{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T10:10:59Z","timestamp":1771495859555,"version":"3.50.1"},"reference-count":52,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"publisher","award":["075-15-2024-536"],"award-info":[{"award-number":["075-15-2024-536"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Despite the clinical success of antibody\u2013drug conjugates (ADCs), their efficacy in solid tumors remains constrained by limited tumor penetration of the IgG format. Smaller antibody fragment\u2013drug conjugates (FDCs) present a compelling alternative, potentially offering superior intratumoral distribution and a wider therapeutic window driven by rapid systemic clearance. This study compares therapeutic activity of ganglioside GD2-specific minibody\u2013drug conjugates against full-length ch14.18 antibody\u2013drug conjugates, and biodistribution of the respective minibody (scFv-CH3 homodimer) and IgG formats in the GD2-positive B78-D14 melanoma syngeneic mouse model. We conjugated the minibody and antibody with MMAE or MMAF via a cathepsin-cleavable linker, generating FDCs with drug\u2013antibody ratio (DAR) of 2 and ADCs with DAR of 2 or 4. The biodistribution analysis showed no significant difference in tumor uptake for both formats early in the analysis (2\u20134 h) and a higher tumor uptake for the IgG at 24 h post-injection. However, the minibody achieved a superior tumor-to-blood ratio (TBR) at all timepoints, reaching a TBR &gt; 1 compared to ~0.2 for the antibody by 24 h. In vitro studies demonstrated higher cytotoxicity for the ADCs regardless of drug load (DAR 2 or 4) compared to the FDCs, although the difference between conjugates with equal DAR was modest in B78-D14 cells. Critically, superior in vitro ADC potency did not translate in vivo. Minibody\u2013MMAF and minibody\u2013MMAE achieved 74% and 55% tumor growth inhibition, respectively, by the study endpoint\u2014demonstrating comparable efficacy to ADCs with twice the drug load when administered to mice at equimass dosing. Stron\/g in vivo efficacy of anti-GD2 FDCs, combined with the superior TBR for the minibody format, underscores the potential of minibody\u2013drug conjugates for treating GD2-positive tumors, particularly when ADC-associated toxicity precludes high-dose regimens.<\/jats:p>","DOI":"10.3390\/ijms27041974","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T08:51:09Z","timestamp":1771491069000},"page":"1974","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GD2-Targeted Minibody\u2013Drug Conjugates Match the Potency of IgG-Based ADCs in a Mouse Cancer Model"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8773-2797","authenticated-orcid":false,"given":"Daniel V.","family":"Kalinovsky","sequence":"first","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matvey M.","family":"Titov","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4079-5210","authenticated-orcid":false,"given":"Irina V.","family":"Kholodenko","sequence":"additional","affiliation":[{"name":"Orekhovich Institute of Biomedical Chemistry, Moscow 119121, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexey V.","family":"Kibardin","sequence":"additional","affiliation":[{"name":"D. Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117997, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena V.","family":"Svirshchevskaya","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3952-0631","authenticated-orcid":false,"given":"Sergey M.","family":"Deyev","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia"},{"name":"Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia"},{"name":"Federal Center for Biotechnology and Medicine Advancement, National Research Ogarev Mordovia State University, Saransk 430005, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6083-6588","authenticated-orcid":false,"given":"Roman V.","family":"Kholodenko","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia"},{"name":"Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wu, D., Yang, K., He, R., Yin, R., and Shui, L. 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