{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T08:00:40Z","timestamp":1790236840442,"version":"4.1.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Toxicol."],"abstract":"<jats:p>\n                    Antibody-drug conjugates (ADCs) enable tumor-specific drug delivery; however, target antigen-independent adverse events, including peripheral neuropathy, remain a significant clinical concern. The mechanisms underlying ADC-induced neurotoxicity, particularly the relationship between payload release and alterations in neuronal function, are not yet fully understood. In this study, we established an analytical platform that integrates microelectrode array (MEA) recordings using human induced pluripotent stem cell (iPSC)-derived sensory neurons with quantitative measurement of payload levels detected after ADC exposure under culture conditions, enabling functional evaluation of the direct effects of ADCs and their payloads on neuronal activity. The microtubule inhibitors monomethyl auristatin E (MMAE) and Lys-SMCC-DM1, when administered as free payloads, suppressed neuronal activity, as indicated by reduced firing rates, decreased spike amplitudes, together with neurite fragmentation. In contrast, their corresponding ADCs, brentuximab vedotin and trastuzumab emtansine, showed limited detectable effects on neuronal activity under the present experimental conditions. Conversely, the topoisomerase I inhibitor SN-38 enhanced neuronal activity, as evidenced by increased firing rates and spike amplitudes without marked morphological disruption. Similar functional changes were observed with sacituzumab govitecan. Furthermore, quantitative analysis revealed substantially higher measured payload levels at the 168-h endpoint following sacituzumab govitecan exposure than following brentuximab vedotin or trastuzumab emtansine exposure under the present experimental conditions. These findings suggest that the neuronal functional responses observed following ADC exposure may be associated with differences in measured payload levels and are consistent with the possibility of target antigen-independent effects. The integrated platform developed in this study enables quantitative assessment of neuronal functional responses to ADCs and payloads and may serve as a complementary tool for\n                    <jats:italic>in vitro<\/jats:italic>\n                    neurotoxicity evaluation during ADC design and development.\n                  <\/jats:p>","DOI":"10.3389\/ftox.2026.1855330","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T07:32:56Z","timestamp":1790235176000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated electrophysiological and payload-release assessment of neuronal responses to antibody-drug conjugates in human iPSC-derived sensory neurons: implications for in vitro neurotoxicity evaluation"],"prefix":"10.3389","volume":"8","author":[{"given":"Taeko","family":"Kuroda","sequence":"first","affiliation":[{"name":"Department of Electronics, Graduate School of Engineering, Tohoku Institute of Technology","place":["Sendai, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobo","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Electronics, Graduate School of Engineering, Tohoku Institute of Technology","place":["Sendai, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiki","family":"Mochizuki","sequence":"additional","affiliation":[{"name":"Global DMPK, Biopharmaceutical Assessment, DHBL, Eisai Co., Ltd.","place":["Tsukuba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuto","family":"Ishibashi","sequence":"additional","affiliation":[{"name":"Department of Electronics, Graduate School of Engineering, Tohoku Institute of Technology","place":["Sendai, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Goto","sequence":"additional","affiliation":[{"name":"Global Drug Safety, Biopharmaceutical Assessment, DHBL, Eisai Co., Ltd.","place":["Tsukuba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Seki","sequence":"additional","affiliation":[{"name":"Integrated ADMET Science, Biopharmaceutical Assessment, DHBL, Eisai Co., Ltd.","place":["Tsukuba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norimasa","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Electronics, Graduate School of Engineering, Tohoku Institute of Technology","place":["Sendai, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Yoshinaga","sequence":"additional","affiliation":[{"name":"Advanced Biosignal Safety Assessment, Biopharmaceutical Assessment, DHBL, Eisai Co., Ltd.","place":["Tsukuba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoji","family":"Asakura","sequence":"additional","affiliation":[{"name":"Global Drug Safety, Biopharmaceutical Assessment, DHBL, Eisai Co., Ltd.","place":["Tsukuba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuro","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Electronics, Graduate School of Engineering, Tohoku Institute of Technology","place":["Sendai, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"B1","volume-title":"L-Type Calcium Channels Link Oxidative Stress to Calcium Signaling Pathway and Membrane Excitability: Insights from Computational Modeling of Dopaminergic Neurons","author":"Andres","year":"2022"},{"key":"B2","doi-asserted-by":"publisher","first-page":"9182","DOI":"10.1039\/d2cs00446a","article-title":"Non-internalising antibody-drug conjugates","volume":"51","author":"Ashman","year":"2022","journal-title":"Chem. 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