免疫化学专刊

基于二硫键桥连构建均一性抗体药物偶联物

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  • ①上海科技大学 免疫化学研究所,上海 201210;②上海科技大学 物质科学与技术学院,上海 201210

收稿日期: 2021-05-19

  网络出版日期: 2021-10-22

Disulfide re-bridging for the construction of homogeneous antibody-drug conjugates

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  • ①Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; ②School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China

Received date: 2021-05-19

  Online published: 2021-10-22

摘要

抗体药物偶联物(ADCs)通过一个化学链接将具高活性药物分子连接到抗体上,协同发挥药物分子的高活性和抗体药物的靶向性的优点,降低毒性,实现靶向精准的疗效。目前已经有10个ADCs陆续上市。在新一代的ADCs发展中定位偶联获得药物–抗体比例(DAR)可控、均一性高的ADCs非常重要。近几年,基于抗体中二硫键先还原再桥连而发展的 “ThioBridge” 技术逐渐显示出其优越性,如用化学方法实现直接对天然抗体的定位修饰、适用性广、DAR值可控、所得 ADCs均一性高等。文章侧重于介绍二硫键桥连构建ADCs的方法和进展。

本文引用格式

黄容, 陈红莉, 姜标 . 基于二硫键桥连构建均一性抗体药物偶联物[J]. 自然杂志, 2021 , 43(5) : 323 -334 . DOI: 10.3969/j.issn.0253-9608.2021.05.002

Abstract

Antibody-drug conjugates (ADCs) combine an antibody with highly potent drugs by chemical linkers, allowing to have both the efficacy of payloads and the targeting ability of antibodies for targeted and precise therapeutics. Currently, 10 ADCs have been approved by FDA. It is very important to develop site-specific conjugation method to obtain homogeneous ADCs with controllable drug-antibody ratio (DAR) for the next generation of ADCs. Recently, the “ThioBridge” method that is based on the reduction and re-bridging of the disulfides in an antibody has demonstrated its advantages: a direct chemical method to site-specific modify native antibody, wide applicability, controllable DAR and high homogeneity. Here, we briefly introduce the recent development and progress of disulfide re-bridging methods to construct homogeneous ADCs.

参考文献

[1] KENNEDY P J, OLIVEIRA C, GRANJA P L, et al. Antibodies and associates: Partners in targeted drug delivery [J]. Pharmacology & Therapeutics, 2017, 177: 129-145. 

[2] ADAIR J R, HOWARD P W, HARTLEY J A, et al. Antibody-drug conjugates - a perfect synergy [J]. Expert Opin Biol Ther, 2012, 12(9): 1191-1206. 

[ 3 ] NEJADMOGHADDAM M R , MINAI-TEHRAN I A , GHAHREMANZADEH R, et al. Antibody-drug conjugates: possibilities and challenges [J]. Avicenna J Med Biotechnol, 2019, 11(1): 3-23. 

[4] LAMB Y N. Inotuzumab ozogamicin: first global approval [J]. Drugs, 2017, 77(14): 1603-1610. 

[5] BALLANTYNE A, DHILLON S. Trastuzumab emtansine: first global approval [J]. Drugs, 2013, 73(7): 755-765. 

[6] DEEKS E D. Polatuzumab vedotin: first global approval [J]. Drugs, 2019, 79(13): 1467-1475. 

[7] HANNA K S. Clinical overview of enfortumab vedotin in the management of locally advanced or metastatic urothelial carcinoma [J]. Drugs, 2020, 80(1): 1-7. 

[8] KEAM S J. Trastuzumab deruxtecan: first approval [J]. Drugs, 2020, 80(5): 501-508. 

[9] LYON R. Drawing lessons from the clinical development of antibody-drug conjugates [J]. Drug Discov Today Technol, 2018, 30: 105-109. 

[10] SADIKI A, VAIDYA S R, ABDOLLAHI M, et al. Site-specific conjugation of native antibody [J]. Antibody Therapeutics, 2020, 3(4): 271-284. 

[11] TSUCHIKAMA K, AN Z. Antibody-drug conjugates: recent advances in conjugation and linker chemistries [J]. Protein Cell, 2018, 9(1): 33-46. 

[12] WALSH S J, BARGH J D, DANNHEIM F M, et al. Site-selective modification strategies in antibody-drug conjugates [J]. Chem Soc Rev, 2021, 50(2): 1305-1353. 

[13] JUNUTULA J R, RAAB H, CLARK S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index [J]. Nat Biotechnol, 2008, 26(8): 925-932. 

[14] CHIN J W. Expanding and reprogramming the genetic code [J]. Nature, 2017, 550(7674): 53-60.

[15] LIU C C, SCHULTZ P G. Adding new chemistries to the genetic code [J]. Annu Rev Biochem, 2010, 79: 413-444. 

[16] HOFER T, SKEFFINGTON L R, CHAPMAN C M, et al. Molecularly defined antibody conjugation through a selenocysteine interface [J]. Biochemistry, 2009, 48(50): 12047-12057. 

[17] HATFIELD D L, GLADYSHEV V N. How selenium has altered our understanding of the genetic code [J]. Mol Cell Biol, 2002, 22(11): 3565-3576. 

[18] LI X, YANG J, RADER C. Antibody conjugation via one and two C-terminal selenocysteines [J]. Methods, 2014, 65(1): 133-138. 

[19] YAMADA K, SHIKIDA N, SHIMBO K, et al. AJICAP: affinity peptide mediated regiodivergent functionalization of native antibodies [J]. Angew Chem Int Ed, 2019, 58(17): 5592-5597. 

[20] MATSUDA Y, ROBLES V, MALINAO M C, et al. Comparison of analytical methods for antibody-drug conjugates produced by chemical site-specific conjugation: first-generation AJICAP [J]. Anal Chem, 2019, 91(20): 12724-12732. 

[21] MATSUDA Y, MALINAO M C, ROBLES V, et al. Proof of sitespecificity of antibody-drug conjugates produced by chemical conjugation technology: AJICAP first generation [J]. J Chromatogr B, 2020, 1140: 121981. 

[22] SCHNEIDER H, DEWEID L, AVRUTINA O, et al. Recent progress in transglutaminase-mediated assembly of antibody-drug conjugates [J]. Anal Biochem, 2020, 595: 113615. 

[23] WALKER J A, BOHN J J, LEDESMA F, et al. Substrate design enables heterobifunctional, dual “click” antibody modification via microbial transglutaminase [J]. Bioconjugate Chem, 2019, 30(9): 2452-2457. 

[24] BEERLI R R, HELL T, MERKEL A S, et al. Sortase enzymemediated generation of site-specifically conjugated antibody drug conjugates with high in vitro and in vivo potency [J]. PLoS One, 2015, 10(7): e0131177. 

[25] D'AMICO L, MENZEL U, PRUMMER M, et al. A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive antitumor immunity and potentiates PD-1 blockade in breast cancer [J]. Journal for Immuno Therapy of Cancer, 2019, 7(1): 16.

 [26] AGARWAL P, KUDIRKA R, ALBERS A E, et al. Hydrazino-PictetSpengler ligation as a biocompatible method for the generation of stable protein conjugates [J]. Bioconjugate Chem, 2013, 24(6): 846- 851. 

[27] DRAKE P M, ALBERS A E, BAKER J, et al. Aldehyde tag coupled with HIPS chemistry enables the production of ADCs conjugated site-specifically to different antibody regions with distinct in vivo efficacy and PK outcomes [J]. Bioconjugate Chem, 2014, 25(7): 1331-1341. 

[28] BARFIELD R M, KIM Y C, CHUPRAKOV S, et al. A novel HER2- targeted antibody-drug conjugate offers the possibility of clinical dosing at trastuzumab-equivalent exposure levels [J]. Mol Cancer Ther, 2020, 19(9): 1866-1874. 

[29] ZUBERBUHLER K, CASI G, BERNARDES G J, et al. Fucose-specific conjugation of hydrazide derivatives to a vascular-targeting monoclonal antibody in IgG format [J]. Chem Commun, 2012, 48(56): 7100-7102. 

[30] LIU C P, TSAI T I, CHENG T, et al. Glycoengineering of antibody (Herceptin) through yeast expression and in vitro enzymatic glycosylation [J]. Proc Natl Acad Sci USA, 2018, 115(4): 720-725. 

[31] BEHRENS C R, HA E H, CHINN L L, et al. Antibody-drug conjugates (ADCs) derived from interchain cysteine cross-linking demonstrate improved homogeneity and other pharmacological properties over conventional heterogeneous ADCs [J]. Mol Pharm, 2015, 12(11): 3986-3998. 

[32] BADESCU G, BRYANT P, BIRD M, et al. Bridging disulfides for stable and defined antibody drug conjugates [J]. Bioconjugate Chem, 2014, 25(6): 1124-1136. 

[33] LIBERATORE F A, COMEAU R D, MCKEARIN J M, et al. Sitedirected chemical modification and cross-linking of a monoclonal antibody using equilibrium transfer alkylating cross-link reagents [J]. Bioconjugate Chem, 1990, 1(1): 36-50. 

[34] DEL ROSARIO R B, WAHL R L, BROCCHINI S J, et al. Sulfhydryl site-specific cross-linking and labeling of monoclonal antibodies by a fluorescent equilibrium transfer alkylation cross-link reagent [J]. Bioconjugate Chem, 1990, 1(1): 51-59. 

[35] BADESCU G, BRYANT P, BIRD M, et al. Bridging disulfides for stable and defined antibody drug conjugates [J]. Bioconjugate Chem, 2014, 25(6): 1124-1136. 

[36] BRYANT P, PABST M, BADESCU G, et al. In vitro and in vivo evaluation of cysteine rebridged trastuzumab-MMAE antibody drug conjugates with defined drug-to-antibody ratios [J]. Mol Pharmaceutics, 2015, 12(6): 1872-1879. 

[37] DORYWALSKA M, STROP P, MELTON-WITT J A, et al. Effect of attachment site on stability of cleavable antibody drug conjugates [J]. Bioconjugate Chem, 2015, 26(4): 650-659. 

[38] DORYWALSKA M, DUSHIN R, MOINE L, et al. Molecular basis of valine-citrulline-PABC linker instability in site-specific ADCs and its mitigation by linker design [J]. Mol Cancer Ther, 2016, 15(5): 958-970.

[39] PABST M, MCDOWELL W, MANIN A, et al. Modulation of druglinker design to enhance in vivo potency of homogeneous antibodydrug conjugates [J]. J Control Release, 2017, 253: 160-164. 

[40] NEWMAN D J. The “utility” of highly toxic marine-sourced compounds [J]. Marine Drugs, 2019, 17(6): 324. 

[41] SMITH M E B, SCHUMACHER F F, RYAN C P, et al. Protein modification, bioconjugation, and disulfide bridging using bromomaleimides [J]. J Am Chem Soc, 2010, 132(6): 1960-1965. 

[42] SCHUMACHER F F, NUNES J P, MARUANI A, et al. Next generation maleimides enable the controlled assembly of antibodydrug conjugates via native disulfide bond bridging [J]. Org Biomol Chem, 2014, 12(37): 7261-7269. 

[43] RAVASCO J, FAUSTINO H, TRINDADE A, et al. Bioconjugation with maleimides: A useful tool for chemical biology [J]. Chemistry, 2019, 25(1): 43-59. 

[44] NUNES J P, MORAIS M, VASSILEVA V, et al. Functional native disulfide bridging enables delivery of a potent, stable and targeted antibody-drug conjugate (ADC) [J]. Chem Commun, 2015, 51(53): 10624-10627. 

[45] ROBINSON E, NUNES J P M, VASSILEVA V, et al. Pyridazinediones deliver potent, stable, targeted and efficacious antibody-drug conjugates (ADCs) with a controlled loading of 4 drugs per antibody [J]. RSC Advances, 2017, 7(15): 9073-9077. 

[46] BEHRENS C R, HA E H, CHINN L L, et al. Antibody-drug conjugates (ADCs) derived from interchain cysteine cross-linking demonstrate improved homogeneity and other pharmacological properties over conventional heterogeneous ADCs [J]. Mol Pharmaceutics, 2015, 12(11): 3986-3998. 

[47] MORAIS M, NUNES J P M, KARU K, et al. Optimisation of the dibromomaleimide (DBM) platform for native antibody conjugation by accelerated post-conjugation hydrolysis [J]. Org Biomol Chem, 2017, 15(14): 2947-2952. 

[48] BRYDEN F, MARTIN C, LETAST S, et al. Impact of cathepsin B-sensitive triggers and hydrophilic linkers on in vitro efficacy of novel site-specific antibody-drug conjugates [J]. Org Biomol Chem, 2018, 16(11): 1882-1889. 

[49] FORTE N, LIVANOS M, MIRANDA E, et al. Tuning the hydrolytic stability of next generation maleimide cross-linkers enables access to albumin-antibody fragment conjugates and tri-scFvs [J]. Bioconjugate Chem, 2018, 29(2): 486-492. 

[50] FEUILLATRE O, GELY C, HUVELLE S, et al. Impact of maleimide disubstitution on chemical and biological characteristics of HER2 antibody-drug conjugates [J]. ACS Omega, 2020, 5(3): 1557-1565. 

[51] MANEIRO M A, FORTE N, SHCHEPINOVA M M, et al. AntibodyPROTAC conjugates enable HER2-dependent targeted protein degradation of BRD4 [J]. ACS Chem Biol, 2020, 15(6): 1306-1312. 

[52] CHUDASAMA V, SMITH M E, SCHUMACHER F F, et al. Bromopyridazinedione-mediated protein and peptide bioconjugation [J]. Chem Commun, 2011, 47(31): 8781-8783. 

[53] MARUANI A, SMITH M E, MIRANDA E, et al. A plug-and-play approach to antibody-based therapeutics via a chemoselective dual click strategy [J]. Nat Commun, 2015, 6: 6645. 

[54] SHAO S, TSAI M H, LU J, et al. Site-specific and hydrophilic ADCs through disulfide-bridged linker and branched PEG [J]. Bioorg Med Chem Lett, 2018, 28(8): 1363-1370. 

[55] LEE M T W, MARUANI A, RICHARDS D A, et al. Enabling the controlled assembly of antibody conjugates with a loading of two modules without antibody engineering [J]. Chem Sci, 2017, 8(3): 2056-2060. 

[56] BRYDEN F, MARUANI A, RODRIGUES J M M, et al. Assembly of high-potency photosensitizer-antibody conjugates through application of dendron multiplier technology [J]. Bioconjugate Chem, 2018, 29(1): 176-181. 

[57] MARQUARD A N, CARLSON J C T, WEISSLEDER R. Expanding the scope of antibody rebridging with new pyridazinedione-TCO constructs [J]. Bioconjugate Chem, 2020, 31(6): 1616-1623. 

[58] SHI B, WU M, LI Z, et al. Antitumor activity of a 5T4 targeting antibody drug conjugate with a novel payload derived from MMAF via C-Lock linker [J]. Cancer Med, 2019, 8(4): 1793-1805. 

[59] GUPTA N, KANCHARLA J, KAUSHIK S, et al. Development of a facile antibody-drug conjugate platform for increased stability and homogeneity [J]. Chem Sci, 2017, 8(3): 2387-2395. 

[60] KONIEV O, DOVGAN I, RENOUX B, et al. Reduction-rebridging strategy for the preparation of ADPN-based antibody-drug conjugates [J]. Medchemcomm, 2018, 9(5): 827-830. 

[61] KOLODYCH S, KONIEV O, BAATARKHUU Z, et al. CBTF: new amine-to-thiol coupling reagent for preparation of antibody conjugates with increased plasma stability [J]. Bioconjugate Chem, 2015, 26(2): 197-200. 

[62] WALSH S J, OMARJEE S, GALLOWAY W, et al. A general approach for the site-selective modification of native proteins, enabling the generation of stable and functional antibody-drug conjugates [J]. Chem Sci, 2019, 10(3): 694-700. 

[63] BARGH J D, WALSH S J, ISIDRO-LLOBET A, et al. Sulfatasecleavable linkers for antibody-drug conjugates [J]. Chem Sci, 2020, 11(9): 2375-2380.

[64] CHAROENPATTARAPREEDA J, WALSH S J, CARROLL J S, et al. Expeditious total synthesis of hemiasterlin through a convergent multicomponent strategy and its use in targeted cancer therapeutics [J]. Angew Chem Int Ed, 2020, 59(51): 23045-23050. 

[65] WALSH S J, IEGRE J, SEKI H, et al. General dual functionalisation of biomacromolecules via a cysteine bridging strategy [J]. Org Biomol Chem, 2020, 18(22): 4224-4230. 

[66] COUNSELL A J, WALSH S J, ROBERTSON N S, et al. Efficient and selective antibody modification with functionalised divinyltriazines [J]. Org Biomol Chem, 2020, 18(25): 4739-4743. 

[67] LI Z, HUANG R, XU H, et al. Divinylsulfonamides as specific linkers for stapling disulfide bonds in peptides [J]. Org Lett, 2017, 19(18): 4972-4975. 

[68] HUANG R, SHENG Y, WEI D, et al. Divinylsulfonamides enable the construction of homogeneous antibody-drug conjugates [J]. Biorg Med Chem, 2020, 28(23): 115793. 

[69] HUANG R, SHENG Y, WEI D, et al. Bis(vinylsulfonyl)piperazines as efficient linkers for highly homogeneous antibody-drug conjugates [J]. Eur J Med Chem, 2020, 190: 112080. 

[70] HUANG R, SHENG Y, XU Z, et al. Combretastatin A4-derived payloads for antibody-drug conjugates [J]. Eur J Med Chem, 2021, 216: 113355.

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