Bibliographic Details
| Title: |
Tumor targeted 4-1BB agonist antibody-albumin fusions with high affinity to FcRn induce anti-tumor immunity without toxicity |
| Authors: |
Oana Hangiu, Marta Compte, Anders Dinesen, Rocio Navarro, Antonio Tapia-Galisteo, Ole A. Mandrup, Ainhoa Erce-Llamazares, Rodrigo Lázaro-Gorines, Daniel Nehme-Álvarez, Carmen Domínguez-Alonso, Seandean L. Harwood, Carlos Alfonso, Belen Blanco, Laura Rubio-Pérez, Anaïs Jiménez-Reinoso, Laura Díez-Alonso, Francisco J. Blanco, Laura Sanz, Kenneth A. Howard, Luis Álvarez-Vallina |
| Source: |
iScience, Vol 25, Iss 9, Pp 104958- (2022) |
| Publisher Information: |
Elsevier, 2022. |
| Publication Year: |
2022 |
| Collection: |
LCC:Science |
| Subject Terms: |
Immunology, immunological methods, immune response, cancer, Science |
| More Details: |
Summary: 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. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2589-0042 |
| Relation: |
http://www.sciencedirect.com/science/article/pii/S2589004222012305; https://doaj.org/toc/2589-0042 |
| DOI: |
10.1016/j.isci.2022.104958 |
| Access URL: |
https://doaj.org/article/c486f101097e4624bed914bc95a337c3 |
| Accession Number: |
edsdoj.486f101097e4624bed914bc95a337c3 |
| Database: |
Directory of Open Access Journals |
