a) and purifying the same; provides a method for preparing an antibody-drug polymer, comprising:
  • the method for producing a novel ADC compound according to the present invention is homogeneously linked to a cysteine residue with respect to positional specificity and has a remarkably high synthesis yield.
  • it provides a technology for securing a single ADC by using a native antibody as it is without requiring antibody engineering, and at the same time provides a novel ADC compound, so that it can be usefully used for effective single ADC synthesis.
  • Figure 1 shows a reaction scheme showing a method for producing a maleimide linker according to one embodiment (Example 1) of the present invention.
  • FIG. 2 illustrates a reaction scheme showing a method for producing a maleimide linker-payload conjugate according to one embodiment of the present invention (Example 2).
  • FIG. 3 illustrates the structure of an antibody (Trastuzumab)-drug (DM1) polymer manufactured according to one embodiment of the present invention (Example 3).
  • FIG. 4 shows the structure of an antibody-drug polymer manufactured according to one embodiment of the present invention (Comparative Example 1 and Comparative Example 2), where (a) is Comparative Example 1 and (b) is Comparative Example 2.
  • Figure 5 shows the results of DAR analysis according to the conjugation method according to Experimental Example 1 of the present invention.
  • FIG. 6 shows the results of DAR analysis of an antibody-drug polymer (ABC-002) according to Experimental Example 2 of the present invention.
  • Figure 7 shows the results of measuring the yield of ADC according to Experimental Example 3 of the present invention.
  • Figure 8 shows the HIC and SEC analysis results of ABC-002 according to Experimental Example 4 of the present invention.
  • Figure 9 shows Q-TOF data of trastuzumab and ABC-002 according to Experimental Example 5 of the present invention.
  • Figure 10 shows the results of purity analysis of a single antibody-drug polymer using SDS-PAGE according to Experimental Example 6 of the present invention.
  • Figure 11 shows the results of measuring the DAR of an antibody-drug polymer manufactured using cetuximab and bevacizumab antibodies according to Experimental Example 7 of the present invention.
  • One aspect of the present invention comprises the steps of: 1) preparing a linker including a di-maleimide group, comprising the steps of dissolving diamine and maleic anhydride in a solvent, reacting them, removing the solvent, and purifying the remaining mixture;
  • step 2) a step of preparing a linker-drug conjugate by contacting the drug with the linker prepared in step 1) at room temperature and optionally isolating the linker-drug conjugate;
  • step 3 a step of reacting and purifying an antibody or an antigen-binding fragment thereof with the linker-drug conjugate prepared in step 2);
  • a method for producing an antibody-drug polymer is provided.
  • the reaction of step 1) may be performed at a temperature of 0 to 100°C. Specifically, it may be 0 to 100°C, 0 to 95°C, 0 to 90°C, 0 to 85°C, 0 to 80°C, 0 to 75°C, 0 to 70°C, 5 to 70°C, 10 to 70°C, 15 to 70°C, 20 to 70°C, 25 to 70°C, 30 to 70°C, 35 to 70°C, 40 to 70°C, 45 to 70°C, 50 to 70°C, and more specifically, 51 to 69°C, 52 to 68°C, 53 to 67°C, 54 to 66°C, 55 to 65°C, 56 to 64°C, 57 to 63°C, 58 to 62°C, 59 to 61°C, 59 to 60°C. However, it is not limited to this.
  • the solvent of step 1) may be selected from the group consisting of acetic acid, dichloromethane, chloroform, DMF (dimethyl formamide), THF (tetrahydrofuran), ethyl acetate, alcohol, toluene, diethyl carbonate, acetone, acetonitrile, DMSO, dimethylacetamide, cyclohexane, N-cyclohexylpyrrolidinone, distilled water, and a mixed solvent of two or more thereof, but is not limited thereto.
  • the linker of step 1) may include any one structure selected from the following chemical formulas II to IV, and may be prepared by the process of the following reaction formula I:
  • the drug of step 2) may be DM1 of the following chemical formula I, and the linker-drug conjugate may be prepared by the process of the following reaction scheme II.
  • the antibody of step 3) may comprise a monoclonal antibody, a polyclonal antibody, an antibody fragment, Fab, Fab' Fab-SH, F(ab')2, Fv, single-chain Fv ("scFv"), diabody, linear antibody, bispecific antibody, multispecific antibody, chimeric antibody, humanized antibody, human antibody or an antigen-binding portion of an antibody.
  • the antibody is muromonab-CD3 abciximab, rituximab, daclizumab, palivizumab, infliximab, trastuzumab, etanercept, basiliximab, gemtuzumab, alemtuzumab, ibritumomab, adalimumab, alefacept, omalizumab, efalizumab, tositumomab, cetuximab, ABT-806, Bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, rilonacept, certolizumab, romiplostim, AMG-531, golimumab, ustekinumab, ABT-874, belatacept, belimumab, atacicept, anti-CD20 antibodies, canakinumab,
  • the reaction of step 3) can be performed at a temperature of 10 to 50°C. Specifically, 11 to 50°C, 12 to 50°C, 13 to 50°C, 14 to 50°C, 15 to 50°C, 16 to 50°C, 17 to 50°C, 18 to 50°C, 19 to 50°C, 20 to 50°C, 21 to 50°C, 22 to 50°C, 23 to 50°C, 24 to 50°C, 25 to 50°C, 26 to 50°C, 27 to 50°C, 28 to 50°C, 29 to 50°C, 30 to 50°C, 30 to 49°C, 30 to 48°C, 30 to 47°C, 30 to 46°C, 30 to 45°C, 30 to 44°C, 30 to It may be 43°C, 30 to 42°C, 30 to 41°C, 30 to 40°C, 31 to 40°C, 32 to 40°C, 33 to 40°C, 34 to 40°C, 35 to 40°C, 36 to 40°C, 36 to 39°
  • the drug of step 2) may be independently selected from:
  • an affinity ligand (wherein the affinity ligand is a substrate), an inhibitor, a stimulant, a neurotransmitter, a radioisotope, or a combination of any of the foregoing;
  • a radiolabel 32 P, 35 S, a fluorescent dye, an electron dense reagent, an enzyme, biotin, streptavidin, dioxigenin, a hapten, an immunogenic protein, a nucleic acid molecule having a sequence complementary to the target, or a combination of any of the foregoing;
  • immunomodulating compounds anticancer agents, antiviral agents, antibacterial agents, antifungal agents, and antiparasitic agents, or a combination of any of the foregoing;
  • the drug may be DM1 of chemical formula I:
  • the antibody-drug polymer may have a structure as shown in Chemical Formula V below:
  • n can be an integer greater than or equal to 2, and specifically, n can be an integer greater than or equal to 30, an integer greater than or equal to 25, an integer greater than or equal to 20, an integer greater than or equal to 19, an integer greater than or equal to 18, an integer greater than or equal to 27, an integer greater than or equal to 16, an integer greater than or equal to 15, an integer greater than or equal to 14, an integer greater than or equal to 13, an integer greater than or equal to 12, an integer greater than or equal to 11, an integer greater than or equal to 10, an integer greater than or equal to 9, an integer greater than or equal to 8, an integer greater than or equal to 27, an integer greater than or equal to 6, an integer greater than or equal to 5, an integer greater than or equal to 3, and an integer greater than or equal to 5, but is not limited thereto.
  • Another aspect of the present invention comprises the steps of: a) preparing a linker-drug conjugate by contacting a drug with a linker comprising any one structure selected from the following chemical formulae II to IV at room temperature and optionally isolating the linker-drug conjugate; and
  • step b) a step of reacting an antibody or an antigen-binding fragment thereof with a linker-drug conjugate prepared in step a) and purifying the same; provides a method for preparing an antibody-drug polymer, comprising:
  • An antibody-drug polymer produced by the method for producing an antibody-drug polymer of the present invention is characterized by having a uniform DAR (Drug-to-Antibody Ratio).
  • the antibody-drug polymer is characterized by having a uniform DAR of 2 to 8, specifically 3 to 8, 3 to 10, 4 to 8, 5 to 8, 6 to 8, or 7 to 8.
  • DM1 and the maleimide linker prepared in Example 1 were added in a ratio of 1:1 to 1:2, 1 equivalent of triethylamine was added, dissolved in dichloromethane, and stirred at room temperature. After the reaction was completed, the solvent was removed, and the resultant was purified by column chromatography and analyzed.
  • an antibody-drug polymer was manufactured in the same manner as in 3-1.
  • Example 2-4 Using the drug linker manufactured in Example 2-4, an antibody-drug polymer was manufactured in the same manner as in 3-1.
  • Example 3 (3-1 to 3-3) Antibody Trastuzumab (anti-HER2 Ab) Drugs DM1 Binding site Cysteine Linker Maleimide (Examples 2-2 to 2-4)
  • the structure is as shown in Fig. 3.
  • the structure is as shown in Fig. 4 (a).
  • the structure is as shown in Fig. 4 (b).
  • the DAR according to the conjugation method was analyzed. Specifically, the DAR was analyzed for each of lysine linkage, cysteine linkage, and Ab engineering.
  • Figure 6 shows the results of measuring DAR of ADC (ABC-002) manufactured in Example 3-2.
  • FIG 9 shows Q-TOF data of trastuzumab and ADC (ABC-002) manufactured in Example 3-1.
  • SDS-PAGE analysis was performed on reduced trastuzumab and the ADC (ABC-002) prepared in Example 3-1. Specifically, SDS-PAGE was performed using Bolt Bolt TM 4-12% Bis-Tris gradient gel.
  • antibody-drug polymers were manufactured using cetuximab and bevacizumab antibodies in addition to trastuzumab in the same manner as in Example 3, and DAR was measured.

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Abstract

La présente invention concerne un procédé de préparation d'un conjugué anticorps-médicament comprenant un lieur contenant une unité maléimide. le procédé de préparation de la présente invention permet d'obtenir un conjugué anticorps-médicament ayant un DAR uniforme.
PCT/KR2024/005739 2023-04-28 2024-04-27 Procédé de préparation d'un conjugué anticorps-médicament présentant un dar uniforme et comprenant un lieur contenant du maléimide Pending WO2024225838A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
KR20230056678 2023-04-28
KR10-2023-0056678 2023-04-28
KR10-2023-0056677 2023-04-28
KR20230056677 2023-04-28
KR1020230161296A KR20250074353A (ko) 2023-11-20 2023-11-20 높은 dar를 갖는 신규한 항체-약물 중합체, 이의 제조방법 및 이의 용도
KR10-2023-0161296 2023-11-20

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WO2024225838A1 true WO2024225838A1 (fr) 2024-10-31

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PCT/KR2024/005738 Pending WO2024225837A1 (fr) 2023-04-28 2024-04-27 Conjugué lieur-charge utile contenant un maléimide et nouveau conjugué anticorps-médicament le comprenant
PCT/KR2024/005739 Pending WO2024225838A1 (fr) 2023-04-28 2024-04-27 Procédé de préparation d'un conjugué anticorps-médicament présentant un dar uniforme et comprenant un lieur contenant du maléimide

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PCT/KR2024/005738 Pending WO2024225837A1 (fr) 2023-04-28 2024-04-27 Conjugué lieur-charge utile contenant un maléimide et nouveau conjugué anticorps-médicament le comprenant

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010044526A1 (en) * 2000-02-22 2001-11-22 Shearwater Corporation N-maleimidyl polymer derivatives
US20050176922A1 (en) * 2003-12-03 2005-08-11 Mcmanus Samuel P. Methods of preparing maleimide functionalized polymers
KR20070037575A (ko) * 2004-06-01 2007-04-05 제넨테크, 인크. 항체 약물 접합체 및 방법
KR20170020384A (ko) * 2014-06-18 2017-02-22 메르사나 테라퓨틱스, 인코포레이티드 Ｈｅｒ２ 에피토프에 대한 단클론 항체 및 이의 이용방법
KR20200038954A (ko) * 2017-08-14 2020-04-14 뉴바이오 테라퓨틱스, 아이엔씨. 테트라말레이미드 링커 및 그 용도

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2021297036A1 (en) * 2020-06-26 2023-01-19 Intocell, Inc. Antibody-drug conjugates comprising anti-b7-h3 antibodies
WO2022078524A2 (fr) * 2021-11-03 2022-04-21 Hangzhou Dac Biotech Co., Ltd. Conjugaison spécifique d'un anticorps

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010044526A1 (en) * 2000-02-22 2001-11-22 Shearwater Corporation N-maleimidyl polymer derivatives
US20050176922A1 (en) * 2003-12-03 2005-08-11 Mcmanus Samuel P. Methods of preparing maleimide functionalized polymers
KR20070037575A (ko) * 2004-06-01 2007-04-05 제넨테크, 인크. 항체 약물 접합체 및 방법
KR20170020384A (ko) * 2014-06-18 2017-02-22 메르사나 테라퓨틱스, 인코포레이티드 Ｈｅｒ２ 에피토프에 대한 단클론 항체 및 이의 이용방법
KR20200038954A (ko) * 2017-08-14 2020-04-14 뉴바이오 테라퓨틱스, 아이엔씨. 테트라말레이미드 링커 및 그 용도

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