2. Academic Validation
  3. Brain Shuttle Antibody for Alzheimer's Disease with Attenuated Peripheral Effector Function due to an Inverted Binding Mode

Brain Shuttle Antibody for Alzheimer's Disease with Attenuated Peripheral Effector Function due to an Inverted Binding Mode

  • Cell Rep. 2018 Jan 2;22(1):149-162. doi: 10.1016/j.celrep.2017.12.019.
Felix Weber 1,  Bernd Bohrmann 2,  Jens Niewoehner 3,  Jens A A Fischer 3,  Petra Rueger 3,  Georg Tiefenthaler 3,  Joerg Moelleken 3,  Alexander Bujotzek 3,  Kevin Brady 1,  Thomas Singer 1,  Martin Ebeling 1,  Antonio Iglesias 4,  Per-Ola Freskgård 5
Affiliations

Affiliations

  • 1 Pharma Research and Early Development (pRED), Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland.
  • 2 Pharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center, Basel, Switzerland.
  • 3 Pharma Research and Early Development (pRED), Therapeutic Modalities, Large Molecule Research, Roche Innovation Center, Munich, Germany.
  • 4 Pharma Research and Early Development (pRED), Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland. Electronic address: antonio.iglesias@roche.com.
  • 5 Pharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center, Basel, Switzerland. Electronic address: per-ola.freskgard@roche.com.
PMID: 29298417 DOI: 10.1016/j.celrep.2017.12.019
Abstract

Receptors show promise for the transport of monoclonal Antibodies (mAbs) across the blood-brain barrier. However, safety liabilities associated with peripheral receptor binding and Fc effector function have been reported. We present the Brain Shuttle-mAb (BS-mAb) technology, and we investigate the role of Fc effector function in vitro and in an Fcγ receptor (FcγR)-humanized mouse model. Strong first infusion reactions (FIRs) were observed for a conventional mAb against Transferrin Receptor (TfR) with a wild-type immunoglobulin G1 (IgG1) Fc. Fc effector-dead constructs completely eliminated all FIRs. Remarkably, no FIR was observed for the BS-mAb construct with a native IgG1 Fc function. Using various BS-mAb constructs, we show that TfR binding through the C-terminal BS module attenuates Fc-FcγR interactions, primarily because of steric hindrance. Nevertheless, BS-mAbs maintain effector function activity when binding their brain target. Thus, mAbs with full effector function can be transported in a stealth mode in the periphery while fully active when engaged with their brain target.

Keywords

Alzheimer’s disease; Brain Shuttle; antibody effector function; antibody engineering; blood-brain barrier; brain delivery.

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