Development of antibody-drug conjugates in cancer: Overview and prospects

Abstract

In recent years, remarkable breakthroughs have been reported on antibody-drug conjugates (ADCs), with 15 ADCs successfully entering the market over the past decade. This substantial development has positioned ADCs as one of the fastest-growing domains in the realm of anticancer drugs, demonstrating their efficacy in treating a wide array of malignancies. Nonetheless, there is still an unmet clinical need for wider application, better efficacy, and fewer side effects of ADCs. An ADC generally comprises an antibody, a linker and a payload, and the combination has profound effects on drug structure, pharmacokinetic profile and efficacy. Hence, optimization of the key components provides an opportunity to develop ADCs with higher potency and fewer side effects. In this review, we comprehensively reviewed the current development and the prospects of ADC, provided an analysis of marketed ADCs and the ongoing pipelines globally as well as in China, highlighted several ADC platforms and technologies specific to different pharmaceutical enterprises and biotech companies, and also discussed the new related technologies, possibility of next-generation ADCs and the directions of clinical research.

References

[1] Tarantino P, Carmagnani Pestana R, Corti C, Modi S, Bardia A, Tolaney SM, et al. Antibody-drug conjugates: Smart chemotherapy delivery across tumor histologies. CA Cancer J Clin. 2022;72(2):165-182.

[2] Coleman N, Yap TA, Heymach JV, Meric-Bernstam F, Le X. Antibody-drug conjugates in lung cancer: dawn of a new era? NPJ Precis Oncol. 2023;7(1):5.

[3] Chau CH, Steeg PS, Figg WD. Antibody-drug conjugates for cancer. Lancet. 2019;394(10200):793-804.

[4] Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13(17):5043-5054.

[5] Sievers EL, Senter PD. Antibody-drug conjugates in cancer therapy. Annu Rev Med. 2013;64:15-29.

[6] Giugliano F, Corti C, Tarantino P, Michelini F, Curigliano G. Bystander effect of antibody-drug conjugates: fact or fiction? Curr Oncol Rep. 2022;24(7):809-817.

[7] Khera E, Thurber GM. Pharmacokinetic and Immunological Considerations for Expanding the Therapeutic Window of Next-Generation Antibody-Drug Conjugates. BioDrugs. 2018;32(5):465-480.

[8] Liu R, Oldham RJ, Teal E, Beers SA, Cragg MS. Fc-Engineering for Modulated Effector Functions-Improving Antibodies for Cancer Treatment. Antibodies (Basel). 2020;9(4):64.

[9] Hudis CA. Trastuzumab–mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39-51.

[10] Malik B, Ghatol A. Understanding How Monoclonal Antibodies Work. [Updated 2023 Jun 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK572118/

[11] Anderl J, Faulstich H, Hechler T, Kulke M. Antibody-drug conjugate payloads. Methods Mol Biol. 2013;1045:51-70.

[12] Hejmady S, Pradhan R, Kumari S, Pandey M, Dubey SK, Taliyan R. Pharmacokinetics and toxicity considerations for antibody-drug conjugates: an overview. Bioanalysis. 2023;15(19):1193-1202.

[13] Diamantis N, Banerji U. Antibody-drug conjugates–an emerging class of cancer treatment. Br J Cancer. 2016;114(4):362-367.

[14] Trail PA, Dubowchik GM, Lowinger TB. Antibody drug conjugates for treatment of breast cancer: Novel targets and diverse approaches in ADC design. Pharmacol Ther. 2018;181:126-142.

[15] Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2020;382(7):610-621.

[16] Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387(1):9-20.

[17] Ferraro E, Drago JZ, Modi S. Implementing antibody-drug conjugates (ADCs) in HER2-positive breast cancer: state of the art and future directions. Breast Cancer Res. 2021;23(1):84.

[18] Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, et al. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021;384(16):1529-1541.

[19] Gray JE, Heist RS, Starodub AN, Camidge DR, Kio EA, Masters GA, et al. Therapy of Small Cell Lung Cancer (SCLC) with a Topoisomerase-I-inhibiting Antibody-Drug Conjugate (ADC) Targeting Trop-2, Sacituzumab Govitecan. Clin Cancer Res. 2017;23(19):5711-5719.

[20] Heist RS, Guarino MJ, Masters G, Purcell WT, Starodub AN, Horn L, et al. Therapy of Advanced Non-Small-Cell Lung Cancer With an SN-38-Anti-Trop-2 Drug Conjugate, Sacituzumab Govitecan. J Clin Oncol. 2017;35(24):2790-2797.

[21] Starodub AN, Ocean AJ, Shah MA, Guarino MJ, Picozzi VJ, Vahdat LT, et al. First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors. Clin Cancer Res. 2015;21(17):3870-3878.

[22] Strebhardt K, Ullrich A. Paul Ehrlich's magic bullet concept: 100 years of progress. Nat Rev Cancer. 2008;8(6):473-480.

[23] Norsworthy KJ, Ko CW, Lee JE, Liu J, John CS, Przepiorka D, et al. FDA Approval Summary: Mylotarg for Treatment of Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia. Oncologist. 2018;23(9):1103-1138.

[24] Chen YF, Xu YY, Shao ZM, Yu KD. Resistance to antibody-drug conjugates in breast cancer: mechanisms and solutions. Cancer Commun (Lond). 2023;43(3):297-337.

[25] Chang HP, Cheung YK, Shah DK. Chapter 7 - Discovery and development of ADCs: obstacles and opportunities. In: He K, Hollenberg PF, Wienkers LC, editors. Overcoming Obstacles in Drug Discovery and Development: Academic Press; 2023. p. 75-106.

[26] Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct Target Ther. 2022;7(1):93.

[27] Tarantino P, Ricciuti B, Pradhan SM, Tolaney SM. Optimizing the safety of antibody-drug conjugates for patients with solid tumours. Nat Rev Clin Oncol. 2023;20(8):558-576.

[28] Dimopoulos MA, Hungria VTM, Radinoff A, Delimpasi S, Mikala G, Masszi T, et al. Efficacy and safety of single-agent belantamab mafodotin versus pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-3): a phase 3, open-label, randomised study. Lancet Haematol. 2023;10(10):e801-e12.

[29] Yang C, He B, Zhang H, Wang X, Zhang Q, Dai W. IgG Fc Affinity Ligands and Their Applications in Antibody-Involved Drug Delivery: A Brief Review. Pharmaceutics. 2023;15(1):187.

[30] Jiang XR, Song A, Bergelson S, Arroll T, Parekh B, May K, et al. Advances in the assessment and control of the effector functions of therapeutic antibodies. Nat Rev Drug Discov. 2011;10(2):101-111.

[31] Herbener P, Schönfeld K, König M, Germer M, Przyborski JM, Bernöster K, et al. Functional relevance of in vivo half antibody exchange of an IgG4 therapeutic antibody-drug conjugate. PLoS One. 2018;13(4):e0195823.

[32] Su Z, Xiao D, Xie F, Liu L, Wang Y, Fan S, et al. Antibody-drug conjugates: Recent advances in linker chemistry. Acta Pharm Sin B. 2021;11(12):3889-3907.

[33] Chari RV. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41(1):98-107.

[34] Cortés J, Kim SB, Chung WP, Im SA, Park YH, Hegg R, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022;386(12):1143-1154.

[35] Fang W, Cheng Y, Chen Z, Wang W, Yin Y, Li Y, et al. SKB264 (TROP2-ADC) for the treatment of patients with advanced NSCLC: Efficacy and safety data from a phase 2 study. Journal of Clinical Oncology. 2023;41(16_suppl):9114.

[36] Qiu MZ, Zhang Y, Guo Y, Guo W, Nian W, Liao W, et al. Evaluation of Safety of Treatment With Anti-Epidermal Growth Factor Receptor Antibody Drug Conjugate MRG003 in Patients With Advanced Solid Tumors: A Phase 1 Nonrandomized Clinical Trial. JAMA Oncol. 2022;8(7):1042-1046.

[37] Xu R-H, Ruan D-Y, Zhang D-S, Liu F-R, Luo S-X, Zhuang Z-X, et al. A phase 1 trial of claudin 18.2-specific antibody-drug conjugate CMG901 in patients with advanced gastric/gastroesophageal junction cancer. 2023;41(36_suppl):434420.

[38] Chang HP, Cheung YK, Shah DK. Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE). J Clin Med. 2021;10(6):1332.

[39] Doronina SO, Mendelsohn BA, Bovee TD, Cerveny CG, Alley SC, Meyer DL, et al. Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. Bioconjug Chem. 2006;17(1):114-124.

[40] Senter PD, Sievers EL. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat Biotechnol. 2012;30(7):631-637.

[41] Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68(22):9280-9290.

[42] Sheyi R, de la Torre BG, Albericio F. Linkers: An Assurance for Controlled Delivery of Antibody-Drug Conjugate. Pharmaceutics. 2022;14(2):396.

[43] Conilh L, Sadilkova L, Viricel W, Dumontet C. Payload diversification: a key step in the development of antibody-drug conjugates. J Hematol Oncol. 2023;16(1):3.

[44] Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, et al. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021;384(16):1529-1541.

[45] Okajima D, Yasuda S, Maejima T, Karibe T, Sakurai K, Aida T, et al. Datopotamab Deruxtecan, a Novel TROP2-directed Antibody-drug Conjugate, Demonstrates Potent Antitumor Activity by Efficient Drug Delivery to Tumor Cells. Mol Cancer Ther. 2021;20(12):2329-2340.

[46] Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387(1):9-20.

[47] Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N, et al. DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1. Clin Cancer Res. 2016;22(20):5097-5108.

[48] Nagai Y, Oitate M, Shiozawa H, Ando O. Comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in cynomolgus monkeys. Xenobiotica. 2019;49(9):1086-1096.

[49] Zhang S, Zheng C, Zhu W, Xiong P, Zhou D, Huang C, et al. A novel anti-DR5 antibody-drug conjugate possesses a high-potential therapeutic efficacy for leukemia and solid tumors. Theranostics. 2019;9(18):5412-5423.

[50] Deeks ED. Disitamab Vedotin: First Approval. Drugs. 2021;81(16):1929-1935.

[51] Lee YT, Tan YJ, Oon CE. Molecular targeted therapy: Treating cancer with specificity. Eur J Pharmacol. 2018;834:188-196.

[52] Boni V, Sharma MR, Patnaik A. The Resurgence of Antibody Drug Conjugates in Cancer Therapeutics: Novel Targets and Payloads. Am Soc Clin Oncol Educ Book. 2020;40:1-17.

[53] Menon S, Parakh S, Scott AM, Gan HK. Antibody-drug conjugates: beyond current approvals and potential future strategies. Explor Target Antitumor Ther. 2022;3(2):252-277.

[54] Guan H, Wu Y, Li LU, Yang Y, Qiu S, Zhao Z, et al. Tumor neoantigens: Novel strategies for application of cancer immunotherapy. Oncol Res. 2023;31(4):437-448.

[55] Schettini F, Barbao P, Brasó-Maristany F, Galván P, Martínez D, Paré L, et al. Identification of cell surface targets for CAR-T cell therapies and antibody-drug conjugates in breast cancer. ESMO Open. 2021;6(3):100102.

[56] Criscitiello C, Morganti S, Curigliano G. Antibody-drug conjugates in solid tumors: a look into novel targets. J Hematol Oncol. 2021;14(1):20.

[57] Drago JZ, Modi S, Chandarlapaty S. Unlocking the potential of antibody-drug conjugates for cancer therapy. Nat Rev Clin Oncol. 2021;18(6):327-344.

[58] Autio KA, Boni V, Humphrey RW, Naing A. Probody Therapeutics: An Emerging Class of Therapies Designed to Enhance On-Target Effects with Reduced Off-Tumor Toxicity for Use in Immuno-Oncology. Clin Cancer Res. 2020;26(5):984-989.

[59] Kast F, Schwill M, Stüber JC, Pfundstein S, Nagy-Davidescu G, Rodríguez JMM, et al. Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action. Nat Commun. 2021;12(1):3790.

[60] Yin F, DeCiantis C, Pinkas J, Das B, Wang F, Zheng N, et al. Quantification of antibody-drug conjugate PYX-201 in rat and monkey plasma via ELISA and its application in preclinical studies. Bioanalysis. 2023;15(1):43-52.

[61] Wu M, Huang W, Yang N, Liu Y. Learn from antibody-drug conjugates: consideration in the future construction of peptide-drug conjugates for cancer therapy. Exp Hematol Oncol. 2022;11(1):93.

[62] Boni V, Fidler MJ, Arkenau HT, Spira A, Meric-Bernstam F, Uboha N, et al. Praluzatamab Ravtansine, a CD166-Targeting Antibody-Drug Conjugate, in Patients with Advanced Solid Tumors: An Open-Label Phase I/II Trial. Clin Cancer Res. 2022;28(10):2020-2029.

[63] Naing A, Thistlethwaite F, De Vries EGE, Eskens F, Uboha N, Ott PA, et al. CX-072 (pacmilimab), a Probody (®) PD-L1 inhibitor, in advanced or recurrent solid tumors (PROCLAIM-CX-072): an open-label dose-finding and first-in-human study. J Immunother Cancer. 2021;9(7):e002447.

[64] Assi HH, Wong C, Tipton KA, Mei L, Wong K, Razo J, et al. Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity Compared with Traditional Anti-PD-1/PD-L1 Agents. Cancer Immunol Res. 2021;9(12):1451-1464.

[65] Andreev J, Thambi N, Perez Bay AE, Delfino F, Martin J, Kelly MP, et al. Bispecific Antibodies and Antibody-Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs. Mol Cancer Ther. 2017;16(4):681-693.

[66] de Goeij BE, Vink T, Ten Napel H, Breij EC, Satijn D, Wubbolts R, et al. Efficient Payload Delivery by a Bispecific Antibody-Drug Conjugate Targeting HER2 and CD63. Mol Cancer Ther. 2016;15(11):2688-2697.

[67] Zhang L, Ma Y, Zhao Y, Fang W, Zhao H, Huang Y, et al. BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic solid tumor: Results from a first-in-human phase 1 study. Journal of Clinical Oncology. 2023;41(16_suppl):3001.

[68] Pegram MD, Hamilton EP, Tan AR, Storniolo AM, Balic K, Rosenbaum AI, et al. First-in-Human, Phase 1 Dose-Escalation Study of Biparatopic Anti-HER2 Antibody-Drug Conjugate MEDI4276 in Patients with HER2-positive Advanced Breast or Gastric Cancer. Mol Cancer Ther. 2021;20(8):1442-1453.

[69] Goldberg SD, Cardoso RM, Lin T, Spinka-Doms T, Klein D, Jacobs SA, et al. Engineering a targeted delivery platform using Centyrins. Protein Eng Des Sel. 2016;29(12):563-572.

[70] Whalen KA, White BH, Quinn JM, Kriksciukaite K, Alargova R, Au Yeung TP, et al. Targeting the Somatostatin Receptor 2 with the Miniaturized Drug Conjugate, PEN-221: A Potent and Novel Therapeutic for the Treatment of Small Cell Lung Cancer. Mol Cancer Ther. 2019;18(11):1926-1936.

[71] Bryden F, Maruani A, Rodrigues JMM, Cheng MHY, Savoie H, Beeby A, et al. Assembly of High-Potency Photosensitizer-Antibody Conjugates through Application of Dendron Multiplier Technology. Bioconjug Chem. 2018;29(1):176-181.

[72] Ito K, Mitsunaga M, Nishimura T, Saruta M, Iwamoto T, Kobayashi H, et al. Near-Infrared Photochemoimmunotherapy by Photoactivatable Bifunctional Antibody-Drug Conjugates Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancer. Bioconjug Chem. 2017;28(5):1458-1469.

[73] Li J, Xiao D, Xie F, Li W, Zhao L, Sun W, et al. Novel antibody-drug conjugate with UV-controlled cleavage mechanism for cytotoxin release. Bioorg Chem. 2021;111:104475.

[74] Wang X, Liu Y, Fan X, Wang J, Ngai WSC, Zhang H, et al. Copper-Triggered Bioorthogonal Cleavage Reactions for Reversible Protein and Cell Surface Modifications. J Am Chem Soc. 2019;141(43):17133-17141.

[75] Soni N, Sarkar S, Bhise A, Ha YS, Park W, Yu AR, et al. “Click-to-Clear”: A Strategy to Minimize Radioactivity from the Blood Pool Utilizing Staudinger Ligation. Pharmaceutics. 2023;15(3):719.

[76] Rossin R, Versteegen RM, Wu J, Khasanov A, Wessels HJ, Steenbergen EJ, et al. Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice. Nat Commun. 2018;9(1):1484.

[77] Bernard S, Audisio D, Riomet M, Bregant S, Sallustrau A, Plougastel L, et al. Bioorthogonal Click and Release Reaction of Iminosydnones with Cycloalkynes. Angew Chem Int Ed Engl. 2017;56(49):15612-15616.

[78] Liu B, Ten Hoeve W, Versteegen RM, Rossin R, Kleijn LHJ, Robillard MS. A Concise Synthetic Approach to Highly Reactive Click-to-Release Trans-Cyclooctene Linkers. Chemistry. 2023:e202300755.

[79] Wright AP, Bradley JD, Hagerty T, Wyatt EA. Efficacy of DAN-222, a novel investigational polymeric nanoparticle with topoisomerase I inhibitor, as monotherapy in breast cancer models and when combined with PARP inhibitor. Journal of Clinical Oncology. 2021;39(15_suppl):1081.

[80] Chelariu-Raicu A, Mahner S, Moore KN, Lorusso D, Coleman RL. Integrating antibody drug conjugates in the management of gynecologic cancers. Int J Gynecol Cancer. 2023;33(3):420-429.

[81] Smith RA, Zammit DJ, Damle NK, Usansky H, Reddy SP, Lin JH, et al. ASN004, A 5T4-targeting scFv-Fc Antibody-Drug Conjugate with High Drug-to-Antibody Ratio, Induces Complete and Durable Tumor Regressions in Preclinical Models. Mol Cancer Ther. 2021;20(8):1327-1337.

[82] Beck A, Goetsch L, Dumontet C, Corvaïa N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16(5):315-337.

[83] Boghaert ER, Cox MC, Vaidya KS. Pathophysiologic and Pharmacologic Considerations to Improve the Design and Application of Antibody-Drug Conjugates. Cancer Res. 2022;82(10):1858-1869.

[84] Negi A, Voisin-Chiret AS. Strategies to Reduce the On-Target Platelet Toxicity of Bcl-x. Chembiochem. 2022;23(12):e202100689.

[85] Nilchan N, Li X, Pedzisa L, Nanna AR, Roush WR, Rader C. Dual-mechanistic antibody-drug conjugate. Antib Ther. 2019;2(4):71-78.

[86] Yamazaki CM, Yamaguchi A, Anami Y, Xiong W, Otani Y, Lee J, et al. Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance. Nat Commun. 2021;12(1):3528.

[87] Tang F, Yang Y, Tang Y, Tang S, Yang L, Sun B, et al. One-pot N-glycosylation remodeling of IgG with non-natural sialylglycopeptides enables glycosite-specific and dual-payload antibody-drug conjugates. Org Biomol Chem. 2016;14(40):9501-9518.

[88] Miyazaki NL, Furusawa A, Choyke PL, Kobayashi H. Review of RM-1929 Near-Infrared Photoimmunotherapy Clinical Efficacy for Unresectable and/or Recurrent Head and Neck Squamous Cell Carcinoma. Cancers (Basel). 2023;15(21):5117.

[89] Subbiah V, Erwin W, Mawlawi O, McCoy A, Wages D, Wheeler C, et al. Phase I Study of P-cadherin-targeted Radioimmunotherapy with. Clin Cancer Res. 2020;26(22):5830-5842.

[90] Cao W, Li R, Pei X, Chai M, Sun L, Huang Y, et al. Antibody-siRNA conjugates (ARC): Emerging siRNA drug formulation. Medicine in Drug Discovery. 2022;15:100128.

[91] Peck M, Rothenberg ME, Deng R, Lewin-Koh N, She G, Kamath AV, et al. A Phase 1, Randomized, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of DSTA4637S, an Anti-. Antimicrob Agents Chemother. 2019;63(6):e02588-18.

[92] Maneiro MA, Forte N, Shchepinova MM, Kounde CS, Chudasama V, Baker JR, et al. Antibody-PROTAC Conjugates Enable HER2-Dependent Targeted Protein Degradation of BRD4. ACS Chem Biol. 2020;15(6):1306-1312.

[93] Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008;358(16):1663-1671.

[94] Hinrichs MJM, Ryan PM, Zheng B, Afif-Rider S, Yu XQ, Gunsior M, et al. Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates. Clin Cancer Res. 2017;23(19):5858-5868.

[95] Coats S, Williams M, Kebble B, Dixit R, Tseng L, Yao NS, et al. Antibody-Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index. Clin Cancer Res. 2019;25(18):5441-5448.

[96] Massicano AVF, Marquez-Nostra BV, Lapi SE. Targeting HER2 in Nuclear Medicine for Imaging and Therapy. Mol Imaging. 2018;17:1536012117745386.

[97] Zhu Z, Hu E, Shen H, Tan J, Zeng S. The functional and clinical roles of liquid biopsy in patient-derived models. J Hematol Oncol. 2023;16(1):36.

[98] Coleman RL, Lorusso D, Gennigens C, González-Martín A, Randall L, Cibula D, et al. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22(5):609-619.

[99] Bogani G, Coleman RL, Vergote I, Raspagliesi F, Lorusso D, Monk BJ. Tisotumab vedotin in recurrent or metastatic cervical cancer. Curr Probl Cancer. 2023;47(3):100952.

[100] Kan S, Koido S, Okamoto M, Hayashi K, Ito M, Kamata Y, et al. Up-regulation of HER2 by gemcitabine enhances the antitumor effect of combined gemcitabine and trastuzumab emtansine treatment on pancreatic ductal adenocarcinoma cells. BMC Cancer. 2015;15:726.

[101] Fuentes-Antrás J, Genta S, Vijenthira A, Siu LL. Antibody-drug conjugates: in search of partners of choice. Trends Cancer. 2023;9(4):339-354.

[102] Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021;385(12):1091-103.

[103] Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, et al. Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study. J Clin Oncol. 2017;35(2):141-148.

[104] Hurvitz SA, Martin M, Jung KH, Huang CS, Harbeck N, Valero V, et al. Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Three-Year Outcomes From the Phase III KRISTINE Study. J Clin Oncol. 2019;37(25):2206-2216.

[105] Krop IE, Im SA, Barrios C, Bonnefoi H, Gralow J, Toi M, et al. Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study. J Clin Oncol. 2022;40(5):438-448.

[106] Borges VF, Ferrario C, Aucoin N, Falkson C, Khan Q, Krop I, et al. Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-Positive Metastatic Breast Cancer: A Phase 1b Clinical Trial. JAMA Oncol. 2018;4(9):1214-1220.

[107] Abraham J, Montero AJ, Jankowitz RC, Salkeni MA, Beumer JH, Kiesel BF, et al. Safety and Efficacy of T-DM1 Plus Neratinib in Patients With Metastatic HER2-Positive Breast Cancer: NSABP Foundation Trial FB-10. J Clin Oncol. 2019;37(29):2601-2609.

[108] Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 2009;28(6):803-814.

[109] O'Malley DM, Matulonis UA, Birrer MJ, Castro CM, Gilbert L, Vergote I, et al. Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2020;157(2):379-385.

[110] O'Donnell PH, Milowsky MI, Petrylak DP, Hoimes CJ, Flaig TW, Mar N, et al. Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2023;41(25):4107-4117.

[111] Jin R, Liu L, Xing Y, Meng T, Ma L, Pei J, et al. Dual Mechanisms of Novel CD73-Targeted Antibody and Antibody-Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function. Mol Cancer Ther. 2020;19(11):2340-2352.

[112] Fabre M, Ferrer C, Domínguez-Hormaetxe S, Bockorny B, Murias L, Seifert O, et al. OMTX705, a Novel FAP-Targeting ADC Demonstrates Activity in Chemotherapy and Pembrolizumab-Resistant Solid Tumor Models. Clin Cancer Res. 2020;26(13):3420-3430.

[113] Walsh SJ, Iegre J, Seki H, Bargh JD, Sore HF, Parker JS, et al. General dual functionalisation of biomacromolecules via a cysteine bridging strategy. Org Biomol Chem. 2020;18(22):4224-4230.

[114] Xu M, Chen R, Xing P, Kong Y, Zhao X, Zhang J, et al. A multicenter, phase II trial of RC48-ADC combined with radiotherapy, PD-1/PD-L1 inhibitor, GM-CSF, and sequential IL-2 (PRaG3.0 regimen) for salvage therapy in patients with HER2-expressing advanced solid tumors. Journal of Clinical Oncology. 2023;41(_supp 16l):e14614-e.

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