Randomized phase I trial outcomes show safe and sustainable inhibition of classical and lectin complement pathways by empasiprubart
Abstract Activation of classical and lectin complement pathways contributes to several human diseases. Empasiprubart is a humanized recycling monoclonal antibody that inhibits both pathways by binding to the CCP2 domain of complement factor 2 (C2), an interaction that is dependent on both Ca2+ and p...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62925-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849329659415625728 |
|---|---|
| author | Inge Van de Walle Laura Bracke Heidi Gytz Olesen Tonke van Bragt Stéphanie Cadour Phillip De Decker Giorgia Ciurlia Erwin Pannecoucke Emma K. Persson Olivier Van de Steen Xinghong Leng Gregers Rom Andersen Domenica Gandini C. Erik Hack |
| author_facet | Inge Van de Walle Laura Bracke Heidi Gytz Olesen Tonke van Bragt Stéphanie Cadour Phillip De Decker Giorgia Ciurlia Erwin Pannecoucke Emma K. Persson Olivier Van de Steen Xinghong Leng Gregers Rom Andersen Domenica Gandini C. Erik Hack |
| author_sort | Inge Van de Walle |
| collection | DOAJ |
| description | Abstract Activation of classical and lectin complement pathways contributes to several human diseases. Empasiprubart is a humanized recycling monoclonal antibody that inhibits both pathways by binding to the CCP2 domain of complement factor 2 (C2), an interaction that is dependent on both Ca2+ and pH. Here, we resolve the crystal structure of empasiprubart complexed with C2, providing the molecular basis of its Ca2+ dependency, and report a randomized, double-blind, placebo-controlled trial to assess the safety and tolerability (primary objectives) in addition to pharmacokinetics, pharmacodynamics, and immunogenicity (secondary objectives) of empasiprubart in 78 healthy participants (NCT04532125). A single intravenous (IV) dose of empasiprubart reduces circulating C2 levels by up to 99% and dose-dependently inhibits the classical and lectin pathways. Multiple IV empasiprubart doses reinforce reductions in free C2 levels, which persist until the endpoint of the study at 41 weeks. This prolonged reduction is in line with the empasiprubart elimination half-life (70–88 days). Single and multiple ascending doses of empasiprubart are generally safe and well tolerated. Overall, our results reveal in atomic detail the mechanism of empasiprubart and demonstrate that it is a first-in-class anti-C2 therapeutic antibody for use in complement-mediated diseases. |
| format | Article |
| id | doaj-art-ec939bfa9eb44ec4b3703c20fa33a631 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ec939bfa9eb44ec4b3703c20fa33a6312025-08-20T03:47:12ZengNature PortfolioNature Communications2041-17232025-08-0116111510.1038/s41467-025-62925-1Randomized phase I trial outcomes show safe and sustainable inhibition of classical and lectin complement pathways by empasiprubartInge Van de Walle0Laura Bracke1Heidi Gytz Olesen2Tonke van Bragt3Stéphanie Cadour4Phillip De Decker5Giorgia Ciurlia6Erwin Pannecoucke7Emma K. Persson8Olivier Van de Steen9Xinghong Leng10Gregers Rom Andersen11Domenica Gandini12C. Erik Hack13argenxargenxDepartment of Molecular Biology and Genetics - Protein ScienceCurare Consulting BVargenxargenxargenxargenxargenxargenxargenxDepartment of Molecular Biology and Genetics - Protein ScienceargenxargenxAbstract Activation of classical and lectin complement pathways contributes to several human diseases. Empasiprubart is a humanized recycling monoclonal antibody that inhibits both pathways by binding to the CCP2 domain of complement factor 2 (C2), an interaction that is dependent on both Ca2+ and pH. Here, we resolve the crystal structure of empasiprubart complexed with C2, providing the molecular basis of its Ca2+ dependency, and report a randomized, double-blind, placebo-controlled trial to assess the safety and tolerability (primary objectives) in addition to pharmacokinetics, pharmacodynamics, and immunogenicity (secondary objectives) of empasiprubart in 78 healthy participants (NCT04532125). A single intravenous (IV) dose of empasiprubart reduces circulating C2 levels by up to 99% and dose-dependently inhibits the classical and lectin pathways. Multiple IV empasiprubart doses reinforce reductions in free C2 levels, which persist until the endpoint of the study at 41 weeks. This prolonged reduction is in line with the empasiprubart elimination half-life (70–88 days). Single and multiple ascending doses of empasiprubart are generally safe and well tolerated. Overall, our results reveal in atomic detail the mechanism of empasiprubart and demonstrate that it is a first-in-class anti-C2 therapeutic antibody for use in complement-mediated diseases.https://doi.org/10.1038/s41467-025-62925-1 |
| spellingShingle | Inge Van de Walle Laura Bracke Heidi Gytz Olesen Tonke van Bragt Stéphanie Cadour Phillip De Decker Giorgia Ciurlia Erwin Pannecoucke Emma K. Persson Olivier Van de Steen Xinghong Leng Gregers Rom Andersen Domenica Gandini C. Erik Hack Randomized phase I trial outcomes show safe and sustainable inhibition of classical and lectin complement pathways by empasiprubart Nature Communications |
| title | Randomized phase I trial outcomes show safe and sustainable inhibition of classical and lectin complement pathways by empasiprubart |
| title_full | Randomized phase I trial outcomes show safe and sustainable inhibition of classical and lectin complement pathways by empasiprubart |
| title_fullStr | Randomized phase I trial outcomes show safe and sustainable inhibition of classical and lectin complement pathways by empasiprubart |
| title_full_unstemmed | Randomized phase I trial outcomes show safe and sustainable inhibition of classical and lectin complement pathways by empasiprubart |
| title_short | Randomized phase I trial outcomes show safe and sustainable inhibition of classical and lectin complement pathways by empasiprubart |
| title_sort | randomized phase i trial outcomes show safe and sustainable inhibition of classical and lectin complement pathways by empasiprubart |
| url | https://doi.org/10.1038/s41467-025-62925-1 |
| work_keys_str_mv | AT ingevandewalle randomizedphaseitrialoutcomesshowsafeandsustainableinhibitionofclassicalandlectincomplementpathwaysbyempasiprubart AT laurabracke randomizedphaseitrialoutcomesshowsafeandsustainableinhibitionofclassicalandlectincomplementpathwaysbyempasiprubart AT heidigytzolesen randomizedphaseitrialoutcomesshowsafeandsustainableinhibitionofclassicalandlectincomplementpathwaysbyempasiprubart AT tonkevanbragt randomizedphaseitrialoutcomesshowsafeandsustainableinhibitionofclassicalandlectincomplementpathwaysbyempasiprubart AT stephaniecadour randomizedphaseitrialoutcomesshowsafeandsustainableinhibitionofclassicalandlectincomplementpathwaysbyempasiprubart AT phillipdedecker randomizedphaseitrialoutcomesshowsafeandsustainableinhibitionofclassicalandlectincomplementpathwaysbyempasiprubart AT giorgiaciurlia randomizedphaseitrialoutcomesshowsafeandsustainableinhibitionofclassicalandlectincomplementpathwaysbyempasiprubart AT erwinpannecoucke randomizedphaseitrialoutcomesshowsafeandsustainableinhibitionofclassicalandlectincomplementpathwaysbyempasiprubart AT emmakpersson randomizedphaseitrialoutcomesshowsafeandsustainableinhibitionofclassicalandlectincomplementpathwaysbyempasiprubart AT oliviervandesteen randomizedphaseitrialoutcomesshowsafeandsustainableinhibitionofclassicalandlectincomplementpathwaysbyempasiprubart AT xinghongleng randomizedphaseitrialoutcomesshowsafeandsustainableinhibitionofclassicalandlectincomplementpathwaysbyempasiprubart AT gregersromandersen randomizedphaseitrialoutcomesshowsafeandsustainableinhibitionofclassicalandlectincomplementpathwaysbyempasiprubart AT domenicagandini randomizedphaseitrialoutcomesshowsafeandsustainableinhibitionofclassicalandlectincomplementpathwaysbyempasiprubart AT cerikhack randomizedphaseitrialoutcomesshowsafeandsustainableinhibitionofclassicalandlectincomplementpathwaysbyempasiprubart |