Increased Brain Penetration and Potency of a Therapeutic Antibody Using a Monovalent Molecular Shuttle
Open accessAbstract
Although biotherapeutics have vast potential for treating brain disorders, their use has been limited due to low exposure across the blood-brain barrier (BBB). We report that by manipulating the binding mode of an antibody fragment to the transferrin receptor (TfR), we have developed a Brain Shuttle module, which can be engineered into a standard therapeutic antibody for successful BBB transcytosis. Brain Shuttle version of an anti-Aβ antibody, which uses a monovalent binding mode to the TfR, increases β-Amyloid target engagement in a mouse model of Alzheimer's disease by 55-fold compared to the parent antibody. We provide in vitro and in vivo evidence that the monovalent binding mode facilitates transcellular transport, whereas a bivalent binding mode leads to lysosome sorting. Enhanced target engagement of the Brain Shuttle module translates into a significant improvement in amyloid reduction. These findings have major implications for the development of biologics-based treatment of brain disorders.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Anti-TfR-Aβ antibody has shown promise in the PS2APP mouse model.
“or anti-TfR-A 𝛃 antibody in PS2APP mouse model (435).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [435]
Patients without brain amyloid who receive aducanumab would have no likelihood of clinical benefit.
“otherwise patients may receiving aducanumab with no likelihood of clinical benefit 109 .”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [109]
Cites
Drug Transport across the Blood–Brain Barrier
Pardridge, W. M. (2012) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2012.126 · Cited by 1,994 · see citing works
Blood‐brain barrier‐specific properties of a human adult brain endothelial cell line
Weksler, B. B., Subileau, E.-A., Perrière, N., Charneau, P., Holloway, K. E., Leveque, M., Tricoire-Leignel, H., Nicotra, A., Bourdoulous, S., Turowski, P., et al. (2005) · The FASEB Journal · doi:10.1096/fj.04-3458fje · Cited by 1,325 · see citing works
Boosting Brain Uptake of a Therapeutic Antibody by Reducing Its Affinity for a Transcytosis Target
Yu, Y. J., Zhang, Y., Kenrick, M., Hoyte, K., Luk, W., Lu, Y., Atwal, J., Elliott, J. M., Prabhu, S., Watts, R. J., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002230 · Cited by 794 · see citing works
Lakadamyali, M., Rust, M., & Zhuang, X. (2006) · Cell · doi:10.1016/j.cell.2005.12.038 · Cited by 589 · see citing works
Transferrin receptor is necessary for development of erythrocytes and the nervous system
Levy, J. E., Jin, O., Fujiwara, Y., Kuo, F., & Andrews, N. (1999) · Nature Genetics · doi:10.1038/7727 · Cited by 574 · see citing works
LaVaute, T., Smith, S., Cooperman, S., Iwai, K., Land, W., Meyron-Holtz, E., Drake, S. K., Miller, G., Abu-Asab, M., Tsokos, M., et al. (2001) · Nature Genetics · doi:10.1038/84859 · Cited by 509 · see citing works
Bohrmann, B., Baumann, K., Benz, J., Gerber, F., Huber, W., Knoflach, F., Messer, J., Oroszlan, K., Rauchenberger, R., Richter, W. F., et al. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2011-110977 · Cited by 448 · see citing works
Self-citationMacromolecular permeability across the blood-nerve and blood-brain barriers.
Poduslo, J. F., Curran, G. L., & Berg, C. T. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.12.5705 · Cited by 377 · see citing works
Local clustering of transferrin receptors promotes clathrin-coated pit initiation
Liu, A. P., Aguet, F., Danuser, G. M., & Schmid, S. L. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.201008117 · Cited by 224 · see citing works
Reengineering Biopharmaceuticals for Targeted Delivery Across the Blood–Brain Barrier
Pardridge, W. M., & Boado, R. J. (2012) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-396962-0.00011-2 · Cited by 199 · see citing works
Richards, J., Higgins, G., Ouagazzal, A., Ozmen, L., Kew, J., Bohrmann, B., Malherbe, P., Brockhaus, M., Loetscher, H., Czech, C., et al. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-26-08989.2003 · Cited by 197 · see citing works
Self-citationStaquicini, F. I., Ozawa, M. G., Moya, C. A., Driessen, W. H. P., Barbu, E. M., Nishimori, H., Soghomonyan, S., Flores, L. G., Liang, X., Paolillo, V., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci44798 · Cited by 163 · see citing works
Indicators of amyloid burden in a population-based study of cognitively normal elderly
Mielke, M. M., Wiste, H. J., Weigand, S. D., Knopman, D. S., Lowe, V. J., Roberts, R. O., Geda, Y. E., Swenson-Dravis, D. M., Boeve, B. F., Senjem, M. L., et al. (2012) · Neurology · doi:10.1212/wnl.0b013e31826e2696 · Cited by 163 · see citing works
Gosk, S., Vermehren, C., Storm, G., & Moos, T. (2004) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/01.wcb.0000135592.28823.47 · Cited by 162 · see citing works
Wang, D., El-Amouri, S. S., Dai, M., Kuan, C.-Y., Hui, D. Y., Brady, R. O., & Pan, D. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1222742110 · Cited by 159 · see citing works
Kozik, P., Hodson, N. A., Sahlender, D. A., Simecek, N., Soromani, C., Wu, J., Collinson, L., & Robinson, M. S. (2012) · Nature Cell Biology · doi:10.1038/ncb2652 · Cited by 112 · see citing works
Small GTPase Rab12 Regulates Constitutive Degradation of Transferrin Receptor
Matsui, T., Itoh, T., & Fukuda, M. (2011) · Traffic · doi:10.1111/j.1600-0854.2011.01240.x · Cited by 104 · see citing works
Rabenosyn-5 defines the fate of the transferrin receptor following clathrin-mediated endocytosis
Navaroli, D. M., Bellve, K., Standley, C., Lifshitz, L. M., Cardia, J., Lambright, D., Leonard, D. M., Fogarty, K., & Corvera, S. (2012) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1115495109 · Cited by 93 · see citing works
Michel, V., Licón-Muñoz, Y., Trujillo, K. A., Bisoffi, M., & Parra, K. J. (2012) · International Journal of Cancer · doi:10.1002/ijc.27811 · Cited by 88 · see citing works
Lesley, J., Schulte, R. J., & Woods, J. W. (1989) · Experimental Cell Research · doi:10.1016/0014-4827(89)90293-0 · Cited by 77 · see citing works
Paris‐Robidas, S., Émond, V., Tremblay, C., Soulet, D., & Calon, F. (2011) · Molecular Pharmacology · doi:10.1124/mol.111.071027 · Cited by 69 · see citing works
Crépin, R., Goenaga, A.-L., Jullienne, B., Bougherara, H., Legay, C., Benihoud, K., Marks, J. D., & Poul, M. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0938 · Cited by 59 · see citing works
Sumbria, R. K., Zhou, Q.-H., Hui, E. K., Lu, J. Z., Boado, R. J., & Pardridge, W. M. (2013) · Molecular Pharmaceutics · doi:10.1021/mp400004a · Cited by 47 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Development and Applications of CRISPR-Cas9 for Genome Engineering
Hsu, P. D., Lander, E. S., & Zhang, F. (2014) · Cell · doi:10.1016/j.cell.2014.05.010 · Cited by 5,762 · see citing works
Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders
Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.188 · Cited by 3,076 · see citing works
Blood-Brain Barrier: From Physiology to Disease and Back
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,294 · see citing works
Overcoming the challenges in administering biopharmaceuticals: Formulation and delivery strategies
Mitragotri, S., Burke, P. A., & Langer, R. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4363 · Cited by 1,702 · see citing works
Saraiva, C., Praça, C., Ferreira, R., Santos, T., Ferreira, L., & Bernardino, L. (2016) · Journal of Controlled Release · doi:10.1016/j.jconrel.2016.05.044 · Cited by 1,609 · see citing works
Bispecific antibodies: a mechanistic review of the pipeline
Labrijn, A. F., Janmaat, M. L., Reichert, J. M., & Parren, P. W. H. I. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0028-1 · Cited by 1,303 · see citing works
From blood–brain barrier to blood–brain interface: new opportunities for CNS drug delivery
Banks, W. A. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.21 · Cited by 1,204 · see citing works
Crossing the blood-brain barrier with nanoparticles
Zhou, Y., Peng, Z., Seven, E. S., & Leblanc, R. M. (2018) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.12.015 · Cited by 837 · see citing works
The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics
Karran, E., & De Strooper, B. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00391-w · Cited by 742 · see citing works
The blood-brain barrier: Physiology and strategies for drug delivery
Pandit, R., Chen, L., & Götz, J. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.11.009 · Cited by 651 · see citing works
Alternative molecular formats and therapeutic applications for bispecific antibodies
Spiess, C., Zhai, Q., & Carter, P. J. (2015) · Molecular Immunology · doi:10.1016/j.molimm.2015.01.003 · Cited by 607 · see citing works
Nanomaterial-based blood-brain-barrier (BBB) crossing strategies
Xie, J., Shen, Z., Anraku, Y., Kataoka, K., & Chen, X. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119491 · Cited by 604 · see citing works
Physiological blood–brain transport is impaired with age by a shift in transcytosis
Yang, A. C., Stevens, M. Y., Chen, M. B., Lee, D. P., Stähli, D., Gate, D., Contrepois, K., Chen, W., Iram, T., Zhang, L., et al. (2020) · Nature · doi:10.1038/s41586-020-2453-z · Cited by 477 · see citing works
Targeting Receptor-Mediated Transport for Delivery of Biologics Across the Blood-Brain Barrier
Lajoie, J. M., & Shusta, E. V. (2015) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010814-124852 · Cited by 399 · see citing works
Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates
Yu, Y. J., Atwal, J. K., Zhang, Y., Tong, R. K., Wildsmith, K. R., Tan, C., Bien-Ly, N., Hersom, M., Maloney, J. A., Meilandt, W. J., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009835 · Cited by 371 · see citing works
Alzheimer's disease: From immunotherapy to immunoprevention
Jucker, M., & Walker, L. C. (2023) · Cell · doi:10.1016/j.cell.2023.08.021 · Cited by 353 · see citing works
Breaking Down the Barriers to Precision Cancer Nanomedicine
von Roemeling, C., Jiang, W., Chan, C. K., Weissman, I. L., & Kim, B. Y. S. (2017) · Trends in Biotechnology · doi:10.1016/j.tibtech.2016.07.006 · Cited by 330 · see citing works
Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region
Schlepckow, K., Monroe, K. M., Kleinberger, G., Cantuti‐Castelvetri, L., Parhizkar, S., Xia, D., Willem, M., Werner, G., Pettkus, N., Brunner, B., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.201911227 · Cited by 324 · see citing works
Iron as a central player and promising target in cancer progression
Jung, M., Mertens, C., Tomat, E., & Brüne, B. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20020273 · Cited by 268 · see citing works
Neuronal and vascular interactions
Andreone, B. J., Lacoste, B., & Gu, C. (2015) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071714-033835 · Cited by 256 · see citing works
Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor
Hultqvist, G., Syvänen, S., Fang, X. T., Lannfelt, L., & Sehlin, D. (2017) · Theranostics · doi:10.7150/thno.17155 · Cited by 224 · see citing works
Georgieva, J., Hoekstra, D., & Zuhorn, I. (2014) · Pharmaceutics · doi:10.3390/pharmaceutics6040557 · Cited by 211 · see citing works
Barker, S. J., Thayer, M. B., Kim, C., Tatarakis, D., Simon, M. J., Dial, R., Nilewski, L., Wells, R. C., Zhou, Y., Afetian, M., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adi2245 · Cited by 142 · see citing works
Exploiting transferrin receptor for delivering drugs across the blood-brain barrier
Paterson, J., & Webster, C. I. (2016) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2016.07.009 · Cited by 87 · see citing works
Engineered extracellular vesicles as brain therapeutics
Lino, M. M., Simões, S., Tomatis, F., Albino, I., Barrera, A., Vivien, D., Sobrino, T., & Ferreira, L. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.08.037 · Cited by 68 · see citing works
Transferrin receptor-targeted anti-amyloid antibody enhances brain delivery and mitigates ARIA.
Pizzo, M. E., Plowey, E. D., Khoury, N., Kwan, W., Abettan, J., DeVos, S. L., Discenza, C. B., Earr, T., Joy, D., Lye-Barthel, M., et al. (2025) · Science · doi:10.1126/science.ads3204 · Cited by 63 · see citing works
Antibody Engineering for Optimized Immunotherapy in Alzheimer's Disease
Sumner, I. L., Edwards, R. A., Asuni, A. A., & Teeling, J. L. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00254 · Cited by 24 · see citing works
Liu, N., Liang, X., Yang, C., Hu, S., Luo, Q., & Luo, H. (2022) · Theranostics · doi:10.7150/thno.76574 · Cited by 21 · see citing works
Santin, M. D., Vandenberghe, M. E., Herard, A.-S., Pradier, L., Cohen, C., Debeir, T., Delzescaux, T., Rooney, T., & Dhenain, M. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00055 · Cited by 20 · see citing works
Ghosh, S., Fan, Y., Laufer, B. I., Stephenson, W., Zang, N., Lawrence, J., Lin, H. H., Sen, S., Miller, S. E., Chu, S., et al. (2026) · Cell Biomaterials · doi:10.1016/j.celbio.2025.100303 · Cited by 3 · see citing works
- Authors
- Niewoehner, J., Bohrmann, B., Collin, L., Urich, E., Sade, H., Maier, P., Rueger, P., Stracke, J. O., Lau, W., Tissot, A. C., Loetscher, H., Ghosh, A., & Freskgård, P.-O.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Ghosh, Anirvan
- Freskgård, Per-Ola
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 81
- Issue
- 1
- Pages
- 49-60
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2025061302
- Cited by
- 622
- References
- 23
- Citations by year
- 2026: 60 · 2025: 71 · 2024: 59 · 2023: 61 · 2022: 59 · 2021: 48 · 2020: 52 · 2019: 39 · 2018: 40 · 2017: 35 · 2016: 37 · 2015: 35 · 2014: 25
- FWCI
- 22.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- blood-brain barrier, brain penetration, therapeutic antibodies, transferrin receptor, bivalent binding, transcytosis, amyloid-beta, Alzheimer's disease, target engagement, brain disorders
- MeSH terms
- Alzheimer Disease, Animals, Blood-Brain Barrier, Brain, Cell Line, Transformed, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors, Humans, Lysosomes, Mice, Transgenic, Protein Binding, Receptors, Transferrin, Subcellular Fractions, Time Factors, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Models, Immunological, Macrolides, Protein Transport, Mice, Presenilin-1, Single-Chain Antibodies, Transcytosis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
