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Tumor targeted 4-1BB agonist antibody-albumin fusions with high affinity to FcRn induce anti-tumor immunity without toxicity
Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review
DOI
- https://doi.org/10.1016/j.isci.2022.104958
Forlagets udgivne version
- Oana Hangiu, Hospital Universitario 12 de Octubre, Leadartis S.L. ,
- Marta Compte, Leadartis S.L. ,
- Anders Dinesen
- Rocio Navarro, Leadartis S.L. ,
- Antonio Tapia-Galisteo, Hospital Universitario 12 de Octubre ,
- Ole A. Mandrup
- Ainhoa Erce-Llamazares, Hospital Universitario 12 de Octubre ,
- Rodrigo Lázaro-Gorines, Hospital Universitario 12 de Octubre ,
- Daniel Nehme-Álvarez, Hospital Universitario 12 de Octubre ,
- Carmen Domínguez-Alonso, Hospital Universitario 12 de Octubre ,
- Seandean L. Harwood
- Carlos Alfonso, CSIC - Biological Research Center ,
- Belen Blanco, Hospital Universitario 12 de Octubre ,
- Laura Rubio-Pérez, Hospital Universitario 12 de Octubre, Francisco de Vitoria University ,
- Anaïs Jiménez-Reinoso, Hospital Universitario 12 de Octubre ,
- Laura Díez-Alonso, Hospital Universitario 12 de Octubre ,
- Francisco J. Blanco, CSIC - Biological Research Center ,
- Laura Sanz, Universidad Autónoma de Madrid ,
- Kenneth A. Howard
- Luis Álvarez-Vallina, Hospital Universitario 12 de Octubre, Francisco de Vitoria University, Instituto de Salud Carlos III
Costimulation of tumor-infiltrating T lymphocytes by anti-4-1BB monoclonal antibodies (mAbs) has shown anti-tumor activity in human trials, but can be associated with significant off-tumor toxicities involving FcγR interactions. Here, we introduce albumin-fused mouse and human bispecific antibodies with clinically favorable pharmacokinetics designed to confine 4-1BB costimulation to the tumor microenvironment. These Fc-free 4-1BB agonists consist of an EGFR-specific VHH antibody, a 4-1BB-specific scFv, and a human albumin sequence engineered for high FcRn binding connected in tandem (LiTCo-Albu). We demonstrate in vitro cognate target engagement, EGFR-specific costimulatory activity, and FcRn-driven cellular recycling similar to non-fused FcRn high-binding albumin. The mouse LiTCo-Albu exhibited a prolonged circulatory half-life and in vivo tumor inhibition, with no indication of 4-1BB mAb-associated toxicity. Furthermore, we show a greater therapeutic effect when used in combination with PD-1-blocking mAbs. These findings demonstrate the feasibility of tumor-specific LiTCo-Albu antibodies for safe and effective costimulatory strategies in cancer immunotherapy.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 104958 |
| Tidsskrift | iScience |
| Vol/bind | 25 |
| Nummer | 9 |
| ISSN | 2589-0042 |
| DOI | |
| Status | Udgivet - 16 sep. 2022 |
Bibliografisk note
Publisher Copyright:
© 2022 The Author(s)
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