{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:23:04Z","timestamp":1792606984099,"version":"4.5.0"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T00:00:00Z","timestamp":1713312000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Many oncology antibody-drug conjugates (ADCs) have failed to demonstrate efficacy in clinic because of dose-limiting toxicity caused by uptake into healthy tissues. We developed an approach that harnesses ADC affinity to broaden the therapeutic index (TI) using two anti-mesenchymal-epithelial transition factor (MET) monoclonal antibodies (mAbs) with high affinity (HAV) or low affinity (LAV) conjugated to monomethyl auristatin E (MMAE). The estimated TI for LAV-ADC was at least 3 times greater than the HAV-ADC. The LAV- and HAV-ADCs showed similar levels of anti-tumor activity in the xenograft model, while the <jats:sup>111<\/jats:sup>In-DTPA studies showed similar amounts of the ADCs in HT29 tumors. Although the LAV-ADC has ~2-fold slower blood clearance than the HAV-ADC, higher liver toxicity was observed with HAV-ADC. While the SPECT\/CT <jats:sup>111<\/jats:sup>In- and <jats:sup>124<\/jats:sup>I- DTPA findings showed HAV-ADC has higher accumulation and rapid clearance in normal tissues, intravital microscopy (IVM) studies confirmed HAV mAb accumulates within hepatic sinusoidal endothelial cells while the LAV mAb does not. These results demonstrated that lowering the MET binding affinity provides a larger TI for MET-ADC. Decreasing the affinity of the ADC reduces the target mediated drug disposition (TMDD) to MET expressed in normal tissues while maintaining uptake\/delivery to the tumor. This approach can be applied to multiple ADCs to improve the clinical outcomes.<\/jats:p>","DOI":"10.1371\/journal.pone.0293703","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T17:36:29Z","timestamp":1713375389000},"page":"e0293703","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":20,"title":["Reducing target binding affinity improves the therapeutic index of anti-MET antibody-drug conjugate in tumor bearing animals"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2365-5360","authenticated-orcid":true,"given":"Amita","family":"Datta-Mannan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiuwan","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyan","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jirong","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Stokell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony T.","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth W.","family":"Dunn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle M.","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqing","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,4,17]]},"reference":[{"issue":"10200","key":"pone.0293703.ref001","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/S0140-6736(19)31774-X","article-title":"Antibody-drug conjugates for cancer","volume":"394","author":"CH Chau","year":"2019","journal-title":"Lancet"},{"issue":"1","key":"pone.0293703.ref002","article-title":"Antibody Conjugates-Recent Advances and Future Innovations","volume":"9","author":"D Leung","year":"2020","journal-title":"Antibodies (Basel)"},{"issue":"4","key":"pone.0293703.ref003","article-title":"Delivery of Drugs into Cancer Cells Using Antibody-Drug Conjugates Based on Receptor-Mediated Endocytosis and the Enhanced Permeability and Retention Effect","volume":"11","author":"T. 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