📇 Rhumatologue · PAU · (64) · Libéral

M CHRISTOPHE MAJESTE-LASSALLE

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Auteur de référence en rhumatologie
25 articles scientifiques publiés — un praticien à la pointe de la recherche
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Rhumatologue

📍 PAU (64)LibéralRPPS 10101558962

✨ Génération du profil synthétique IA en cours…

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Top publications · les plus citées

A fully humanized von Willebrand disease type 1 mouse model as unique platform to investigate novel therapeutic options

Haematologica · 2025

📚 9 citations🎯 RCR 3.93🔓 Open Access📄 PDF gratuit ↗

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Patients suffering from von Willebrand disease (VWD) have reduced quality-of-life despite current treatment options. Moreover, innovation in VWD therapeutic strategies has essentially stalled, and available treatments have remained unchanged for decades. Therefore, there is an unmet need to develop new therapeutic strategies for VWD patients, especially for the large portion of those with VWD-type 1. Due to species differences, the available VWD murine models are not suitable for preclinical studies, making it difficult to test new therapeutic approaches in vivo. With this in mind, we generated mice selectively expressing human von Willebrand factor (VWF) and human GPIbα. Because this fully humanized model was found to express low VWF (12%) and factor VIII (FVIII) (40%) levels with normal multimer profile and activity/antigen ratio, we repositioned it as a VWD-type 1 model (hVWD1 mice). In depth characterization of this model confirmed VWD-type 1 features with a decrease in platelet adhesion and thrombus formation in vitro. In vivo, a moderate bleeding phenotype was observed which was corrected upon the administration of recombinant-VWF or upon histamine-induced release of endothelial VWF. In search of new therapeutic options for VWD, we designed a bispecific single-domain antibody that bridges VWF to albumin (KB-V13A12). Remarkably, a single subcutaneous administration of KB-V13A12 coincided with a sustained 2-fold increase in VWF antigen levels for up to ten days and normalized hemostasis in a tail-clip model in hVWD1 mice. Here, we describe the development of our unique humanized mouse model for VWD-type 1 and a promising new therapeutic that corrected hemostasis in these mice.

A bispecific nanobody for the treatment of von Willebrand disease type 1

Blood · 2025

📚 4 citations🔓 Open Access

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Abstract 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 ± 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 ± 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.

Genetics in medicine : official journal of the American College of Medical Genetics · 2025

📚 4 citations🔓 Open Access

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M CHRISTOPHE MAJESTE-LASSALLE

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Top publications · les plus citées

Publications scientifiques (25) — classées par pathologie

Transversal11

Essai clinique3

Épidémiologie & registres2

Pédiatrie2

Pharmacovigilance2

Qualité de vie / PROMs2

Revue / méta-analyse2

Revue générale2

Case report / série1

Lupus1

Santé mentale / fatigue1

SAPL1

Vascularites des gros vaisseaux1

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