{{Short description|Technology assisting antibody uptake}} '''Brainshuttle''' or '''brain shuttle''' is a technology developed by Roche to help molecules such as monoclonal antibodies to cross the blood-brain barrier more than they would otherwise. It has been tested with anti-amyloid monoclonal antibodies such as trontinemab.<ref>{{cite journal |last1=Ruderisch |first1=Nadine |last2=Schlatter |first2=Daniel |last3=Kuglstatter |first3=Andreas |last4=Guba |first4=Wolfgang |last5=Huber |first5=Sylwia |last6=Cusulin |first6=Carlo |last7=Benz |first7=Jörg |last8=Rufer |first8=Arne Christian |last9=Hoernschemeyer |first9=Joerg |last10=Schweitzer |first10=Christophe |last11=Bülau |first11=Tina |last12=Gärtner |first12=Achim |last13=Hoffmann |first13=Eike |last14=Niewoehner |first14=Jens |last15=Patsch |first15=Christoph |last16=Baumann |first16=Karlheinz |last17=Loetscher |first17=Hansruedi |last18=Kitas |first18=Eric |last19=Freskgård |first19=Per-Ola |title=Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport |journal=eBioMedicine |date=October 2017 |volume=24 |pages=76–92 |doi=10.1016/j.ebiom.2017.09.004 |language=en|doi-access=free |pmid=28923680 |pmc=5652008 }}</ref><ref>{{cite journal |last1=Morito |first1=Takahiro |last2=Harada |first2=Ryuichi |last3=Iwata |first3=Ren |last4=Du |first4=Yiqing |last5=Okamura |first5=Nobuyuki |last6=Kudo |first6=Yukitsuka |last7=Yanai |first7=Kazuhiko |title=Synthesis and pharmacokinetic characterisation of a fluorine-18 labelled brain shuttle peptide fusion dimeric affibody |journal=Scientific Reports |date=28 January 2021 |volume=11 |issue=1 |page=2588 |doi=10.1038/s41598-021-82037-2 |language=en |issn=2045-2322|doi-access=free |pmid=33510301 |pmc=7844286 }}</ref><ref>{{cite journal |last1=Campos |first1=Christopher R. |last2=Kemble |first2=Alicia M. |last3=Niewoehner |first3=Jens |last4=Freskgård |first4=Per-Ola |last5=Urich |first5=Eduard |title=Brain Shuttle Neprilysin reduces central Amyloid-β levels |journal=PLOS ONE |date=10 March 2020 |volume=15 |issue=3 |article-number=e0229850 |doi=10.1371/journal.pone.0229850 |language=en |issn=1932-6203 |doi-access=free |pmid=32155191 |pmc=7064168 |bibcode=2020PLoSO..1529850C }}</ref><ref>{{cite journal |last1=Hultqvist |first1=Greta |last2=Syvänen |first2=Stina |last3=Fang |first3=Xiaotian T. |last4=Lannfelt |first4=Lars |last5=Sehlin |first5=Dag |title=Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor |journal=Theranostics |date=2017 |volume=7 |issue=2 |pages=308–318 |doi=10.7150/thno.17155 |pmid=28042336 |pmc=5197066 |language=en}}</ref><ref>{{cite journal |last1=Grimm |first1=Hans Peter |last2=Schumacher |first2=Vanessa |last3=Schäfer |first3=Martin |last4=Imhof-Jung |first4=Sabine |last5=Freskgård |first5=Per-Ola |last6=Brady |first6=Kevin |last7=Hofmann |first7=Carsten |last8=Rüger |first8=Petra |last9=Schlothauer |first9=Tilman |last10=Göpfert |first10=Ulrich |last11=Hartl |first11=Maximilian |last12=Rottach |first12=Sylvia |last13=Zwick |first13=Adrian |last14=Seger |first14=Shanon |last15=Neff |first15=Rachel |last16=Niewoehner |first16=Jens |last17=Janssen |first17=Niels |title=Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans |journal=mAbs |date=2023 |volume=15 |issue=1 |article-number=2261509 |doi=10.1080/19420862.2023.2261509 |pmid=37823690 |pmc=10572082 |issn=1942-0870}}</ref><ref>{{cite journal |last1=Kulic |first1=Luka |last2=Vogt |first2=Annamarie |last3=Alcaraz |first3=Fabien |last4=Barrington |first4=Philip |last5=Marchesi |first5=Maddalena |last6=Klein |first6=Gregory |last7=Croney |first7=Ruth |last8=Agnew |first8=David |last9=Abrantes |first9=João A. |last10=Svoboda |first10=Hanno |title=053 Brainshuttle AD: Investigating safety, tolerability, and PK/PD of RG6102 in prodromal/mild-to-moderate AD |journal=Journal of Neurology, Neurosurgery & Psychiatry |date=1 September 2022 |volume=93 |issue=9 |pages=e2 |doi=10.1136/jnnp-2022-abn2.97 |url=https://jnnp.bmj.com/content/93/9/e2.249 |language=en |issn=0022-3050|url-access=subscription }}</ref><ref>{{cite journal |last1=Gehrlein |first1=Alexandra |last2=Udayar |first2=Vinod |last3=Anastasi |first3=Nadia |last4=Morella |first4=Martino L. |last5=Ruf |first5=Iris |last6=Brugger |first6=Doris |last7=von der Mark |first7=Sophia |last8=Thoma |first8=Ralf |last9=Rufer |first9=Arne |last10=Heer |first10=Dominik |last11=Pfahler |first11=Nina |last12=Jochner |first12=Anton |last13=Niewoehner |first13=Jens |last14=Wolf |first14=Luise |last15=Fueth |first15=Matthias |last16=Ebeling |first16=Martin |last17=Villaseñor |first17=Roberto |last18=Zhu |first18=Yanping |last19=Deen |first19=Matthew C. |last20=Shan |first20=Xiaoyang |last21=Ehsaei |first21=Zahra |last22=Taylor |first22=Verdon |last23=Sidransky |first23=Ellen |last24=Vocadlo |first24=David J. |last25=Freskgård |first25=Per-Ola |last26=Jagasia |first26=Ravi |title=Targeting neuronal lysosomal dysfunction caused by β-glucocerebrosidase deficiency with an enzyme-based brain shuttle construct |journal=Nature Communications |date=12 April 2023 |volume=14 |issue=1 |page=2057 |doi=10.1038/s41467-023-37632-4 |language=en |issn=2041-1723|pmc=10097658 }}</ref>
==Mechanism== The formulation reported in a 2013 paper by Niewoehner et al. used a single-chain Fab fragment of a monoclonal antibody against the transferrin receptor,<ref name=NiewoehnerNeuron>{{cite journal |last1=Niewoehner |first1=Jens |last2=Bohrmann |first2=Bernd |last3=Collin |first3=Ludovic |last4=Urich |first4=Eduard |last5=Sade |first5=Hadassah |last6=Maier |first6=Peter |last7=Rueger |first7=Petra |last8=Stracke |first8=Jan Olaf |last9=Lau |first9=Wilma |last10=Tissot |first10=Alain C. |last11=Loetscher |first11=Hansruedi |last12=Ghosh |first12=Anirvan |last13=Freskgård |first13=Per-Ola |title=Increased Brain Penetration and Potency of a Therapeutic Antibody Using a Monovalent Molecular Shuttle |journal=Neuron |date=January 2014 |volume=81 |issue=1 |pages=49–60 |doi=10.1016/j.neuron.2013.10.061}}</ref> which normally mediates transcytosis of a 76 kDa glycoprotein across the blood–brain barrier. Epitope mapping of the anti-TfR antibody showed that the Brain Shuttle module binds at the apical domain of TfR, which is distant to the binding site of transferrin.<ref name=NiewoehnerNeuron /> This anti-TfR fragment was fused to the Fc region at the C-terminal end of either one or both of the heavy chains of an anti-amyloid beta antibody, mAb31.<ref name=NiewoehnerNeuron /> The version with two anti-TfR fragments had higher affinity to TfR than the single form but the two-fragment version was sorted to lysosomes and disappeared.<ref name=NiewoehnerNeuron /> The single form was successfully transported into the CNS compartment and rapidly attached to plaques in the brain, reaching maximum coverage at 8 hours after injection compared to 7 days for the original mAb31.<ref name=NiewoehnerNeuron /> The double form did not reach the plaques even at a high dose (17.44 mg/kg), whereas the single form showed a significant reduction in plaque numbers over mAb31 both in cortex and hippocampus at the middose of 2.67 mg/kg, and a smaller reduction at the low dose of 0.53 mg/kg.<ref name=NiewoehnerNeuron />
==Usage== The system has been further developed into the experimental drug trontinemab, consisting of a Brainshuttle module fused to the anti-amyloid antibody gantenerumab, which started a Phase III trial in 2025.<ref>{{cite news |last1=Taylor |first1=Emma |title=Potential Alzheimer's treatment, trontinemab, hits the news – how does it work and is it available? |url=https://www.alzheimersresearchuk.org/news/potential-alzheimers-treatment-trontinemab-hits-the-news-how-does-it-work-and-is-it-available/ |access-date=9 October 2025 |work=Alzheimer's Research UK |date=3 October 2025}}</ref> It has also been tested with peptide inhibitors of beta-secretase 1 (BACE-1).<ref>{{cite journal |last1=Ruderisch |first1=Nadine |last2=Schlatter |first2=Daniel |last3=Kuglstatter |first3=Andreas |last4=Guba |first4=Wolfgang |last5=Huber |first5=Sylwia |last6=Cusulin |first6=Carlo |last7=Benz |first7=Jörg |last8=Rufer |first8=Arne Christian |last9=Hoernschemeyer |first9=Joerg |last10=Schweitzer |first10=Christophe |last11=Bülau |first11=Tina |last12=Gärtner |first12=Achim |last13=Hoffmann |first13=Eike |last14=Niewoehner |first14=Jens |last15=Patsch |first15=Christoph |last16=Baumann |first16=Karlheinz |last17=Loetscher |first17=Hansruedi |last18=Kitas |first18=Eric |last19=Freskgård |first19=Per-Ola |title=Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport |journal=EBioMedicine |date=October 2017 |volume=24 |pages=76–92 |doi=10.1016/j.ebiom.2017.09.004|doi-access=free |pmc=5652008 }}</ref> ==References== {{reflist}}
Category:Neuroscience Category:Pharmacokinetics Category:Therapeutic antibodies Category:Treatment of Alzheimer's disease