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Tumor targeted 4-1BB agonist antibody-albumin fusions with high affinity to FcRn induce anti-tumor immunity without toxicity

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  • 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
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  • 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.

Original languageEnglish
Article number104958
JournaliScience
Volume25
Issue9
ISSN2589-0042
DOIs
Publication statusPublished - 16 Sep 2022

Bibliographical note

Funding Information:
Financial support for this work was obtained from the MCIN/ AEI / 10.13039/501100011033 ( SAF2017-89437-P and PDC2021-121711-100 to LA-V, PID2019-104544GB-I00 to CA, and PID2020-113225GB-I00 to FJB), partially supported by the European Regional Development Fund (ERDF); the Carlos III Health Institute (ISCIII) ( PI19/00132 to LS; PI20/01030 to BB), partially supported by the ERDF; the ISCIII-RICORS within the Next Generation EU program (plan de Recuperación, Transformación y Resilencia); the Spanish Association Against Cancer ( AECC 19084 to LA-V); the CRIS Cancer Foundation ( FCRIS-2018-0042 and FCRIS-2021-0090 to LA-V), the BBVA Foundation (Ayudas Fundación BBVA a Equipos de Investigación Científica SARS-CoV-2 years COVID-19 to LA-V); and the Fundació “La Caixa” ( HR21-00761 project IL7R_LungCan to LA-V). AD, OAM, and KAH were funded by the Novo Nordisk Foundation , Grant; CEMBID (Center for Multifunctional Biomolecular Drug Design, Grant Number: NNF17OC0028070 ). OH was supported by an industrial PhD fellowship from the Comunidad de Madrid ( IND2020/BMD-17668 ). AE-L was supported industrial PhD fellowship from the Carlos III Health Institute ( IFI18/00045 ). CD-A was supported by a predoctoral fellowship from the Spanish Ministry of Science Innovation and Universities ( PRE2018-083445 ). LR-P was supported by a predoctoral fellowship from the Immunology Chair, Universidad Francisco de Vitoria /Merck. LD-A was supported by a Rio Hortega fellowship from the Carlos III Health Institute ( CM20/00004 ).

Publisher Copyright:
© 2022 The Author(s)

    Research areas

  • cancer, immune response, immunological methods, Immunology

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