{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:42:54Z","timestamp":1785426174675,"version":"3.56.0"},"reference-count":31,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"BIDMC Chief Academic Officer Pilot Grant"},{"name":"NIH","award":["P01 CA92644"],"award-info":[{"award-number":["P01 CA92644"]}]},{"award":["P01 CA92644"],"award-info":[{"award-number":["P01 CA92644"]}],"id":[{"id":"https:\/\/ror.org\/044zkrt47","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Antibody\u2013drug conjugates (ADCs) are a promising therapeutic modality for treating cancer. TM4SF1 is an integral membrane protein that internalizes from the cell surface along microtubules to the nucleus and is highly expressed on the surface of both tumor endothelium and tumor cells. We previously reported that in human tumor xenografts in mice, an ADC directed to mouse TM4SF1 (2A7A-LP2) effectively regressed tumors through an anti-vascular mechanism, and an ADC directed to human TM4SF1 (v1.10-LP2) effectively regressed tumors through an anti-tumor cell mechanism. In this study, we investigated the actions of the mouse TM4SF1-directed ADC on VEGF-A-provoked angiogenic vessels. We employed an adenovirus expressing mouse VEGF-A164 (Ad-VEGF-A) to induce surrogate tumor blood vessels in the ears of nude mice. We showed that an immune effector function-ablated ADC, 3m2A7A-LP2, was better tolerated than its parent 2A7A-LP2. Homing of 3m2A7A to Ad-VEGF-A-induced new blood vessels became evident within six hours after intraperitoneal injection. A single dose of 3m2A7A-LP2 at 3 mg\/kg disrupted evolving Ad-VEGF-A-provoked blood vessels within forty-eight hours, and three doses of 3m2A7A-LP2 at 48 h intervals caused striking local ear necrosis; in each case, there was no apparent harm to vessels in the corresponding control virus-injected ears and the surrounding tissues of the same mice. Our studies demonstrate that an ADC-directed against mouse TM4SF1 specifically targeted the newly formed blood vessels induced by Ad-VEGF-A at multiple stages of their development. Thus, TM4SF1-directed ADCs, through their ability to target angiogenic vessels, represent an alternative anti-angiogenic approach for treating solid tumors.<\/jats:p>","DOI":"10.3390\/ijms27104437","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T14:40:31Z","timestamp":1779115231000},"page":"4437","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TM4SF1-Directed Antibody\u2013Drug Conjugates Selectively Destroy Newly Formed Blood Vessels Induced by VEGF-A"],"prefix":"10.3390","volume":"27","author":[{"given":"Chi-Iou","family":"Lin","sequence":"first","affiliation":[{"name":"Center for Vascular Biology Research, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02130, USA"},{"name":"Riverview Hospital, 395 Westfield Rd., Noblesville, IN 46060, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2004-4900","authenticated-orcid":false,"given":"Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Vascular Biology Research, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02130, USA"},{"name":"Department of Pharmacology, Shanxi Medical University, Xinjiannanlu 56, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey E.","family":"Sciuto","sequence":"additional","affiliation":[{"name":"Center for Vascular Biology Research, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02130, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Merley","sequence":"additional","affiliation":[{"name":"Center for Vascular Biology Research, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02130, USA"},{"name":"Center for Animal Resources and Education, Brown University, Providence, RI 02912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harold F.","family":"Dvorak","sequence":"additional","affiliation":[{"name":"Center for Vascular Biology Research, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02130, USA"},{"name":"Angiex Inc., Cambridge, MA 02140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6358-7574","authenticated-orcid":false,"given":"Shou-Ching S.","family":"Jaminet","sequence":"additional","affiliation":[{"name":"Center for Vascular Biology Research, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02130, USA"},{"name":"Angiex Inc., Cambridge, MA 02140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1055\/s-0030-1253454","article-title":"Heterogeneity of the tumor vasculature","volume":"36","author":"Nagy","year":"2010","journal-title":"Semin. 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