Programmable half-life and anti-tumour effects of bispecific T-cell engager-albumin fusions with tuned FcRn affinity

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  • Ole A Mandrup
  • Sui Ching Ong, Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus University, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • ,
  • Simon Lykkemark
  • ,
  • Anders Dinesen
  • Imke Rudnik-Jansen
  • Niels Frederik Dagnæs-Hansen
  • ,
  • Jan Terje Andersen, Oslo University Hospital, National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital, Oslo, Norway; Cancer Registry of Norway, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: sdf@ous-hf.no., Oslo University Hospital-Rikshospitalet, Department of Neuroscience and Pharmacology, Panum Institute, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine and Department of Nuclear Medicine, University of Southern Denmark, Odense, Denmark.
  • ,
  • Luis Alvarez-Vallina, Cancer Immunotherapy Unit (UNICA), IVI Madrid, Madrid, Spain., Immuno-Oncology and Immunotherapy Group
  • ,
  • Kenneth A Howard

Fc-less bispecific T-cell engagers have reached the immuno-oncology market but necessitate continual infusion due to rapid clearance from the circulation. This work introduces a programmable serum half-life extension platform based on fusion of human albumin sequences engineered with either null (NB), wild type (WT) or high binding (HB) FcRn affinity combined with a bispecific T-cell engager. We demonstrate in a humanised FcRn/albumin double transgenic mouse model (AlbuMus) the ability to tune half-life based on the albumin sequence fused with a BiTE-like bispecific (anti-EGFR nanobody x anti-CD3 scFv) light T-cell engager (LiTE) construct [(t½ 0.6 h (Fc-less LiTE), t½ 19 hours (Albu-LiTE-NB), t½ 26 hours (Albu-LiTE-WT), t½ 37 hours (Albu-LiTE-HB)]. We show in vitro cognate target engagement, T-cell activation and discrimination in cellular cytotoxicity dependent on EGFR expression levels. Furthermore, greater growth inhibition of EGFR-positive BRAF mutated tumours was measured following a single dose of Albu-LiTE-HB construct compared to the Fc-less LiTE format and a full-length anti-EGFR monoclonal antibody in a new AlbuMus RAG1 knockout model introduced in this work. Programmable half-life extension facilitated by this albumin platform potentially offers long-lasting effects, better patient compliance and a method to tailor pharmacokinetics to maximise therapeutic efficacy and safety of immuno-oncology targeted biologics.

Original languageEnglish
Article number310
JournalCommunications Biology
Volume4
Issue1
Number of pages11
DOIs
Publication statusPublished - Mar 2021

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