Biology:Brainshuttle

From HandWiki

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.[1][2][3][4][5][6][7]

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,[8] 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.[8] 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.[8] 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.[8] 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.[8] 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 0.53mg/kg.[8]

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.[9] It has also been tested with peptide inhibitors of beta-secretase 1 (BACE-1).[10]

References

  1. ↑ Ruderisch, Nadine; Schlatter, Daniel; Kuglstatter, Andreas; Guba, Wolfgang; Huber, Sylwia; Cusulin, Carlo; Benz, Jörg; Rufer, Arne Christian et al. (October 2017). "Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport" (in en). eBioMedicine 24: 76–92. doi:10.1016/j.ebiom.2017.09.004. PMID 28923680. 
  2. ↑ Morito, Takahiro; Harada, Ryuichi; Iwata, Ren; Du, Yiqing; Okamura, Nobuyuki; Kudo, Yukitsuka; Yanai, Kazuhiko (28 January 2021). "Synthesis and pharmacokinetic characterisation of a fluorine-18 labelled brain shuttle peptide fusion dimeric affibody" (in en). Scientific Reports 11 (1): 2588. doi:10.1038/s41598-021-82037-2. ISSN 2045-2322. PMID 33510301. 
  3. ↑ Campos, Christopher R.; Kemble, Alicia M.; Niewoehner, Jens; Freskgård, Per-Ola; Urich, Eduard (10 March 2020). "Brain Shuttle Neprilysin reduces central Amyloid-β levels" (in en). PLOS ONE 15 (3). doi:10.1371/journal.pone.0229850. ISSN 1932-6203. PMID 32155191. Bibcode: 2020PLoSO..1529850C. 
  4. ↑ Hultqvist, Greta; Syvänen, Stina; Fang, Xiaotian T.; Lannfelt, Lars; Sehlin, Dag (2017). "Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor" (in en). Theranostics 7 (2): 308–318. doi:10.7150/thno.17155. PMID 28042336. 
  5. ↑ Grimm, Hans Peter; Schumacher, Vanessa; Schäfer, Martin; Imhof-Jung, Sabine; Freskgård, Per-Ola; Brady, Kevin; Hofmann, Carsten; Rüger, Petra et al. (2023). "Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans". mAbs 15 (1). doi:10.1080/19420862.2023.2261509. ISSN 1942-0870. PMID 37823690. 
  6. ↑ Kulic, Luka; Vogt, Annamarie; Alcaraz, Fabien; Barrington, Philip; Marchesi, Maddalena; Klein, Gregory; Croney, Ruth; Agnew, David et al. (1 September 2022). "053 Brainshuttle AD: Investigating safety, tolerability, and PK/PD of RG6102 in prodromal/mild-to-moderate AD" (in en). Journal of Neurology, Neurosurgery & Psychiatry 93 (9): e2. doi:10.1136/jnnp-2022-abn2.97. ISSN 0022-3050. https://jnnp.bmj.com/content/93/9/e2.249. 
  7. ↑ Gehrlein, Alexandra; Udayar, Vinod; Anastasi, Nadia; Morella, Martino L.; Ruf, Iris; Brugger, Doris; von der Mark, Sophia; Thoma, Ralf et al. (12 April 2023). "Targeting neuronal lysosomal dysfunction caused by β-glucocerebrosidase deficiency with an enzyme-based brain shuttle construct" (in en). Nature Communications 14 (1): 2057. doi:10.1038/s41467-023-37632-4. ISSN 2041-1723. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 Niewoehner, Jens; Bohrmann, Bernd; Collin, Ludovic; Urich, Eduard; Sade, Hadassah; Maier, Peter; Rueger, Petra; Stracke, Jan Olaf et al. (January 2014). "Increased Brain Penetration and Potency of a Therapeutic Antibody Using a Monovalent Molecular Shuttle". Neuron 81 (1): 49–60. doi:10.1016/j.neuron.2013.10.061. 
  9. ↑ Taylor, Emma (3 October 2025). "Potential Alzheimer’s treatment, trontinemab, hits the news – how does it work and is it available?". Alzheimer's Research UK. https://www.alzheimersresearchuk.org/news/potential-alzheimers-treatment-trontinemab-hits-the-news-how-does-it-work-and-is-it-available/. 
  10. ↑ Ruderisch, Nadine; Schlatter, Daniel; Kuglstatter, Andreas; Guba, Wolfgang; Huber, Sylwia; Cusulin, Carlo; Benz, Jörg; Rufer, Arne Christian et al. (October 2017). "Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport". EBioMedicine 24: 76–92. doi:10.1016/j.ebiom.2017.09.004. 



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