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The anti-mesothelin single-domain antibody (sdAb, or \u201cnanobody\n                      <jats:sup>\u00ae<\/jats:sup>\n                      \u201d) DOTA-A1K2, previously validated for positron emission tomography (PET) imaging using site-specific\n                      <jats:sup>68<\/jats:sup>\n                      Ga radiolabeling, may also serve as a radio-theranostic agent when labeled with\n                      <jats:sup>177<\/jats:sup>\n                      Lu. Moreover,\n                      <jats:sup>161<\/jats:sup>\n                      Tb has recently been proposed as an alternative to\n                      <jats:sup>177<\/jats:sup>\n                      Lu that might provide additional efficacy due to the emission of Auger electrons. The aim of this study was to evaluate\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      the therapeutic effect of [\n                      <jats:sup>177<\/jats:sup>\n                      Lu]Lu-DOTA-A1K2 and [\n                      <jats:sup>161<\/jats:sup>\n                      Tb]Tb-DOTA-A1K2.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Biodistribution was assessed in mice from 1 to 168\u00a0h post-injection. Therapeutic efficacy was tested using MDA-MB-231 TNBC cells transfected or not with MSLN. Clonogenic assays were performed after 24\u00a0h incubation with either radiotracer.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , efficacy was evaluated over 9 weeks after a single intravenous injection of 2, 5, 10, or 20 MBq.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      DOTA-A1K2 was successfully radiolabeled with both isotopes with RCP\u2009&gt;\u200995%.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , [\n                      <jats:sup>161<\/jats:sup>\n                      Tb]Tb-DOTA-A1K2 was significantly more potent than [\n                      <jats:sup>177<\/jats:sup>\n                      Lu]Lu-DOTA-A1K2 in inhibiting colony formation (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01).\n                      <jats:italic>In vivo<\/jats:italic>\n                      in mice, the radiotracers exhibited similar biodistribution profiles. The administration of 5, 10 or 20 MBq of either [\n                      <jats:sup>177<\/jats:sup>\n                      Lu]Lu-DOTA-A1K2 or [\n                      <jats:sup>161<\/jats:sup>\n                      Tb]Tb-DOTA-A1K2 inhibited tumor growth compared to controls (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01 vs. vehicle), while no effect was observed at 2 MBq (p\u2009=\u2009NS). However, no differences in efficacy were observed between the two isotopes at any dose.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This work provides the first sdAb-based theranostic approach targeting mesothelin-positive tumors.\n                      <jats:italic>In vivo<\/jats:italic>\n                      in mice, both [\n                      <jats:sup>177<\/jats:sup>\n                      Lu]Lu-DOTA-A1K2 and [\n                      <jats:sup>161<\/jats:sup>\n                      Tb]Tb-DOTA-A1K2 accumulated in tumors.\n                      <jats:italic>In vivo<\/jats:italic>\n                      efficacy was found to be comparable, despite the superior\n                      <jats:italic>in vitro<\/jats:italic>\n                      efficacy of\n                      <jats:sup>161<\/jats:sup>\n                      Tb. Further studies are warranted to clarify this discrepancy, which could potentially result from mesothelin shedding that prevents Auger electrons from reaching tumor cells.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00259-025-07723-z","type":"journal-article","created":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T01:11:03Z","timestamp":1766797863000},"page":"3775-3788","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparative theranostic efficacy of 177Lu- and 161Tb-labeled A1K2 SdAb in mesothelin-positive tumors"],"prefix":"10.1007","volume":"53","author":[{"given":"\u00c9milien","family":"N\u2019Guessan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Raes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitra","family":"Ahmadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Bacot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Dumas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Leenhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amaury","family":"du Moulinet d\u2019Hardemare","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marl\u00e8ne","family":"Debiossat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e9mence","family":"Andr\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Boutonnat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Durivault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Montemagno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Luc","family":"Lenormand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lo\u00efc","family":"Dja\u00efleb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulli","family":"K\u00f6ster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiel","family":"Van de Voorde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stijn","family":"Ramaekers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Verguts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Ghezzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Perret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Lombardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4265-8463","authenticated-orcid":false,"given":"Alexis","family":"Broisat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,27]]},"reference":[{"key":"7723_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9040397","volume":"9","author":"S Weidemann","year":"2021","unstructured":"Weidemann S, Gagelmann P, Gorbokon N, Lennartz M, Menz A, Luebke AM, et al. 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