{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:15:53Z","timestamp":1790741753619,"version":"4.1.0"},"reference-count":44,"publisher":"American Society of Hematology","issue":"21","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,11,20]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>von Willebrand disease (VWD) type 1 is a bleeding disorder characterized by a quantitative deficiency of functional von Willebrand factor (VWF). We designed a novel bispecific nanobody, named KB-V13A12, that aims to increase endogenous VWF levels by bridging it to albumin. KB-V13A12 comprises 2 single-domain antibodies, 1 targeting VWF and 1 targeting albumin. VWF bound efficiently to the albumin\/KB-V13A12 complex (2.0 \u00b1 0.4 nM) in immunosorbent assays, and binding was stable at pH 5.6 and 7.4. VWF ristocetin activity and factor VIII binding remained unaffected in the presence of a 100- to 200-fold molar excess of KB-V13A12\/albumin. Humanized VWD type 1 mice were used for in vivo analysis. A single subcutaneous dose of KB-V13A12 (5 mg\/kg) was associated with a nanobody half-life of 3.0 \u00b1 0.7 days, and dose-dependently increased VWF in VWD type 1 mice 1.4- to 2.1-fold for up to 14 days. Factor VIII activity was also increased during this period. The VWF propeptide\/VWF antigen ratio (a marker for VWF clearance) was significantly reduced in the presence of KB-V13A12, suggesting that delayed clearance contributes to increased VWF levels. Clearance experiments in wild-type mice using recombinant VWF preincubated with KB-V13A12 indeed confirmed a prolonged survival, while this prolongation was absent in FcRn-deficient mice. Finally, treatment with KB-V13A12 resulted in a significantly improved bleeding tendency in VWD type 1 mice when using the saphenous vein puncture model. In conclusion, KB-V13A12 is a bispecific nanobody that efficiently increases functional levels of endogenous VWF, and could be a therapeutic option to treat VWD type 1.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025029401","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T19:24:06Z","timestamp":1757013846000},"page":"2597-2607","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":12,"title":["A bispecific nanobody for the treatment of von Willebrand disease type 1"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3843-642X","authenticated-orcid":false,"given":"Ivan","family":"Peyron","sequence":"first","affiliation":[{"name":"1H\u00e9mostase Inflammation Thrombose U1176, INSERM, Universit\u00e9 Paris-Saclay, Le Kremlin-Bic\u00eatre, 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