Un inhibiteur ultra-sélectif de la Trypsine-3, conçu à partir de nanobodies, ouvre une nouvelle voie contre les métastases cancéreuses
La Trypsine-3, une protéase impliquée dans la progression tumorale et le mauvais pronostic des cancers, représente une cible thérapeutique prometteuse mais difficile à bloquer spécifiquement. Cette étude menée par l'équipe du Docteur Céline Deraison avec en étroite collaboration le docteur Aurélien Olichon (MCU DéTROI) a permis de développer le premier inhibiteur sélectif de la Trypsine-3 en utilisant une approche innovante : la combinaison de deux nanobodies humains synthétiques pour créer une molécule biphasique. Ce candidat-médicament montre :
Mots-clés : Trypsine-3, Nanobody, Inhibiteur de protéase, Métastases, Ingénierie thérapeutique.
- Une affinité et sélectivité exceptionnelles contre la Trypsine-3 in vitro
- Une capacité à inhiber la migration des cellules cancéreuses (lignée PC-3) ex vivo
Mots-clés : Trypsine-3, Nanobody, Inhibiteur de protéase, Métastases, Ingénierie thérapeutique.
Br J Pharmacol
2025 Jun 12.
doi: 10.1111/bph.70100. Online ahead of print.
Bispecific nanobody® as a new pharmacological drug for the selective inhibition of Trypsin-3
Melissa David 1, Anaïs Faihy 2, Corinne Rolland 1, Anissa Edir 1, Astrid Canivet 1, Laetitia Ligat 3, Mireille Sebbag 1, Nathalie Vergnolle 1 4, Aurélien Olichon 5, Céline Deraison 1Affiliations
Abstract :
Background and purpose: Proteolytic balance is dysregulated in many diseases, with proteases playing critical roles in pathological pathways. A high level of Trypsin-3 expression has been implicated as a significant mediator of tumour progression and metastasis, and this protease is associated with poor prognosis for patients in various cancers. Therefore, Trypsin-3 inhibition has emerged as a promising therapeutic target. However, no physiological or pharmacological inhibitor has yet been described that specifically targets Trypsin-3. A major challenge in developing a druggable inhibitor for this protease lies in achieving selectivity, as proteases belong to a large enzymatic family with close homologues that share similarities in the three-dimensional folding of their active conformation.
Experimental approach: An advanced screening strategy of a large library of synthetic humanised nanobodies was employed to isolate highly selective recombinant antibodies targeting the active conformation of Trypsin-3. Among five hits, we combined two domains with distinct paratopes and inhibitory mechanisms to generate a macrodrug candidate capable to efficiently block Trypsin-3 activity.
Key results: This bispecific nanobody demonstrated exceptionally high selectivity and affinity for Trypsin-3 in vitro, as well as a strong ability to inhibit cancer cell migration ex vivo for the PC-3 cancer cell line.
Conclusions and implications: This study underscores the versatility and potential of synthetic nanobody engineering in the development of highly selective protease inhibitors, paving the way for their consideration as drug candidates for clinical development.
Keywords: Trypsin‐3; nanobody® (registered term by SANOFI); protease inhibitor; single domain antibody.
- 1IRSD, UMR U1220, INSERM, INRAE, ENVT, Université de Toulouse, Toulouse, France.
- 2Centre de Recherches en Cancérologie de Toulouse (CRCT), UMR1037, Inserm, CNRS, Université de Toulouse, Toulouse, France.
- 3Le Pôle Technologique du Centre de Recherches en Cancérologie de Toulouse, plateau de protéomique, Toulouse, France.
- 4Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
- 5INSERM, UMR 1188 Diabète athérothrombose Thérapie Réunion Océan Indien (DéTROI), Université de La Réunion, Saint Pierre de La Réunion, France.
Abstract :
Background and purpose: Proteolytic balance is dysregulated in many diseases, with proteases playing critical roles in pathological pathways. A high level of Trypsin-3 expression has been implicated as a significant mediator of tumour progression and metastasis, and this protease is associated with poor prognosis for patients in various cancers. Therefore, Trypsin-3 inhibition has emerged as a promising therapeutic target. However, no physiological or pharmacological inhibitor has yet been described that specifically targets Trypsin-3. A major challenge in developing a druggable inhibitor for this protease lies in achieving selectivity, as proteases belong to a large enzymatic family with close homologues that share similarities in the three-dimensional folding of their active conformation.
Experimental approach: An advanced screening strategy of a large library of synthetic humanised nanobodies was employed to isolate highly selective recombinant antibodies targeting the active conformation of Trypsin-3. Among five hits, we combined two domains with distinct paratopes and inhibitory mechanisms to generate a macrodrug candidate capable to efficiently block Trypsin-3 activity.
Key results: This bispecific nanobody demonstrated exceptionally high selectivity and affinity for Trypsin-3 in vitro, as well as a strong ability to inhibit cancer cell migration ex vivo for the PC-3 cancer cell line.
Conclusions and implications: This study underscores the versatility and potential of synthetic nanobody engineering in the development of highly selective protease inhibitors, paving the way for their consideration as drug candidates for clinical development.
Keywords: Trypsin‐3; nanobody® (registered term by SANOFI); protease inhibitor; single domain antibody.