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Nanobodies as Modulators of Inflammation: Potential Applications for Acute Brain Injury

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Nanobodies as Modulators of Inflammation: Potential Applications for Acute Brain Injury

Björn Rissiek et al. Front Cell Neurosci.

Abstract

Nanobodies are single domain antibodies derived from llama heavy-chain only antibodies (HCAbs). They represent a new generation of biologicals with unique properties: nanobodies show excellent tissue distribution, high temperature and pH stability, are easy to produce recombinantly and can readily be converted into different formats such as Fc-fusion proteins or hetero-dimers. Moreover, nanobodies have the unique ability to bind molecular clefts, such as the active site of enzymes, thereby interfering with the function of the target protein. Over the last decade, numerous nanobodies have been developed against proteins involved in inflammation with the aim to modulate their immune functions. Here, we give an overview about recently developed nanobodies that target immunological pathways linked to neuroinflammation. Furthermore, we highlight strategies to modify nanobodies so that they can overcome the blood brain barrier and serve as highly specific therapeutics for acute inflammatory brain injury.

Keywords: VHH; blood-brain barrier; nanobodies; neuroinflammation; single domain antibodies.

Figures

Figure 1
Figure 1
Nanobodies are single-domain antibodies derived from llama heavy-chain-only antibodies. (A) Conventional antibodies from mammals are composed of two heavy- and two light chains, camelidae additionally express antibodies devoid of ligh chains, so called heavy-chain only antibodies. (B) Heavy-chain-only antibodies can bind to molecular crevices thereby blocking the active site of enzymes. (C) Nanobodies derived from heavy-chain-only antibodies can be engineered as dimers, half-life-extended heterotrimers containing an anti-albumin nanobody or as dimeric Fc-fusionprotein. (D) Anti-inflammatory nanobodies are currently evaluated in clinical trials.
Figure 2
Figure 2
Delivery of nanobodies to the brain. The blood-brain-barrier (BBB) hampers the delivery of intravenously injected nanobodies (VHH) to the brain. To overcome this, diverse strategies are being developed: (1) Nanobody FC5, binding to a putative α(2,3)-sialoglycoprotein receptor, can potentially be used as shuttling-nanobody to deliver other therapeutic proteins e.g., nanobodies to the brain. (2) Apolipoprotein E (ApoE) binds to low density lipoprotein receptor-related protein 1 (LRP1) inducing transcytosis, which can be exploited as shuttle for therapeutic nanobodies. (3) In a similare fashion, other receptors triggering transcytosis across the BBB such as the transferrin receptor (TrfR) could be targeted for the transfer of therapeutic nanobodies. (4) Finally, shifting the isoelectric point (pI) of therapeutic nanobodies to a basic level facilitates crossing of the BBB by these nanobodies.

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