Antibody–Drug Conjugates in Oncology: Principles, Clinical Development, and Future Directions

Abstract

Antibody–drug conjugates (ADCs) have emerged as a major therapeutic modality in oncology, enabling the targeted delivery of highly potent cytotoxic agents while expanding the therapeutic window in solid tumors. Recent clinical successes across breast, lung, and genitourinary cancers have highlighted that ADC efficacy is governed not only by target expression, but also by the integrated optimization of antibody engineering, linker chemistry, payload selection, and tumor-specific biology. In this review, we summarize the fundamental principles underpinning ADC design, including antibody format and Fc engineering, linker stability, payload classes, drug-to-antibody ratio optimization, and the bystander effect. We then discuss tumor antigen biology and target landscapes across solid tumors, with particular emphasis on how antigen density, heterogeneity, internalization kinetics, and intracellular trafficking shape clinical activity. Uro-oncological malignancies—especially urothelial carcinoma—are presented as a clinically advanced and instructive paradigm for ADC development. Experience from these tumors illustrates both the opportunities and limitations of ADC therapy, including mechanisms of response and resistance, biomarker-driven patient selection, rational combination strategies, and safety management in real-world practice. Finally, we provide a forward-looking perspective on next-generation ADC development, highlighting emerging conjugation technologies, bispecific and conditionally activated ADCs, strategies to overcome resistance, and evolving clinical trial designs. By integrating engineering principles with tumor biology and clinical execution, this review aims to offer a translational framework to guide the future development and implementation of ADCs across oncology.

Keywords

antibody–drug conjugates / drug resistance / therapeutic index / tumor microenvironment

References

[1] Z. Fu, S. Li, S. Han, C. Shi, and Y. Zhang, “Antibody Drug Conjugate: The “Biological Missile” for Targeted Cancer Therapy,” Signal Transduction and Targeted Therapy 7, no. 1 (2022): 93.

[2] A. Kondrashov, S. Sapkota, A. Sharma, I. Riano, R. Kurzrock, and J. J. Adashek, “Antibody-Drug Conjugates in Solid Tumor Oncology: An Effectiveness Payday With a Targeted Payload,” Pharmaceutics 15 (2023): 2160.

[3] Z. X. Phuna, P. A. Kumar, E. Haroun, D. Dutta, and S. H. Lim, “Antibody-Drug Conjugates: Principles and Opportunities,” Life Sciences 347 (2024): 122676.

[4] Y. Hao and Z. Song, “Mechanisms of Resistance to Antibody-Drug Conjugates in Cancer Therapy: Molecular Basis and Therapeutic Strategies,” Cancer Drug Resistance (Alhambra, California) 8 (2025): 59.

[5] Q. Fan, H. Chen, and G. Wei, “A Review of Conjugation Technologies for Antibody Drug Conjugates,” Antibody Therapeutics 8 (2025): 157–170.

[6] T. Powles, B. P. Valderrama, and S. Gupta, “Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer,” New England Journal of Medicine 390 (2024): 875–888.

[7] T. Powles, J. E. Rosenberg, and G. Sonpavde, “Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma,” New England Journal of Medicine 384 (2021): 1125–1135.

[8] S. Jain, J. I. Griffith, and K. A. Porath, “Bystander Effects, Pharmacokinetics, and Linker-Payload Stability of EGFR-Targeting Antibody-Drug Conjugates Losatuxizumab Vedotin and Depatux-M in Glioblastoma Models,” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 30 (2024): 3287–3297.

[9] Y. Wang, X. Cheng, X. Li, W. Chen, X. Zhang, and Y. Liu, “Bystander Effect in Antibody-Drug Conjugates: Navigating the Fine Line in Tumor Heterogeneity,” Critical Reviews in Oncology/Hematology 216 (2025): 104979.

[10] B. Ricciuti, S. M. Pradhan, and S. M. Tolaney, “Optimizing the Safety of Antibody-Drug Conjugates for Patients With Solid Tumours,” Nature Reviews Clinical Oncology 20 (2023): 558–576.

[11] G. Villacampa, P. Cresta Morgado, L. Carità, V. Navarro, T. Pascual, and R. Dienstmann, “Safety and Efficacy of Antibody-Drug Conjugates plus Immunotherapy in Solid Tumours: A Systematic Review and Meta-Analysis,” Cancer Treatment Reviews 131 (2024): 102847.

[12] Y. Loriot, D. P. Petrylak, and A. Rezazadeh Kalebasty, “TROPHY-U-01, a Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors: Updated Safety and Efficacy Outcomes,” Annals of Oncology: official Journal of the European Society for Medical Oncology 35 (2024): 392–401.

[13] S. T. Tagawa, A. V. Balar, and D. P. Petrylak, “TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors,” Journal of Clinical Oncology 39 (2021): 2474–2485.

[14] J. E. Rosenberg, T. Powles, and G. P. Sonpavde, “EV-301 Long-Term Outcomes: 24-Month Findings From the Phase III Trial of Enfortumab Vedotin Versus Chemotherapy in Patients With Previously Treated Advanced Urothelial Carcinoma,” Annals of Oncology: Official Journal of the European Society for Medical Oncology 34 (2023): 1047–1054.

[15] C. Dumontet, J. M. Reichert, P. D. Senter, J. M. Lambert, and A. Beck, “Antibody-Drug Conjugates Come of Age in Oncology,” Nature Reviews Drug Discovery 22 (2023): 641–661.

[16] K. Tsuchikama, Y. Anami, S. Y. Y. Ha, and C. M. Yamazaki, “Exploring the Next Generation of Antibody-Drug Conjugates,” Nature Reviews Clinical Oncology 21 (2024): 203–223.

[17] G. Hale, J. De Vos, A. D. Davy, K. Sandra, and I. Wilkinson, “Systematic Analysis of Fc Mutations Designed to Reduce Binding to Fc-Gamma Receptors,” MABS-AUSTIN 16 (2024): 2402701.

[18] J. Golay, A. E. Andrea, and I. Cattaneo, “Role of Fc Core Fucosylation in the Effector Function of IgG1 Antibodies,” Frontiers in Immunology 13 (2022): 929895.

[19] D. L. Niquille, K. M. Fitzgerald, and N. Gera, “Biparatopic Antibodies: Therapeutic Applications and Prospects,” MABS-AUSTIN 16 (2024): 2310890.

[20] Y. Gu, Z. Wang, and Y. Wang, “Bispecific Antibody Drug Conjugates: Making 1+1>2,” Acta Pharmaceutica Sinica B 14 (2024): 1965–1986.

[21] A. Dal Corso, L. Pignataro, L. Belvisi, and C. Gennari, “Innovative Linker Strategies for Tumor-Targeted Drug Conjugates,” Chemistry (Weinheim an der Bergstrasse, Germany) 25 (2019): 14740–14757.

[22] T. Watanabe, N. Arashida, and T. Fujii, “Exo-Cleavable Linkers: Enhanced Stability and Therapeutic Efficacy in Antibody-Drug Conjugates,” Journal of Medicinal Chemistry 67 (2024): 18124–18138.

[23] L. Tsao, J. S. Wang, and X. Ma, “Effective Extracellular Payload Release and Immunomodulatory Interactions Govern the Therapeutic Effect of Trastuzumab Deruxtecan (T-DXd),” Nature Communications 16 (2025): 3167.

[24] S. Forveille, M. Leduc, A. Sauvat, G. Kroemer, and O. Kepp, “Datopotamab Deruxtecan Induces Hallmarks of Immunogenic Cell Death,” Cell Stress 9 (2025): 194–200.

[25] O. Kepp and G. Kroemer, “Immunogenic Cell Death and Bystander Killing: Expanding the Therapeutic Potential of Modern Antibody-Drug Conjugates,” Oncoimmunology 14 (2025): 2533488.

[26] D. V. Hingorani, “An Overview of Site-Specific Methods for Achieving Antibody Drug Conjugates With Homogenous Drug to Antibody Ratio,” Expert Opinion on Biological Therapy 24 (2024): 31–36.

[27] D. M. Markides, A. G. Hita, J. Merlin, C. Reyes-Gibby, and S. J. Yeung, “Antibody-Drug Conjugates: The Toxicities and Adverse Effects That Emergency Physicians Must Know,” Annals of Emergency Medicine 85 (2025): 214–229.

[28] B. Rubahamya, S. Dong, and G. M. Thurber, “Clinical Translation of Antibody Drug Conjugate Dosing in Solid Tumors From Preclinical Mouse Data,” Science Advances 10: eadk1894.

[29] X. Yi, X. Jin, and Y. Hu, “Drug Delivery Systems for Overcoming Physical Barriers in Cancer Therapy,” Molecular Pharmaceutics 22 (2025): 6413–6429.

[30] L. Ascione, E. Crimini, D. Trapani, A. Marra, C. Criscitiello, and G. Curigliano, “Predicting Response to Antibody Drug Conjugates: A Focus on Antigens' Targetability,” Oncologist 28 (2023): 944–960.

[31] J. Katrini, L. Boldrini, C. Santoro, C. Valenza, D. Trapani, and G. Curigliano, “Biomarkers for Antibody-Drug Conjugates in Solid Tumors,” Molecular Cancer Therapeutics 23 (2024): 436–446.

[32] C. Bosi, Á. Bartha, and B. Galbardi, “Pan-Cancer Analysis of Antibody-Drug Conjugate Targets and Putative Predictors of Treatment Response,” European Journal of Cancer (Oxford, England: 1990) 195 (2023): 113379.

[33] H. Maecker, V. Jonnalagadda, S. Bhakta, V. Jammalamadaka, and J. R. Junutula, “Exploration of the Antibody–Drug Conjugate Clinical Landscape,” MABS-AUSTIN 15 (2023): 2229101.

[34] C. E. Chu, M. Sjöström, and E. A. Egusa, “Heterogeneity in NECTIN4 Expression Across Molecular Subtypes of Urothelial Cancer Mediates Sensitivity to Enfortumab Vedotin,” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 27 (2021): 5123–5130.

[35] L. Gong, J. Luo, and Y. Zhang, “Nasopharyngeal Carcinoma Cells Promote Regulatory T Cell Development and Suppressive Activity via CD70-CD27 Interaction,” Nature Communications 14 (2023): 1912.

[36] N. Klümper and M. Eckstein, “Biomarkers of Response to Anti-NECTIN4 Antibody-Drug Conjugate Enfortumab Vedotin in Urothelial Cancer,” European Urology Focus 10 (2024): 224–226.

[37] C. Lin, M. J. Hadfield, and A. Santopietro, “The Evolving Landscape of Antibody-Drug Conjugates (ADCs) for Treatment of Prostate Cancer,” npj Precision Oncology 9 (2025): 351.

[38] B. Scheuher, K. R. Ghusinga, and K. McGirr, “Towards a Platform Quantitative Systems Pharmacology (QSP) Model for Preclinical to Clinical Translation of Antibody Drug Conjugates (ADCs),” Journal of Pharmacokinetics and Pharmacodynamics 51 (2024): 429–447.

[39] D. Gong, J. M. Arbesfeld-Qiu, E. Perrault, J. W. Bae, and W. L. Hwang, “Spatial Oncology: Translating Contextual Biology to the Clinic,” Cancer Cell 42 (2024): 1653–1675.

[40] A. Kapil, A. Spitzmüller, and N. Brieu, “HER2 quantitative Continuous Scoring for Accurate Patient Selection in HER2 Negative Trastuzumab Deruxtecan Treated Breast Cancer,” Scientific Reports-UK 14 (2024): 12129.

[41] M. A. Hempenius, M. A. Eenkhoorn, and H. Høeg, “Quantitative Comparison of Immunohistochemical HER2-Low Detection in an Interlaboratory Study,” Histopathology 85 (2024): 920–928.

[42] S. Modi, W. Jacot, and T. Yamashita, “Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer,” New England Journal of Medicine 387 (2022): 9–20.

[43] C. Parisi, L. Mahjoubi, A. Gazzah, and F. Barlesi, “TROP-2 Directed Antibody-Drug Conjugates (ADCs): The Revolution of Smart Drug Delivery in Advanced Non-Small Cell Lung Cancer (NSCLC),” Cancer Treatment Reviews 118 (2023): 102572.

[44] H. S. Rugo, A. Bardia, and F. Marmé, “Sacituzumab Govitecan in Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer,” Journal of Clinical Oncology 40 (2022): 3365–3376.

[45] N. Klümper, D. J. Ralser, and J. Ellinger, “Membranous NECTIN-4 Expression Frequently Decreases During Metastatic Spread of Urothelial Carcinoma and Is Associated With Enfortumab Vedotin Resistance,” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 29 (2023): 1496–1505.

[46] J. Wu, B. Cheng, and Y. Song, “Targeting Sialylation Enhances the Therapeutic Efficacy of the Nectin-4-Targeted Antibody-Drug Conjugate Enfortumab Vedotin in Bladder Cancer,” Cancer Research 86 (2026): 519–539.

[47] A. M. Mahmoud, R. Nabavizadeh, and R. Rodrigues Pessoa, “Antibody-Based Therapeutics for the Treatment of Renal Cell Carcinoma: Challenges and Opportunities,” Oncologist 28 (2023): 297–308.

[48] J. Imamura, S. Ganguly, and A. Muskara, “Lineage Plasticity and Treatment Resistance in Prostate Cancer: The Intersection of Genetics, Epigenetics, and Evolution,” Frontiers in Endocrinology 14 (2023): 1191311.

[49] P. Yu, C. Zhu, and X. You, “The Combination of Immune Checkpoint Inhibitors and Antibody-Drug Conjugates in the Treatment of Urogenital Tumors: A Review Insights From Phase 2 and 3 Studies,” Cell Death & Disease 15 (2024): 433.

[50] J. Thomas, M. Sun, T. Getz, B. Ho, J. T. Nauseef, and S. T. Tagawa, “Antibody-Drug Conjugates for Urothelial Carcinoma,” Urologic Oncology: Seminars and Original Investigations 41 (2023): 420–428.

[51] M. S. van der Heijden, T. Powles, and S. Gupta, “Exploratory Subgroup Analyses of EV-302: A Phase III Global Study to Evaluate Enfortumab Vedotin in Combination With Pembrolizumab Versus Chemotherapy in Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma,” ESMO Open 10 (2025): 105544.

[52] B. McGregor, P. H. O'Donnell, and A. Balar, “Health-Related Quality of Life of Patients With Locally Advanced or Metastatic Urothelial Cancer Treated With Enfortumab Vedotin After Platinum and PD-1/PD-L1 Inhibitor Therapy: Results From Cohort 1 of the Phase 2 EV-201 Clinical Trial,” European Urology 81 (2022): 515–522.

[53] D. P. Petrylak, S. T. Tagawa, and R. K. Jain, “TROPHY-U-01 Cohort 2: A Phase II Study of Sacituzumab Govitecan in Cisplatin-Ineligible Patients with Metastatic Urothelial Cancer Progressing after Previous Checkpoint Inhibitor Therapy,” Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 42 (2024): 3410–3420.

[54] T. B. Powles, E. Grande, and N. Alimohamed, “SGNDV-001: Disitamab Vedotin With Pembrolizumab in HER2-Expressing Locally Advanced or Metastatic Urothelial Carcinoma,” Future oncology (London, England) 21 (2025): 2705–2712.

[55] J. C. Bendell, T. Doi, and M. R. Patel, “A Phase I/II, Two-Part, Multicenter, First-in-Human Study of DS-7300a in Patients With Advanced Solid Malignant Tumors,” Journal of Clinical Oncology 38: S3646.

[56] J. S. de Bono, N. Concin, and D. S. Hong, “Tisotumab Vedotin in Patients With Advanced or Metastatic Solid Tumours (InnovaTV 201): A First-in-Human, Multicentre, Phase 1-2 Trial,” Lancet Oncology 20 (2019): 383–393.

[57] R. R. Aggarwal, J. Vuky, and D. VanderWeele, “Phase I, First-in-Human Study of FOR46 (FG-3246), an Immune-Modulating Antibody-Drug Conjugate Targeting CD46, in Patients With Metastatic Castration-Resistant Prostate Cancer,” Journal of clinical oncology: official journal of the American Society of Clinical Oncology 43 (2025): 1824–1834.

[58] J. C. Bendell, “A Phase I/II, Two-Part, Multicenter, First-in-Human Study of DS-7300a in Patients With Advanced Solid Malignant Tumors,” Journal of Clinical Oncology 38 (2020): S3646.

[59] R. Aggarwal, T. Zhang, E. J. Small, and M. R. Smith, “Phase I Study of ARX517, a PSMA-Targeted Antibody-Drug Conjugate, in Patients With Metastatic Castration-Resistant Prostate Cancer,” Journal of Clinical Oncology 23, no. 12 (2024): 1842–1853.

[60] B. Cornelissen and J. A. O'Donoghue, “Prostate-Specific Membrane Antigen as a Target for Antibody-Drug Conjugates in Prostate Cancer,” Cells 14, no. 7 (2022): 513.

[61] D. C. Danila, R. Z. Szmulewitz, and U. Vaishampayan, “Phase I Study of DSTP3086S, an Antibody-Drug Conjugate Targeting Six-Transmembrane Epithelial Antigen of Prostate 1, in Metastatic Castration-Resistant Prostate Cancer,” Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 37 (2019): 3518–3527.

[62] K. Tanaka, K. Isse, and T. Fujihira, “Prevalence of Delta-Like Protein 3 Expression in Patients With Small Cell Lung Cancer,” Lung Cancer (Amsterdam, Netherlands) 115 (2018): 116–120.

[63] T. Doi, K. Kato, and A. Patnaik, “Phase 1/2 Study of DS-6000a (Cadherin-6–Directed DXd Antibody–Drug Conjugate) in Patients With Advanced Solid Tumors,” Annals of Oncology 33 (2022): S493.

[64] B. T. Li, E. F. Smit, and Y. Goto, “Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer,” New England Journal of Medicine 386 (2022): 241–251.

[65] J. E. Rosenberg, P. H. O'Donnell, and A. V. Balar, “Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy,” Journal of Clinical Oncology: official Journal of the American Society of Clinical Oncology 37 (2019): 2592–2600.

[66] S. T. Tagawa, A. V. Balar, and D. P. Petrylak, “TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors,” Journal Of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 39 (2021): 2474–2485.

[67] X. Sheng, L. Wang, and Z. He, “Efficacy and Safety of Disitamab Vedotin in Patients With Human Epidermal Growth Factor Receptor 2-Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II,” Clinical Trials Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 42 (2024): 1391–1402.

[68] D. P. Petrylak, N. J. Vogelzang, and K. Chatta, “PSMA ADC Monotherapy in Patients With Progressive Metastatic Castration-Resistant Prostate Cancer Following Abiraterone and/or Enzalutamide: Efficacy and Safety in Open-Label Single-Arm Phase 2 Study,” Prostate 80 (2020): 99–108.

[69] O. Sartor, J. de Bono, and K. N. Chi, “Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer,” New England Journal of Medicine 385 (2021): 1091–1103.

[70] L. K. Skidmore, D. Mills, and J. Y. Kim, “Preclinical Characterization of ARX517, a Site-Specific Stable PSMA-Targeted Antibody-Drug Conjugate for the Treatment of Metastatic Castration-Resistant Prostate Cancer,” Molecular Cancer Therapeutics 23 (2024): 1842–1853.

[71] R. R. McKay, R. Eapen, E. M. Wulff-Burchfield, and M. S. Hofman, “Emerging Paradigms in Genitourinary Cancers: Integrating Molecular Imaging, Hypoxia-Inducible Factor–Targeted Therapies, and Antibody-Drug Conjugates in Renal Cell and Urothelial Carcinomas,” American Society of Clinical Oncology Educational Book 45 (2025): e473862.

[72] C. Kollmannsberger, T. K. Choueiri, and D. Y. C. Heng, “A Randomized Phase II Study of AGS-16C3F Versus Axitinib in Previously Treated Patients With Metastatic Renal Cell Carcinoma,” Oncologist 26 (2021): 182–361.

[73] S. K. Pal, A. Forero-Torres, and J. A. Thompson, “A Phase 1 Trial of SGN-CD70A in Patients With CD70-Positive, Metastatic Renal Cell Carcinoma,” Cancer— American Cancer Society 125 (2019): 1124–1132.

[74] L. Ascione, L. Guidi, and A. Prakash, “Unlocking the Potential: Biomarkers of Response to Antibody-Drug Conjugates,” American Society of Clinical Oncology Educational Book 44 (2024): e431766.

[75] J. Henning, C. Brezden-Masley, and K. Gelmon, “Managing the Risk of Lung Toxicity With Trastuzumab Deruxtecan (T-DXd): A Canadian Perspective,” Current Oncology (Toronto, Ontario) 30, no. 9 (2023): 8019–8038.

[76] M. Mileva, E. G. E. de Vries, and T. Guiot, “Molecular Imaging Predicts Lack of T-DM1 Response in Advanced HER2-Positive Breast Cancer (Final Results of ZEPHIR Trial),” npj Breast Cancer 10 (2024): 4.

[77] S. Li, X. Zhao, and K. Fu, “Resistance to Antibody-Drug Conjugates: A Review,” Acta Pharmaceutica Sinica B 15 (2025): 737–756.

[78] B. Cerci, O. Saatci, M. Basik, and O. Sahin, “Mechanisms of Resistance to Antibody-Drug Conjugates in Breast Cancer,” Drug Resistance Updates 85 (2026): 101353.

[79] R. Tomabechi, H. Kishimoto, and T. Sato, “SLC46A3 is a Lysosomal Proton-Coupled Steroid Conjugate and Bile Acid Transporter Involved in Transport of Active Catabolites of T-DM1,” PNAS Nexus 1 (2022): pgac063.

[80] A. Bartolomucci, M. Nobrega, and T. Ferrier, “Circulating Tumor DNA to Monitor Treatment Response in Solid Tumors and Advance Precision Oncology,” npj Precision Oncology 9 (2025): 84.

[81] K. R. Reyes, T. Jindal, and B. Mitchell, “Circulating Tumor DNA (ctDNA) Monitoring in Patients (pts) With Advanced Urothelial Carcinoma (aUC) Treated With Enfortumab Vedotin +/- Pembrolizumab (EVP),” Journal of Clinical Oncology 43 (2025): 4560.

[82] S. Gupta, Y. Loriot, and M. S. Van der Heijden, “Enfortumab Vedotin Plus Pembrolizumab Versus Chemotherapy in Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer (EV-302): Patient-Reported Outcomes From an Open-Label, Randomised, Controlled, Phase 3 Study,” Lancet Oncology 26 (2025): 795–805.

[83] M. Eiber, K. Herrmann, and J. Calais, “Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE): Proposed miTNM Classification for the Interpretation of PSMA-Ligand PET/CT,” Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine 59 (2018): 469–478.

[84] W. P. Fendler, M. Eiber, and M. Beheshti, “PSMA PET/CT: Joint EANM Procedure Guideline/SNMMI Procedure Standard for Prostate Cancer Imaging 2.0,” European Journal of Nuclear Medicine and Molecular Imaging 50 (2023): 1466–1486.

[85] E. L. Brown, S. Shmuel, and K. Mandleywala, “Immuno-PET Detects Antibody-Drug Potency on Coadministration With Statins,” Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine 64 (2023): 1638–1646.

[86] P. Adumeau, D. Vivier, and S. K. Sharma, “Site-Specifically Labeled Antibody-Drug Conjugate for Simultaneous Therapy and ImmunoPET,” Molecular Pharmaceutics 15 (2018): 892–898.

[87] S. Morganti, R. J. Kusmick, and M. E. Hughes, “Survival Outcomes and the Role of DNADX ctDNA Testing in Patients Treated With Sacituzumab Govitecan for Metastatic Breast Cancer,” ESMO Open 10 (2025): 105828.

[88] M. Andre, A. Caobi, J. S. Miles, A. Vashist, M. A. Ruiz, and A. D. Raymond, “Diagnostic Potential of Exosomal Extracellular Vesicles in Oncology,” BMC Cancer 24 (2024): 322.

[89] A. Makler and W. Asghar, “Exosomal Biomarkers for Cancer Diagnosis and Patient Monitoring,” Expert Review of Molecular Diagnostics 20 (2020): 387–400.

[90] S. Krishnamurthy, S. J. Schnitt, and A. Vincent-Salomon, “Fully Automated Artificial Intelligence Solution for Human Epidermal Growth Factor Receptor 2 Immunohistochemistry Scoring in Breast Cancer: A Multireader Study,” JCO Precision Oncology 8 (2024): e2400353.

[91] C. Palm, C. E. Connolly, and R. Masser, “Determining HER2 Status by Artificial Intelligence: An Investigation of Primary, Metastatic, and HER2 Low Breast Tumors,” Diagnostics (Basel, Switzerland) 13 (2023): 168.

[92] M. Eyers, J. Irlam, and G. Marshall, “Digital Spatial Profiling of the Microenvironment of Muscle Invasive Bladder Cancer,” Communications Biology 7 (2024): 737.

[93] M. A. Cilento, C. J. Sweeney, and L. M. Butler, “Spatial Transcriptomics in Cancer Research and Potential Clinical Impact: A Narrative Review,” Journal of Cancer Research and Clinical Oncology 150 (2024): 296.

[94] M. Hammood, A. W. Craig, and J. V. Leyton, “Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)-A Necessity for Future ADC Research and Development,” Pharmaceuticals (Basel, Switzerland) 14 (2021): 674.

[95] R. M. DeVay, K. Delaria, and G. Zhu, “Improved Lysosomal Trafficking Can Modulate the Potency of Antibody Drug Conjugates,” Bioconjugate Chemistry 28 (2017): 1102–1114.

[96] T. Riedl, E. van Boxtel, M. Bosch, P. W. H. I. Parren, and A. F. Gerritsen, “High-Throughput Screening for Internalizing Antibodies by Homogeneous Fluorescence Imaging of a pH-Activated Probe,” Journal of Biomolecular Screening 21 (2016): 12–23.

[97] P. Mohr, J. van Sluis, M. N. Lub-de Hooge, A. A. Lammertsma, A. H. Brouwers, and C. Tsoumpas, “Advances and Challenges in ImmunoPET Methodology,” Frontiers in Nuclear Medicine 4 (2024): 1360710.

[98] J. R. Bading and J. E. Mortimer, “The Role of HER2 PET in Treatment of Breast Cancer,” Journal of Nuclear Medicine 125 (2025): 271364.

[99] A. Mansur, J. E. McConathy, and E. Stringer-Reasor, “Quantitative[(89)Zr]Zr-Trastuzumab PET and Diffusion- Weighted MRI for Characterization of Metastatic HER2-Positive Breast Cancer With PET/MRI,” Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine 66 (2025): 1018–1026.

[100] C. Dello Russo, I. G. Asiimwe, S. Pushpakom, C. Palmieri, and M. Pirmohamed, “UGT1A1 and Sacituzumab Govitecan Toxicity: A Systematic Review and Meta-Analysis,” Clinical Pharmacology & Therapeutics 119 (2026): 63–73.

[101] S. Li, X. Zhao, and K. Fu, “Resistance to Antibody–Drug Conjugates: A Review,” Acta Pharmaceutica Sinica B 15 (2025): 737–756.

[102] R. O. Abelman, B. Wu, L. M. Spring, L. W. Ellisen, and A. Bardia, “Mechanisms of Resistance to Antibody–Drug Conjugates,” Cancers (Basel) 15, no. 4 (2023): 1278.

[103] D. H. Aggen, C. E. Chu, and J. E. Rosenberg, “Scratching the Surface: NECTIN-4 as a Surrogate for Enfortumab Vedotin Resistance,” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 29 (2023): 1377–1380.

[104] F. W. Hunter, H. R. Barker, and B. Lipert, “Mechanisms of Resistance to Trastuzumab Emtansine (T-DM1) in HER2-Positive Breast Cancer,” British Journal of Cancer 122 (2020): 603–612.

[105] F. Loganzo, M. Sung, and H. Gerber, “Mechanisms of Resistance to Antibody-Drug Conjugates,” Molecular Cancer Therapeutics 15 (2016): 2825–2834.

[106] N. Takegawa, Y. Nonagase, and K. Yonesaka, “DS-8201a, a New HER2-Targeting Antibody–Drug Conjugate Incorporating a Novel DNA Topoisomerase I Inhibitor, Overcomes HER2-Positive Gastric Cancer T-DM1 Resistance,” International Journal of Cancer 141 (2017): 1682–1689.

[107] Y. Murase, S. Nanjo, and S. Arai, “Therapeutic Strategies to Overcome Payload Resistance of Trastuzumab Deruxtecan in HER2-Positive Cancers,” Cancer Science, ahead of print, 2026, https://doi.org/10.1111/cas.70319.

[108] L. Yin, S. Zhou, and H. Zhang, “Reprogramming the Tumor Microenvironment: Synergistic Mechanisms of Antibody–Drug Conjugates and Immune Checkpoint Inhibitors,” Antibody Therapeutics 8 (2025): 262–274.

[109] F. Li, M. Ulrich, and M. Jonas, “Tumor-Associated Macrophages Can Contribute to Antitumor Activity Through FcγR-Mediated Processing of Antibody-Drug Conjugates,” Molecular Cancer Therapeutics 16 (2017): 1347–1354.

[110] H. Jang and J. Chang, “Strategic Combinations of Antibody–Drug Conjugates From 2023 to 2025: From Dual Therapies to Innovative ADC-Based Regimens,” Pharmaceutics 17, no. 12 (2025): 1581.

[111] G. Villacampa, P. Cresta Morgado, L. Carità, V. Navarro, T. Pascual, and R. Dienstmann, “Safety and Efficacy of Antibody-Drug Conjugates Plus Immunotherapy in Solid Tumours: A Systematic Review and Meta-Analysis,” Cancer Treatment Reviews 131 (2024): 102847.

[112] A. B. Apolo, J. Bellmunt, and L. Cordes, “The Clinical Use of Enfortumab Vedotin and Pembrolizumab in Patients With Advanced Urothelial Carcinoma: Using Clinical Judgement Over Treatment Criteria,” ESMO Open 9, no. 9 (2024): 103725.

[113] S. Nucera, C. Conti, F. Martorana, B. Wilson, and S. Genta, “Antibody-Drug Conjugates to Promote Immune Surveillance: Lessons Learned From Breast Cancer,” Biomedicines 12 (2024): 1491.

[114] B. Brower, A. McCoy, and H. Ahmad, “Managing Potential Adverse Events During Treatment With Enfortumab Vedotin + Pembrolizumab in Patients With Advanced Urothelial Cancer,” Frontiers in Oncology 14 (2024): 1326715.

[115] L. Gong, J. Luo, and E. Yang, “Cancer Immunology Data Engine Reveals Secreted AOAH as a Potential Immunotherapy,” Cell 188 (2025): 5062–5080.

[116] L. Zhang, Y. Yan, and Y. Gao, “Antibody–Drug Conjugates and Immune Checkpoint Inhibitors in Cancer Treatment: A Systematic Review and Meta-Analysis,” Scientific Reports-UK 14 (2024): 22357.

[117] Y. Pommier and A. Thomas, “New Life of Topoisomerase I Inhibitors as Antibody-Drug Conjugate Warheads,” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 29 (2023): 991–993.

[118] A. H. Staudacher, V. Liapis, W. Tieu, N. L. Wittwer, and M. P. Brown, “Tumour-Associated Macrophages Process Drug and Radio-Conjugates of the Dead Tumour Cell-Targeting APOMAB® Antibody,” Journal of Controlled Release 327 (2020): 779–787.

[119] S. Wang, Y. Yang, and P. Ma, “Landscape and Perspectives of Macrophage-Targeted Cancer Therapy in Clinical Trials,” Molecular Therapy—Oncolytics 24 (2022): 799–813.

[120] J. Wang, H. Yuan, J. Xu, and C. Yang, “Advances in PSMA-Targeted Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer,” Cancer Management and Research 17 (2025): 1859–1869.

[121] M. Zhou, Z. Huang, and Z. Ma, “The Next Frontier in Antibody-Drug Conjugates: Challenges and Opportunities in Cancer and Autoimmune Therapy,” Cancer Drug Resistance 8 (2025): 34.

[122] A. Glasmacher, E. Garralda, C. Gwaltney, K. Rupalla, C. Li, and H. Weber, “Dose Optimization in Cancer Drug Development: Review and Outcome of a Multi-Stakeholder Workshop,” European Journal of Cancer (Oxford, England: 1990) 226 (2025): 115593.

[123] M. E. Lacouture, A. B. Patel, J. E. Rosenberg, and P. H. O'Donnell, “Management of Dermatologic Events Associated With the Nectin-4-Directed Antibody-Drug Conjugate Enfortumab Vedotin,” Oncologist 27 (2022): e223–e232.

[124] U.S. Food and Drug Administration. Enfortumab Vedotin-Ejfv (PADCEV) Prescribing Information (U.S. Food and Drug Administration, 2013).

[125] B. Xu, L. Shen, and J. Wang, “Efficacy and Safety of DV in HER2-Negative and HER2-Low Locally Advanced or Metastatic Urothelial Carcinoma: Results of a Phase 2 Study,” Med 6, no. 7 (2025): 100637.

[126] R. Aggarwal, T. Zhang, and E. J. Small, “Phase I Study of FOR46, a CD46-Targeted Antibody-Drug Conjugate, in Metastatic Castration-Resistant Prostate Cancer,” Journal of Clinical Oncology (2022).

[127] D. C. Danila, D. E. Rathkopf, and M. J. Morris, “Phase I Study of DSTP3086S, an Antibody-Drug Conjugate Targeting STEAP1, in Metastatic Castration-Resistant Prostate Cancer,” Journal of Clinical Oncology 37, no. 36 (2019): 3518–3527.

[128] H. Donaghy, “Effects of Antibody, Drug and Linker on the Preclinical and Clinical Toxicities of Antibody–Drug Conjugates,” MABS-AUSTIN 8 (2016): 659–671.

[129] S. Modi, C. Saura, and T. Yamashita, “Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer,” New England Journal of Medicine 382 (2020): 610–621.

[130] T. K. Owonikoko, L. Byers, Y. Cheng, et al., “IDeate-Lung02: A Phase 3 Study of Second-Line Ifinatamab Deruxtecan in Patients With Relapsed Small Cell Lung Cancer,” Future Oncology 21, no. 25 (2025): 3275–3282, https://doi.org/10.1080/14796694.2025.2565995.

[131] R. Chen, Z. Ren, L. Bai, et al., “Novel Antibody-Drug Conjugates Based on DXd-ADC Technology,” Bioorganic Chemistry 151 (2024): 107697, https://doi.org/10.1016/j.bioorg.2024.107697.

[132] A. Bardia, S. A. Hurvitz, and S. M. Tolaney, “Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer,” New England Journal of Medicine 384 (2021): 1529–1541.

[133] U.S. Food and Drug Administration. Sacituzumab Govitecan-Hziy (TRODELVY) Prescribing Information (U.S. Food and Drug Administration, 2023).

[134] A. J. Ocean and A. N. Starodub, “UGT1A1 genotype and the Risk of Neutropenia With Sacituzumab Govitecan,” Clinical Cancer Research 27 (2021): 4019–4025.

[135] Gilead Sciences, Study of Sacituzumab Govitecan in Patients With Advanced Solid Tumors (Gilead Sciences, 2020).

[136] C. Brignole, E. Calarco, V. Bensa, et al., “Antitumor Activity of the Investigational B7-H3 Antibody-Drug Conjugate, Vobramitamab Duocarmazine, in Preclinical Models of Neuroblastoma,” Journal for ImmunoTherapy of Cancer 11, no. 9 (2023): e007174, https://doi.org/10.1136/jitc-2023-007174.

[137] J. A. Scribner, J. G. Brown, T. Son, et al., “Preclinical Development of MGC018, A Duocarmycin-Based Antibody–Drug Conjugate Targeting B7-H3 for Solid Cancer,” Molecular Cancer Therapeutics 19, no. 11 (2020): 2235–2244, https://doi.org/10.1158/1535-7163.mct-20-0116.

[138] W. H. Vogel, “Infusion Reactions: Diagnosis, Assessment, and Management,” Clinical Journal of Oncology Nursing 14 (2010): E10–E21.

[139] S. Roselló, I. Blasco, L. García Fabregat, and A. Cervantes, “Management of Infusion Reactions to Systemic Anticancer Therapy: ESMO Clinical Practice Guidelines,” Annals of Oncology 28 (2017): v100–v118.

[140] U.S. Food and Drug Administration, Enfortumab Vedotin-Ejfv (PADCEV) Prescribing Information (U.S. Food and Drug Administration, 2023).

[141] A. Nizam, C. B. Nguyen, and J. Li, “Treatment-Related Adverse Events and Associated Outcomes in Patients With Advanced Urothelial Carcinoma Treated With Enfortumab Vedotin: Analysis of the UNITE Study,” Cancer Medicine-US 14 (2025): e71284.

[142] M. Yu, L. Zhou, M. Cao, C. Ji, and Y. Zheng, “Post-Marketing Drug Safety Surveillance of Enfortumab Vedotin: An Observational Pharmacovigilance Study Based on a Real-World Database,” Frontiers in Immunology 15 (2024): 1397692.

[143] S. M. Tolaney, G. P. Sonpavde, P. Tarantino, M. B. Lustberg, and H. S. Rugo, “Clinical Perspective on Management of Key Adverse Events With Sacituzumab Govitecan,” Oncologist 30 (2025): oyaf311.

[144] J. M. Pérez-García, M. Gion, and M. Ruiz-Borrego, “Prevention of Sacituzumab Govitecan-Related Neutropenia and Diarrhea in Patients With HER2-Negative Advanced Breast Cancer (PRIMED): An Open-Label, Single-Arm, Phase 2 Trial,” eClinicalMedicine 85 (2025): 103309.

[145] C. Xu, Z. Chen, and Y. Xia, “Clinical Best Practices in Interdisciplinary Management of Human Epidermal Growth Factor Receptor 2 Antibody-Drug Conjugates–Induced Interstitial Lung Disease/Pneumonitis: An Expert Consensus in China,” Cancer—American Cancer Society 130 (2024): 3054–3066.

[146] G. Bianchini, A. Fabi, and V. Guarneri, “Management of Trastuzumab Deruxtecan-Related Adverse Events in Breast Cancer: Italian Expert Panel Recommendations,” Future Oncology (London, England) 21 (2025): 2565–2573.

[147] T. Powles, M. Lapuente, and B. Garmezy, “Treatment Optimization and Management of AEs With Enfortumab Vedotin + Pembrolizumab for Untreated Locally Advanced/Metastatic Urothelial Cancer: A Podcast,” Oncology and Therapy 13 (2025): 811–823.

[148] E. Basch, A. M. Deal, and M. G. Kris, “Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial,” Journal of clinical oncology: official journal of the American Society of Clinical Oncology 34 (2016): 557–565.

[149] R. D. Nipp, N. K. Horick, and C. L. Qian, “Effect of a Symptom Monitoring Intervention for Patients Hospitalized With Advanced Cancer: A Randomized Clinical Trial,” JAMA Oncology 8 (2022): 571–578.

[150] M. Grairi and M. Le Borgne, “Antibody–Drug Conjugates: Prospects for the Next Generation,” Drug Discovery Today 29 (2024): 104241.

[151] H. Liu, H. Zeng, and X. Qin, “The Icarian Flight of Antibody-Drug Conjugates: Target Selection Amidst Complexity and Tackling Adverse Impacts,” Protein Cell 16 (2025): 532–556.

[152] A. D'Angelo, M. Catalano, I. De Gennaro Aquino, V. Gangi, and G. Roviello, “Antibody-Drug Conjugates in Metastatic Urothelial Cancer: Highway to Heaven,” World Journal of Clinical Oncology 16 (2025): 106646.

[153] K. K. Zarrabi, A. Saxena, K. W. Mouw, V. S. Koshkin, and T. Friedlander, “Unmet Potential of Antibody-Drug Conjugates: An Evaluation of the Past, Present, and Future of Antibody-Drug Conjugate Development in Advanced Urothelial Carcinoma,” American Society of Clinical Oncology Educational Book 45 (2025): e471924.

[154] I. A. Alradwan, M. K. Alnefaie, and N. Al Fayez, “Strategic and Chemical Advances in Antibody-Drug Conjugates,” Pharmaceutics 17 (2025): 1164.

[155] Y. Lei, M. Zheng, P. Chen, C. Seng Ng, T. Peng Loh, and H. Liu, “Linker Design for the Antibody Drug Conjugates: A Comprehensive Review,” ChemMedChem 20 (2025): e202500262.

[156] R. Wang, B. Hu, and Z. Pan, “Antibody-Drug Conjugates (ADCs): Current and Future Biopharmaceuticals,” Journal of Hematology & Oncology 18 (2025): 51.

[157] Y. Lu, W. Huang, and Y. Li, “Leveraging Artificial Intelligence in Antibody-Drug Conjugate Development: From Target Identification to Clinical Translation in Oncology,” npj Precision Oncology 9 (2025): 374.

[158] C. Fu, W. Tong, and L. Yu, “When Will the Immune-Stimulating Antibody Conjugates (ISACs) Be Transferred From Bench to Bedside?,” Pharmacological Research 203 (2024): 107160.

[159] F. Zhao, Y. Wu, and K. Schaefer, “Hijacking Extracellular Targeted Protein Degrader–Drug Conjugates for Enhanced Drug Delivery,” Journal of the American Chemical Society 147 (2025): 39912–39925.

RIGHTS & PERMISSIONS

2026 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.