{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:04:18Z","timestamp":1790762658193,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Soongsil University Research Fund (New Professor Support Research) of 2025","id":[{"id":"https:\/\/ror.org\/017xnm587","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002561","name":"Ministry of Education","doi-asserted-by":"publisher","award":["RS-2025-25441317"],"award-info":[{"award-number":["RS-2025-25441317"]}],"id":[{"id":"10.13039\/501100002561","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2025-25441317"],"award-info":[{"award-number":["RS-2025-25441317"]}],"id":[{"id":"https:\/\/ror.org\/01p262204","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Bispecific antibody\u2013drug conjugates (bsADCs) are being developed to address limitations of conventional ADCs, including heterogeneous antigen expression, insufficient tumor\u2013normal discrimination, and suboptimal intracellular trafficking. This review evaluates bsADCs from a preclinical-to-clinical translational perspective and defines the evidence needed to justify the added complexity of bispecific design. A structured search of PubMed\/MEDLINE, Embase, Web of Science, Scopus, clinical-trial registries, and major oncology conference proceedings was conducted through 29 July 2026. Dual-antigen bsADCs were classified as coverage-oriented, co-expression-dependent, trafficking-assisted, or multifunctional, while biparatopic ADCs were considered mechanistically related comparators. Dual recognition can broaden tumor coverage, enhance avidity-dependent selectivity, improve intracellular trafficking, or add biological functions. These effects depend on target-pair biology, molecular format, valency, epitope geometry, arm affinity, linker\u2013payload properties, drug-to-antibody ratio, pharmacokinetics, normal-tissue exposure, manufacturability, and biomarker feasibility. Clinically, izalontamab brengitecan supports the feasibility of selected architectures, whereas MEDI4276 and TQB2102 illustrate how complete molecular design shapes therapeutic index. We propose an integrated translational framework and functional design parsimony, defined as selecting the least complex ADC architecture capable of achieving the intended biological and translational objective. Bispecificity should be used only when it provides a demonstrable advantage over a simpler ADC design.<\/jats:p>","DOI":"10.3390\/ijms27198748","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:25:42Z","timestamp":1790760342000},"page":"8748","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Dual Targeting to Clinical Validation: A Translational Framework for Bispecific Antibody\u2013Drug Conjugates"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9115-8278","authenticated-orcid":false,"given":"Jun","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Chemistry, Graduate School, Soongsil University, Seoul 06978, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seounghun","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Graduate School, Soongsil University, Seoul 06978, Republic of Korea"},{"name":"AI-Bio Convergence Research Institute, Soongsil University, Seoul 06978, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1208\/s12248-014-9710-8","article-title":"Antibody drug conjugates: Design and selection of linker, payload and conjugation chemistry","volume":"17","author":"McCombs","year":"2015","journal-title":"AAPS J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1208\/s12248-015-9738-4","article-title":"Antibody drug conjugates: Preclinical considerations","volume":"17","author":"Bornstein","year":"2015","journal-title":"AAPS J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3470","DOI":"10.1007\/s11095-014-1584-z","article-title":"Preclinical pharmacokinetic considerations for the development of antibody drug conjugates","volume":"32","author":"Kamath","year":"2015","journal-title":"Pharm. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1158\/2159-8290.CD-21-0702","article-title":"Parallel genomic alterations of antigen and payload targets mediate polyclonal acquired clinical resistance to sacituzumab govitecan in triple-negative breast cancer","volume":"11","author":"Coates","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/s41571-023-00783-w","article-title":"Optimizing the safety of antibody\u2013drug conjugates for patients with solid tumours","volume":"20","author":"Tarantino","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1208\/s12248-015-9766-0","article-title":"Antibody drug conjugates: Application of quantitative pharmacology in modality design and target selection","volume":"17","author":"Sadekar","year":"2015","journal-title":"AAPS J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1208\/s12248-015-9790-0","article-title":"Antibody drug conjugates: Nonclinical safety considerations","volume":"17","author":"Hinrichs","year":"2015","journal-title":"AAPS J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41573-019-0028-1","article-title":"Bispecific antibodies: A mechanistic review of the pipeline","volume":"18","author":"Labrijn","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1016\/j.apsb.2024.01.009","article-title":"Bispecific antibody drug conjugates: Making 1 + 1 > 2","volume":"14","author":"Gu","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1158\/1535-7163.MCT-18-1313","article-title":"Manipulation of cell-type selective antibody internalization by a guide\u2013effector bispecific design","volume":"18","author":"Lee","year":"2019","journal-title":"Mol. Cancer Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s40164-025-00624-9","article-title":"Development of a bispecific antibody\u2013drug conjugate targeting EpCAM and CLDN3 for the treatment of multiple solid tumors","volume":"14","author":"Luo","year":"2025","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2441411","DOI":"10.1080\/19420862.2024.2441411","article-title":"A bispecific antibody\u2013drug conjugate targeting pCAD and CDH17 has antitumor activity and improved tumor specificity","volume":"17","author":"Synan","year":"2025","journal-title":"mAbs"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.ccell.2015.12.008","article-title":"A biparatopic HER2-targeting antibody\u2013drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy","volume":"29","author":"Li","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1158\/1535-7163.MCT-20-0014","article-title":"First-in-human, phase 1 dose-escalation study of biparatopic anti-HER2 antibody\u2013drug conjugate MEDI4276 in patients with HER2-positive advanced breast or gastric cancer","volume":"20","author":"Pegram","year":"2021","journal-title":"Mol. Cancer Ther."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Faria, M., Peay, M., Lam, B., Ma, E., Yuan, M., Waldron, M., Mylott, W.R., Liang, M., and Rosenbaum, A.I. (2019). Multiplex LC-MS\/MS assays for clinical bioanalysis of MEDI4276, an antibody\u2013drug conjugate of tubulysin analogue attached via cleavable linker to a biparatopic humanized antibody against HER2. Antibodies, 8.","DOI":"10.3390\/antib8010011"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/S1470-2045(24)00159-1","article-title":"BL-B01D1, a first-in-class EGFR\u2013HER3 bispecific antibody\u2013drug conjugate, in patients with locally advanced or metastatic solid tumours: A first-in-human, open-label, multicentre, phase 1 study","volume":"25","author":"Ma","year":"2024","journal-title":"Lancet Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1016\/S0140-6736(25)01954-3","article-title":"Izalontamab brengitecan, an EGFR and HER3 bispecific antibody\u2013drug conjugate, versus chemotherapy in heavily pretreated recurrent or metastatic nasopharyngeal carcinoma: A multicentre, randomised, open-label, phase 3 study in China","volume":"406","author":"Yang","year":"2025","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3584","DOI":"10.1007\/s11095-015-1742-y","article-title":"An introduction to the regulatory and nonclinical aspects of the nonclinical development of antibody drug conjugates","volume":"32","author":"Lansita","year":"2015","journal-title":"Pharm. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s11095-023-03649-z","article-title":"Antibody-drug conjugate overview: A state-of-the-art manufacturing process and control strategy","volume":"41","author":"Li","year":"2024","journal-title":"Pharm. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s12272-026-01595-z","article-title":"Bispecific antibody\u2013drug conjugates: A modular blueprint for next-generation cancer therapeutics","volume":"49","author":"Bai","year":"2026","journal-title":"Arch. Pharm. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"107582","DOI":"10.1016\/j.pharmthera.2020.107582","article-title":"Fine-tuning bispecific therapeutics","volume":"212","author":"Lim","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/j.chembiol.2024.07.004","article-title":"Therapeutic potential of cis-targeting bispecific antibodies","volume":"31","author":"Oslund","year":"2024","journal-title":"Cell Chem. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1016\/j.csbj.2020.05.006","article-title":"Format and geometries matter: Structure-based design defines the functionality of bispecific antibodies","volume":"18","author":"Dickopf","year":"2020","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zhuang, W., Zhang, W., Wang, L., Xie, L., Feng, J., Zhang, B., and Hu, Y. (2023). Generation of a novel SORT1\u00d7HER2 bispecific antibody\u2013drug conjugate targeting HER2-low-expression tumor. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242216056"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/psp4.12369","article-title":"Target-mediated drug disposition model for bispecific antibodies: Properties, approximation, and optimal dosing strategy","volume":"8","author":"Schropp","year":"2019","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1111\/cas.12966","article-title":"Bystander killing effect of DS-8201a, a novel anti-HER2 antibody\u2013drug conjugate, in tumors with HER2 heterogeneity","volume":"107","author":"Ogitani","year":"2016","journal-title":"Cancer Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"28","DOI":"10.21037\/tbcr-23-38","article-title":"New-generation technologies for spatial tissue analysis, indispensable tools for deciphering intratumor heterogeneity in the development of antibody\u2013drug conjugates and radio-immunoconjugates for cancer treatment","volume":"4","author":"Kossai","year":"2023","journal-title":"Transl. Breast Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2688","DOI":"10.1158\/1535-7163.MCT-16-0364","article-title":"Efficient payload delivery by a bispecific antibody\u2013drug conjugate targeting HER2 and CD63","volume":"15","author":"Vink","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2551205","DOI":"10.1080\/19420862.2025.2551205","article-title":"A bispecific antibody-drug conjugate targeting CD7 and CD33 shows anti-tumor activity and improved tumor selectivity in an aggressive subtype of acute myeloid leukemia","volume":"17","author":"Griffiths","year":"2025","journal-title":"mAbs"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3581","DOI":"10.1158\/1078-0432.CCR-25-0634","article-title":"Preclinical evaluation of DB-1419, a novel bifunctional and bispecific anti-B7-H3\u00d7PD-L1 antibody\u2013drug conjugate","volume":"31","author":"Li","year":"2025","journal-title":"Clin. Cancer Res."},{"key":"ref_31","first-page":"1253","article-title":"Preclinical characterization and phase I results of TQB2102, a first-in-class HER2 biparatopic antibody\u2013drug conjugate, in patients with advanced solid tumors","volume":"37","author":"Ruan","year":"2026","journal-title":"Ann. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1158\/1538-7445.AM2023-2642","article-title":"BL-B01D1, a novel EGFR\u00d7HER3-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation","volume":"83","author":"Wan","year":"2023","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3485","DOI":"10.1038\/s41591-025-03792-7","article-title":"A bispecific antibody\u2013drug conjugate targeting EGFR and HER3 in metastatic esophageal squamous cell carcinoma: A phase 1b trial","volume":"31","author":"Liu","year":"2025","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.annonc.2026.01.009","article-title":"Izalontamab brengitecan for patients with EGFR-mutated non-small-cell lung cancer: Pooled analysis of phase I and phase II trials","volume":"37","author":"Hong","year":"2026","journal-title":"Ann. Oncol."},{"key":"ref_35","first-page":"1045","article-title":"Izalontamab brengitecan in locally advanced or metastatic non-small-cell lung cancer with actionable genomic alterations outside classical EGFR mutations: A phase Ib study","volume":"44","author":"Zhou","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"28.","DOI":"10.1200\/JCO-26-00243","article-title":"Izalontamab brengitecan, a first-in-class EGFR\u2013HER3 bispecific antibody\u2013drug conjugate, in extensive-stage small-cell lung cancer: Results from a phase Ib study","volume":"44","author":"Zhao","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4008","DOI":"10.1200\/JCO.2026.44.16_suppl.4008","article-title":"Izalontamab brengitecan (iza-bren) versus chemotherapy in patients with recurrent or metastatic esophageal squamous cell carcinoma (ESCC): A multicenter, randomized, open-label, phase III study","volume":"44","author":"Lu","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"LBA1003","DOI":"10.1200\/JCO.2026.44.17_suppl.LBA1003","article-title":"Izalontamab brengitecan (iza-bren) versus physician\u2019s choice of chemotherapy in patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC): A randomized phase III study","volume":"44","author":"Wu","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1200\/JCO.2026.44.16_suppl.1123","article-title":"JSKN016, a first-in-class anti-TROP2\/HER3 bispecific antibody-drug conjugate (ADC), in patients (pts) with HER2-negative locally advanced or metastatic breast cancer: Results from a phase I study","volume":"44","author":"Yao","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Fisher, J.E. (2021). Considerations for the nonclinical safety evaluation of antibody\u2013drug conjugates. Antibodies, 10.","DOI":"10.3390\/antib10020015"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5667","DOI":"10.1038\/s41467-020-19498-y","article-title":"Co-administered antibody improves penetration of antibody\u2013dye conjugate into human cancers with implications for antibody\u2013drug conjugates","volume":"11","author":"Lu","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1007\/s11095-024-03715-0","article-title":"Optimizing solid tumor treatment with antibody\u2013drug conjugates using agent-based modeling: Considering the role of a carrier dose and payload class","volume":"41","author":"Calopiz","year":"2024","journal-title":"Pharm. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2403156","DOI":"10.1080\/19420862.2024.2403156","article-title":"A comparative study of the developability of full-length antibodies, fragments, and bispecific formats reveals higher stability risks for engineered constructs","volume":"16","author":"Dingfelder","year":"2024","journal-title":"mAbs"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"124085","DOI":"10.1016\/j.jchromb.2024.124085","article-title":"Identification and quantification of chain-pairing variants or mispaired species of asymmetric monovalent bispecific IgG1 monoclonal antibody format using reverse-phase polyphenyl chromatography coupled electrospray ionization mass spectrometry","volume":"1237","author":"Poskute","year":"2024","journal-title":"J. Chromatogr. B"},{"key":"ref_45","unstructured":"International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (2004). ICH Q5E: Comparability of Biotechnological\/Biological Products Subject to Changes in Their Manufacturing Process, ICH."},{"key":"ref_46","unstructured":"U.S. Food and Drug Administration (2024). Clinical Pharmacology Considerations for Antibody\u2013Drug Conjugates: Guidance for Industry."},{"key":"ref_47","unstructured":"U.S. Food and Drug Administration (2024). Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases: Guidance for Industry."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"eadk1894","DOI":"10.1126\/sciadv.adk1894","article-title":"Clinical translation of antibody drug conjugate dosing in solid tumors from preclinical mouse data","volume":"10","author":"Rubahamya","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1208\/s12248-021-00584-y","article-title":"Quantitative evaluation of the effect of antigen expression level on antibody\u2013drug conjugate exposure in solid tumor","volume":"23","author":"Bussing","year":"2021","journal-title":"AAPS J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1007\/s10928-013-9329-x","article-title":"On translation of antibody drug conjugates efficacy from mouse experimental tumors to the clinic: A PK\/PD approach","volume":"40","author":"Shah","year":"2013","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s10928-023-09884-6","article-title":"Towards a platform quantitative systems pharmacology model for preclinical-to-clinical translation of antibody drug conjugates","volume":"51","author":"Scheuher","year":"2024","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"ref_52","first-page":"325","article-title":"Tissue cross-reactivity studies of CPGJ701 in humans, cynomolgus monkeys and Sprague\u2013Dawley rats and correlation analysis with in vivo toxicity","volume":"8","author":"Qu","year":"2020","journal-title":"Transl. Cancer Res."},{"key":"ref_53","first-page":"189","article-title":"A case study of a bispecific antibody manufacturability assessment and optimization during discovery stage and its implications","volume":"7","author":"Wang","year":"2024","journal-title":"Antib. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8748\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:33:26Z","timestamp":1790760806000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8748"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":53,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198748"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198748","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]}}}