{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:03:54Z","timestamp":1789967034695,"version":"4.0.1"},"reference-count":170,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibodies"],"abstract":"<jats:p>The blood-brain barrier (BBB) is permeable only to small lipophilic molecules, whereas hydrophilic nutrients, such as glucose and amino acids, cross the BBB via carrier-mediated transport systems. In contrast, circulating proteins do not cross the BBB. However, the BBB expresses receptors able to induce receptor-mediated transcytosis (RMT) of selective proteins across the BBB, as in the case of insulin, transferrin, and insulin-like growth factor 1 (IGF1). This led to the hypothesis that the transport of protein-based biologics to the brain may be possible by targeting BBB receptors that induce RMT. Monoclonal antibodies targeting these receptors penetrate the BBB via RMT and are distributed throughout the brain, acting as molecular Trojan horses and\/or shuttle systems. A generation of brain-penetrating fusion proteins was produced targeting BBB insulin, transferrin, and IGF1 receptors, respectively, with full antibodies and\/or antibody fragments acting as transport domains. These antibody-based fusion proteins were validated in various experimental models, including lysosomal storage disorders (LSDs), stroke, Parkinson\u2019s disease, and Alzheimer\u2019s disease (AD), respectively. Clinical trials with brain-penetrating antibody-based biologicals targeting BBB transferrin and insulin receptors have been completed or are in progress in LSDs and in AD. The aim of this review is to examine the progress made in antibody-based biologicals for CNS disorders from genetic engineering to clinical trials.<\/jats:p>","DOI":"10.3390\/antib15050086","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:07:29Z","timestamp":1789574849000},"page":"86","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antibody-Based Biologics for CNS Disorders"],"prefix":"10.3390","volume":"15","author":[{"given":"Eric Ka-Wai","family":"Hui","sequence":"first","affiliation":[{"name":"Department of Research and Development, Thermo Fisher Scientific, West Hills, CA 91304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben J.","family":"Boado","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Pardridge, W.M. (2022). A Historical Review of Brain Drug Delivery. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14061283"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.nbd.2009.07.030","article-title":"Structure and function of the blood-brain barrier","volume":"37","author":"Abbott","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1016\/j.cell.2015.10.067","article-title":"Establishment and Dysfunction of the Blood-Brain Barrier","volume":"163","author":"Zhao","year":"2015","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s12987-020-00230-3","article-title":"A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity","volume":"17","author":"Kadry","year":"2020","journal-title":"Fluids Barriers CNS"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6564585","DOI":"10.1155\/2021\/6564585","article-title":"Blood-Brain Barrier Overview: Structural and Functional Correlation","volume":"2021","author":"Alahmari","year":"2021","journal-title":"Neural Plast."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Pardridge, W.M. (2022). Advanced Blood-Brain Barrier Drug Delivery. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15010093"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Haqqani, A.S., B\u00e9langer, K., and Stanimirovic, D.B. (2024). Receptor-mediated transcytosis for brain delivery of therapeutics: Receptor classes and criteria. Front. Drug Deliv., 4.","DOI":"10.3389\/fddev.2024.1360302"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/1044-7431(90)90005-O","article-title":"Molecular cloning of the bovine blood-brain barrier glucose transporter cDNA and demonstration of phylogenetic conservation of the 5\u2032-untranslated region","volume":"1","author":"Boado","year":"1990","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12079","DOI":"10.1073\/pnas.96.21.12079","article-title":"Selective expression of the large neutral amino acid transporter at the blood-brain barrier","volume":"96","author":"Boado","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1111\/j.1471-4159.1985.tb07167.x","article-title":"Human blood-brain barrier insulin receptor","volume":"44","author":"Pardridge","year":"1985","journal-title":"J. Neurochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/jnr.490180206","article-title":"Receptor-mediated transcytosis of transferrin across the blood-brain barrier","volume":"18","author":"Fishman","year":"1987","journal-title":"J. Neurosci. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1046\/j.1471-4159.1998.71041761.x","article-title":"Up-regulation of blood-brain barrier short-form leptin receptor gene products in rats fed a high fat diet","volume":"71","author":"Boado","year":"1998","journal-title":"J. Neurochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/S0026-0495(98)90007-5","article-title":"Human blood-brain barrier insulin-like growth factor receptor","volume":"37","author":"Duffy","year":"1988","journal-title":"Metabolism"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s12987-025-00659-4","article-title":"The legacy of William M. Pardridge (1947\u20132024) on the science and fields concerned with the physiology of the blood-brain barrier and the transport of drugs to the brain","volume":"22","author":"Boado","year":"2025","journal-title":"Fluids Barriers CNS"},{"key":"ref_15","first-page":"333","article-title":"Analysis of lymphopoietic stem cells with a monoclonal antibody to the rat transferrin receptor","volume":"54","author":"Jefferies","year":"1985","journal-title":"Immunology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1016\/S0022-3565(24)35388-1","article-title":"Targeting rat anti-mouse transferrin receptor monoclonal antibodies through blood-brain barrier in mouse","volume":"292","author":"Lee","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5217","DOI":"10.1073\/pnas.86.14.5217","article-title":"Monoclonal antibodies to the insulin receptor mimic metabolic effects of insulin but do not stimulate receptor autophosphorylation in transfected NIH 3T3 fibroblasts","volume":"86","author":"Soos","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/S0022-3565(25)20567-5","article-title":"Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo","volume":"259","author":"Pardridge","year":"1991","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1023\/A:1016244500596","article-title":"Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vitro and rapid transcytosis through the blood-brain barrier in vivo in the primate","volume":"12","author":"Pardridge","year":"1995","journal-title":"Pharm. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1126\/science.8420006","article-title":"Blood-brain barrier penetration and in vivo activity of an NGF conjugate","volume":"259","author":"Friden","year":"1993","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1073\/pnas.90.7.2618","article-title":"Pharmacologic effects in vivo in brain by vector-mediated peptide drug delivery","volume":"90","author":"Bickel","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0090-9556(25)08314-X","article-title":"Pharmacokinetics and saturable blood-brain barrier transport of biotin bound to a conjugate of avidin and a monoclonal antibody to the transferrin receptor","volume":"22","author":"Kang","year":"1994","journal-title":"Drug Metab. Dispos."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/S0022-3565(25)12250-7","article-title":"Pharmacokinetics and blood-brain barrier transport of [3H]-biotinylated phosphorothioate oligodeoxynucleotide conjugated to a vector-mediated drug delivery system","volume":"276","author":"Wu","year":"1996","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1172\/JCI119708","article-title":"Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor","volume":"100","author":"Wu","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.1007\/s11095-007-9460-8","article-title":"Intravenous siRNA of brain cancer with receptor targeting and avidin-biotin technology","volume":"24","author":"Xia","year":"2007","journal-title":"Pharm. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1023\/A:1007592720793","article-title":"Transport across the primate blood-brain barrier of a genetically engineered chimeric monoclonal antibody to the human insulin receptor","volume":"17","author":"Coloma","year":"2000","journal-title":"Pharm. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1002\/bit.21120","article-title":"Humanization of anti-human insulin receptor antibody for drug targeting across the human blood-brain barrier","volume":"96","author":"Boado","year":"2007","journal-title":"Biotechnol. Bioeng."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1358\/dnp.2008.21.9.1290820","article-title":"A new generation of neurobiological drugs engineered to overcome the challenges of brain drug delivery","volume":"21","author":"Boado","year":"2008","journal-title":"Drug News Perspect."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1021\/bc800148t","article-title":"Re-engineering biopharmaceuticals for delivery to brain with molecular Trojan horses","volume":"19","author":"Pardridge","year":"2008","journal-title":"Bioconjug. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1002\/bit.22135","article-title":"Engineering and expression of a chimeric transferrin receptor monoclonal antibody for blood-brain barrier delivery in the mouse","volume":"102","author":"Boado","year":"2009","journal-title":"Biotechnol. Bioeng."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/B978-0-12-396962-0.00011-2","article-title":"Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier","volume":"503","author":"Pardridge","year":"2012","journal-title":"Methods Enzymol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s13023-018-0849-8","article-title":"Neurocognitive and somatic stabilization in pediatric patients with severe Mucopolysaccharidosis Type I after 52 weeks of intravenous brain-penetrating insulin receptor antibody-iduronidase fusion protein (valanafusp alpha): An open label phase 1\u20132 trial","volume":"13","author":"Giugliani","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.ymthe.2024.01.009","article-title":"A-L-iduronidase fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa) for mucopolysaccharidosis type I: A phase 1\/2 trial","volume":"32","author":"Harmatz","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.ymthe.2020.09.039","article-title":"A Phase 2\/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II","volume":"29","author":"Okuyama","year":"2021","journal-title":"Mol. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2261509","DOI":"10.1080\/19420862.2023.2261509","article-title":"Delivery of the Brainshuttle\u2122 amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans","volume":"15","author":"Grimm","year":"2023","journal-title":"mAbs"},{"key":"ref_36","first-page":"e145445","article-title":"Iduronate-2-sulfatase transport vehicle rescues behavioral and skeletal phenotypes in a mouse model of Hunter syndrome","volume":"6","author":"Arguello","year":"2021","journal-title":"J. Clin. Investig. Insight"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1039\/D5PM00204D","article-title":"Brain delivery of biotherapeutics via receptor-mediated transcytosis across the blood\u2013brain barrier","volume":"2","author":"Boado","year":"2025","journal-title":"RSC Pharm."},{"key":"ref_38","unstructured":"(2025, April 21). JCR Pharmaceuticals Announces Approval of IZCARGO\u00ae (Pabinafusp Alfa) for Treatment of MPS II (Hunter Syndrome) in Japan. Available online: https:\/\/www.businesswire.com\/news\/home\/20210323005577\/en\/JCR-Pharmaceuticals-Announces-Approval-of-IZCARGO-Pabinafusp-Alfa-for-Treatment-of-MPS-II-Hunter-Syndrome-in-Japan."},{"key":"ref_39","unstructured":"(2026, August 30). Denali Therapeutics Announces U.S. FDA Approval of AVLAYAH(TM) (Tividenofusp Alfa-Eknm) for Treatment of Hunter Syndrome (MPS II). Available online: https:\/\/investors.denalitherapeutics.com\/news-releases\/news-release-details\/denali-therapeutics-announces-us-fda-approval-avlayahtm."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Boado, R.J. (2022). IgG Fusion Proteins for Brain Delivery of Biologics via Blood-Brain Barrier Receptor-Mediated Transport. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14071476"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1021\/bc400319d","article-title":"Blood-brain barrier molecular trojan horse enables imaging of brain uptake of radioiodinated recombinant protein in the rhesus monkey","volume":"24","author":"Boado","year":"2013","journal-title":"Bioconjug. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s40259-023-00590-w","article-title":"Characterization of a HIR-Fab-IDS, Novel Iduronate 2-Sulfatase Fusion Protein for the Treatment of Neuropathic Mucopolysaccharidosis Type II (Hunter Syndrome)","volume":"37","author":"Gusarova","year":"2023","journal-title":"BioDrugs"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1002\/bit.24795","article-title":"Pharmacokinetics and brain uptake in the rhesus monkey of a fusion protein of arylsulfatase a and a monoclonal antibody against the human insulin receptor","volume":"110","author":"Boado","year":"2013","journal-title":"Biotechnol. Bioeng."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2928","DOI":"10.1021\/mp500258p","article-title":"Insulin receptor antibody-sulfamidase fusion protein penetrates the primate blood-brain barrier and reduces glycosoaminoglycans in Sanfilippo type A cells","volume":"11","author":"Boado","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1021\/acs.molpharmaceut.6b00037","article-title":"Insulin Receptor Antibody-\u03b1-N-Acetylglucosaminidase Fusion Protein Penetrates the Primate Blood-Brain Barrier and Reduces Glycosoaminoglycans in Sanfilippo Type B Fibroblasts","volume":"13","author":"Boado","year":"2016","journal-title":"Mol. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18632","DOI":"10.1038\/s41598-019-55136-4","article-title":"Bi-functional IgG-lysosomal enzyme fusion proteins for brain drug delivery","volume":"9","author":"Boado","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1002\/bit.22576","article-title":"IgG-single chain Fv fusion protein therapeutic for Alzheimer\u2019s disease: Expression in CHO cells and pharmacokinetics and brain delivery in the rhesus monkey","volume":"105","author":"Boado","year":"2010","journal-title":"Biotechnol. Bioeng."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jbiotec.2010.01.011","article-title":"Selective targeting of a TNFR decoy receptor pharmaceutical to the primate brain as a receptor-specific IgG fusion protein","volume":"146","author":"Boado","year":"2010","journal-title":"J. Biotechnol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1124\/jpet.109.165092","article-title":"Drug targeting of erythropoietin across the primate blood-brain barrier with an IgG molecular Trojan horse","volume":"333","author":"Boado","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1124\/dmd.109.028787","article-title":"Comparison of blood-brain barrier transport of glial-derived neurotrophic factor (GDNF) and an IgG-GDNF fusion protein in the rhesus monkey","volume":"37","author":"Boado","year":"2009","journal-title":"Drug Metab. Dispos."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1002\/bit.21369","article-title":"Genetic engineering, expression, and activity of a fusion protein of a human neurotrophin and a molecular Trojan horse for delivery across the human blood-brain barrier","volume":"97","author":"Boado","year":"2007","journal-title":"Biotechnol. Bioeng."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1002\/bit.22907","article-title":"CHO cell expression, long-term stability, and primate pharmacokinetics and brain uptake of an IgG-paroxonase-1 fusion protein","volume":"108","author":"Boado","year":"2011","journal-title":"Biotechnol. Bioeng."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1021\/bc7004076","article-title":"Genetic engineering, expression, and activity of a chimeric monoclonal antibody-avidin fusion protein for receptor-mediated delivery of biotinylated drugs in humans","volume":"19","author":"Boado","year":"2008","journal-title":"Bioconjug. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1021\/mp200136x","article-title":"Reversal of lysosomal storage in brain of adult MPS-I mice with intravenous Trojan horse-iduronidase fusion protein","volume":"8","author":"Boado","year":"2011","journal-title":"Mol. Pharm."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1124\/dmd.111.042903","article-title":"Brain-penetrating IgG-iduronate 2-sulfatase fusion protein for the mouse","volume":"40","author":"Zhou","year":"2012","journal-title":"Drug Metab. Dispos."},{"key":"ref_56","unstructured":"(2026, August 30). JCR Pharmaceuticals Announces First Patient Dosed in a Global Phase I\/II Clinical Trial of JR-441 for the Treatment of MPS IIIA. Available online: https:\/\/ssl4.eir-parts.net\/doc\/4552\/tdnet\/2496993\/00.pdf."},{"key":"ref_57","unstructured":"(2026, August 30). Denali Announces DNL126 Demonstrates \u201cRobust Reduction from Baseline in CSF Heparan Sulfate Levels, Including Normalization\u201d. Available online: https:\/\/curesanfilippofoundation.org\/2024\/11\/denali-announces-dnl126-demonstrate-robust-reduction-from-baseline-in-csf-heparan-sulfate-levels-including-normalization\/."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1021\/acs.molpharmaceut.7b00958","article-title":"Reduction in Brain Heparan Sulfate with Systemic Administration of an IgG Trojan Horse-Sulfamidase Fusion Protein in the Mucopolysaccharidosis Type IIIA Mouse","volume":"15","author":"Boado","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_59","unstructured":"(2026, August 30). JR-446 Enzyme Replacement|MPS IIIB|Phase I-II|MEDIPAL\/JCR. Available online: https:\/\/curesanfilippofoundation.org\/2024\/07\/jr-446-enzyme-replacement-mps-iiib-phase-i-ii\/."},{"key":"ref_60","unstructured":"(2026, August 30). Pompe Disease-Denali Therapeutics. Available online: https:\/\/www.denalitherapeutics.com\/patients\/therapeutic-areas\/pompe-disease\/."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1021\/mp900235k","article-title":"Pharmacokinetics and brain uptake of a genetically engineered bifunctional fusion antibody targeting the mouse transferrin receptor","volume":"7","author":"Boado","year":"2010","journal-title":"Mol. Pharm."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1124\/dmd.110.036012","article-title":"Brain-penetrating tumor necrosis factor decoy receptor in the mouse","volume":"39","author":"Zhou","year":"2011","journal-title":"Drug Metab. Dispos."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1021\/mp1001763","article-title":"Re-engineering erythropoietin as an IgG fusion protein that penetrates the blood-brain barrier in the mouse","volume":"7","author":"Zhou","year":"2010","journal-title":"Mol. Pharm."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1124\/dmd.109.031534","article-title":"Monoclonal antibody-glial-derived neurotrophic factor fusion protein penetrates the blood-brain barrier in the mouse","volume":"38","author":"Zhou","year":"2010","journal-title":"Drug Metab. Dispos."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1021\/bc200174x","article-title":"Delivery of a peptide radiopharmaceutical to brain with an IgG-avidin fusion protein","volume":"22","author":"Zhou","year":"2011","journal-title":"Bioconjug. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"308","DOI":"10.7150\/thno.17155","article-title":"Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor","volume":"7","author":"Hultqvist","year":"2017","journal-title":"Theranostics"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s12987-024-00617-6","article-title":"In vivo brain delivery of BBB-enabled iduronate 2-sulfatase in rats","volume":"22","author":"Costain","year":"2025","journal-title":"Fluids Barriers CNS"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/0006-291X(91)90639-O","article-title":"The two isotypes of the human insulin receptor (HIR-A and HIR-B) follow different internalization kinetics","volume":"177","author":"Vogt","year":"1991","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1172\/JCI115431","article-title":"Evidence for entry of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. Quantitative aspects and implications for transport","volume":"88","author":"Schwartz","year":"1991","journal-title":"J. Clin. Investig."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1006\/hbeh.1996.0034","article-title":"Sequestration of centrally administered insulin by the brain: Effects of starvation, aluminum, and TNF-alpha","volume":"30","author":"Cashion","year":"1996","journal-title":"Horm. Behav."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Pemberton, S., Galindo, D.C., Schwartz, M.W., Banks, W.A., and Rhea, E.M. (2022). Endocytosis of insulin at the blood-brain barrier. Front. Drug Deliv., 2.","DOI":"10.3389\/fddev.2022.1062366"},{"key":"ref_72","first-page":"757","article-title":"Insulin receptor ribonucleic acid levels and alternative splicing in human liver, muscle, and adipose tissue: Tissue specificity and relation to insulin action","volume":"78","author":"Norgren","year":"1994","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1002\/bies.20151","article-title":"Insulin and its receptor: Structure, function and evolution","volume":"26","year":"2004","journal-title":"Bioessays"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Hill, J.J., Haqqani, A.S., and Stanimirovic, D.B. (2021). Proteome of the Luminal Surface of the Blood-Brain Barrier. Proteomes, 9.","DOI":"10.3390\/proteomes9040045"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1602\/neurorx.2.1.27","article-title":"Localization of brain endothelial luminal and abluminal transporters with immunogold electron microscopy","volume":"2","author":"Cornford","year":"2005","journal-title":"NeuroRx"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.pharmthera.2012.07.006","article-title":"Insulin in the brain: There and back again","volume":"136","author":"Banks","year":"2012","journal-title":"Pharmacol. Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1093\/brain\/awac309","article-title":"Cerebrovascular insulin receptors are defective in Alzheimer\u2019s disease","volume":"146","author":"Leclerc","year":"2023","journal-title":"Brain"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2232","DOI":"10.2337\/db14-0568","article-title":"Insulin action in brain regulates systemic metabolism and brain function","volume":"63","author":"Kleinridders","year":"2014","journal-title":"Diabetes"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nrneurol.2017.185","article-title":"Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums","volume":"14","author":"Arnold","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Rhea, E.M., and Banks, W.A. (2019). Role of the Blood-Brain Barrier in Central Nervous System Insulin Resistance. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00521"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/S0196-9781(99)00045-5","article-title":"Uptake and degradation of blood-borne insulin by the olfactory bulb","volume":"20","author":"Banks","year":"1999","journal-title":"Peptides"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1210\/mend-5-5-734","article-title":"Different ligand affinities of the two human insulin receptor splice variants are reflected in parallel changes in sensitivity for insulin action","volume":"5","author":"McClain","year":"1991","journal-title":"Mol. Endocrinol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1210\/er.2017-00073","article-title":"Insulin Receptor Isoforms in Physiology and Disease: An Updated View","volume":"38","author":"Belfiore","year":"2017","journal-title":"Endocr. Rev."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1403206","DOI":"10.1155\/2017\/1403206","article-title":"The Role of Insulin Receptor Isoforms in Diabetes and Its Metabolic and Vascular Complications","volume":"2017","author":"Escribano","year":"2017","journal-title":"J. Diabetes Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1210\/edrv-7-3-314","article-title":"Receptor-mediated peptide transport through the blood-brain barrier","volume":"7","author":"Pardridge","year":"1986","journal-title":"Endocr. Rev."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Pardridge, W.M. (2023). Receptor-mediated drug delivery of bispecific therapeutic antibodies through the blood-brain barrier. Front. Drug Deliv., 3.","DOI":"10.3389\/fddev.2023.1227816"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"a009191","DOI":"10.1101\/cshperspect.a009191","article-title":"Insulin receptor signaling in normal and insulin-resistant states","volume":"6","author":"Boucher","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/BF02244106","article-title":"Benzodiazepine concentrations in brain directly reflect receptor occupancy: Studies of diazepam, lorazepam, and oxazepam","volume":"102","author":"Greenblatt","year":"1990","journal-title":"Psychopharmacology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1021\/acs.molpharmaceut.6b01166","article-title":"Brain and Organ Uptake in the Rhesus Monkey in Vivo of Recombinant Iduronidase Compared to an Insulin Receptor Antibody-Iduronidase Fusion Protein","volume":"14","author":"Boado","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1146\/annurev.bi.60.070191.001353","article-title":"Lysosomal storage diseases","volume":"60","author":"Neufeld","year":"1991","journal-title":"Annu. Rev. Biochem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jbiotec.2009.08.019","article-title":"AGT-181: Expression in CHO cells and pharmacokinetics, safety, and plasma iduronidase enzyme activity in Rhesus monkeys","volume":"144","author":"Boado","year":"2009","journal-title":"J. Biotechnol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1002\/bit.21602","article-title":"Genetic engineering of a lysosomal enzyme fusion protein for targeted delivery across the human blood-brain barrier","volume":"99","author":"Boado","year":"2008","journal-title":"Biotechnol. Bioeng."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1136\/jcp.36.4.415","article-title":"Biochemical and histopathological studies on patients with mucopolysaccharidoses, two of whom had been treated by fibroblast transplantation","volume":"36","author":"Crow","year":"1983","journal-title":"J. Clin. Pathol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.omtm.2023.05.010","article-title":"Enzyme replacement with transferrin receptor-targeted \u03b1-L-iduronidase rescues brain pathology in mucopolysaccharidosis I mice","volume":"29","author":"Kida","year":"2023","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e37","DOI":"10.1542\/peds.2006-2156","article-title":"Enzyme replacement therapy in patients who have mucopolysaccharidosis I and are younger than 5 years: Results of a multinational study of recombinant human alpha-L-iduronidase (laronidase)","volume":"120","author":"Wraith","year":"2007","journal-title":"Pediatrics"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1146\/annurev-nutr-082117-051749","article-title":"Crossing the Iron Gate: Why and How Transferrin Receptors Mediate Viral Entry","volume":"38","year":"2018","journal-title":"Annu. Rev. Nutr."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Thomsen, M.S., Johnsen, K.B., Kucharz, K., Lauritzen, M., and Moos, T. (2022). Blood-Brain Barrier Transport of Transferrin Receptor-Targeted Nanoparticles. Pharmaceutics, 14.","DOI":"10.20944\/preprints202210.0194.v1"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Shen, X., Li, H., Zhang, B., Li, Y., and Zhu, Z. (2025). Targeting Transferrin Receptor 1 for Enhancing Drug Delivery Through the Blood-Brain Barrier for Alzheimer\u2019s Disease. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26199793"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1177\/42.11.7930531","article-title":"In vivo demonstration of subcellular localization of anti-transferrin receptor monoclonal antibody-colloidal gold conjugate in brain capillary endothelium","volume":"42","author":"Bickel","year":"1994","journal-title":"J. Histochem. Cytochem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"H1149","DOI":"10.1152\/ajpheart.1996.270.4.H1149","article-title":"Receptor-mediated transcytosis of transferrin through blood-brain barrier endothelial cells","volume":"270","author":"Descamps","year":"1996","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1002\/ijch.201600034","article-title":"Metalloneurochemistry and the Pierian Spring: \u201cShallow draughts intoxicate the brain.\u201d","volume":"56","author":"Goldberg","year":"2016","journal-title":"Isr. J. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s10571-010-9558-0","article-title":"Transient expression of iron transport proteins in the capillary of the developing rat brain","volume":"31","author":"Yang","year":"2011","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1007\/s00018-014-1771-4","article-title":"Iron transport across the blood-brain barrier: Development, neurovascular regulation and cerebral amyloid angiopathy","volume":"72","author":"McCarthy","year":"2015","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1177\/0271678X251361997","article-title":"Transferrin receptor-mediated transport at the blood-brain barrier is elevated during early development and maintained across aging and in an Alzheimer\u2019s mouse model","volume":"46","author":"Torres","year":"2026","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1073\/pnas.80.8.2258","article-title":"PH and the recycling of transferrin during receptor-mediated endocytosis","volume":"80","author":"Ciechanover","year":"1983","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"13089","DOI":"10.1073\/pnas.1105786108","article-title":"How the binding of human transferrin primes the transferrin receptor potentiating iron release at endosomal pH","volume":"108","author":"Eckenroth","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"4553","DOI":"10.1073\/pnas.82.13.4553","article-title":"Transferrin receptors in rat brain: Neuropeptide-like pattern and relationship to iron distribution","volume":"82","author":"Hill","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1021\/acs.biochem.8b00006","article-title":"Transferrin Receptors TfR1 and TfR2 Bind Transferrin through Differing Mechanisms","volume":"57","author":"Kleven","year":"2018","journal-title":"Biochemistry"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0304-4165(02)00146-0","article-title":"Iodination significantly influences the binding of human transferrin to the transferrin receptor","volume":"1570","author":"Fuchs","year":"2002","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"84ra44","DOI":"10.1126\/scitranslmed.3002230","article-title":"Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target","volume":"3","author":"Yu","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"10706","DOI":"10.1073\/pnas.162362999","article-title":"An anti-transferrin receptor-avidin fusion protein exhibits both strong proapoptotic activity and the ability to deliver various molecules into cancer cells","volume":"99","author":"Ng","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1182\/blood-2006-04-020263","article-title":"Molecular events contributing to cell death in malignant human hematopoietic cells elicited by an IgG3-avidin fusion protein targeting the transferrin receptor","volume":"108","author":"Ng","year":"2006","journal-title":"Blood"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1124\/dmd.111.038349","article-title":"Chronic dosing of mice with a transferrin receptor monoclonal antibody-glial-derived neurotrophic factor fusion protein","volume":"39","author":"Zhou","year":"2011","journal-title":"Drug Metab. Dispos."},{"key":"ref_114","first-page":"100758","article-title":"Nonclinical safety evaluation of pabinafusp alfa, an anti-human transferrin receptor antibody and iduronate-2-sulfatase fusion protein, for the treatment of neuronopathic mucopolysaccharidosis type II","volume":"27","author":"Yamamoto","year":"2021","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Pardridge, W.M. (2021). Kinetics of Blood-Brain Barrier Transport of Monoclonal Antibodies Targeting the Insulin Receptor and the Transferrin Receptor. Pharmaceuticals, 15.","DOI":"10.3390\/ph15010003"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"3534","DOI":"10.1021\/acs.molpharmaceut.9b00369","article-title":"Plasma Pharmacokinetics of High-Affinity Transferrin Receptor Antibody-Erythropoietin Fusion Protein is a Function of Effector Attenuation in Mice","volume":"16","author":"Sun","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2515414","DOI":"10.1080\/19420862.2025.2515414","article-title":"Translational minimal physiologically based pharmacokinetic model for transferrin receptor-mediated brain delivery of antibodies","volume":"17","author":"Muliaditan","year":"2025","journal-title":"mAbs"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.medj.2022.09.007","article-title":"Enhanced delivery of antibodies across the blood-brain barrier via TEMs with inherent receptor-mediated phagocytosis","volume":"3","author":"Edavettal","year":"2022","journal-title":"Med"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"e00492","DOI":"10.1016\/j.neurot.2024.e00492","article-title":"Lowering the affinity of single-chain monovalent BBB shuttle scFc-scFv8D3 prolongs its half-life and increases brain concentration","volume":"22","author":"Rosa","year":"2025","journal-title":"Neurotherapeutics"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s12987-025-00643-y","article-title":"The effects of dose, valency, and affinity on TfR-mediated brain delivery in vivo","volume":"22","author":"Bonvicini","year":"2025","journal-title":"Fluids Barriers CNS"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Choi, E.S., Sahota, S., Burnham, E., Ding, Y., and Shusta, E.V. (2025). Strategies to Screen and Evaluate Brain Targeting Antibodies Using an iPSC-Derived Blood-Brain Barrier Model. Antibodies, 14.","DOI":"10.3390\/antib14040102"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1016\/j.ymthe.2018.02.032","article-title":"A Blood-Brain-Barrier-Penetrating Anti-human Transferrin Receptor Antibody Fusion Protein for Neuronopathic Mucopolysaccharidosis II","volume":"26","author":"Sonoda","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.ymthe.2018.12.005","article-title":"Iduronate-2-Sulfatase with Anti-human Transferrin Receptor Antibody for Neuropathic Mucopolysaccharidosis II: A Phase 1\/2 Trial","volume":"27","author":"Okuyama","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"3140","DOI":"10.1002\/bcp.70612","article-title":"Infusion rate adjustment in enzyme replacement therapy with pabinafusp alfa for mucopolysaccharidosis II","volume":"92","author":"Nakamura","year":"2026","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"23212","DOI":"10.1016\/S0021-9258(17)31641-1","article-title":"Molecular cloning and expression of palmitoyl-protein thioesterase","volume":"269","author":"Camp","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_126","first-page":"100930","article-title":"Treatment of CLN1 disease with a blood-brain barrier penetrating lysosomal enzyme","volume":"33","author":"Hahn","year":"2022","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"eaay1163","DOI":"10.1126\/scitranslmed.aay1163","article-title":"Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice","volume":"12","author":"Ullman","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_128","unstructured":"(2026, August 30). Trontinemab Fuels Hope for Brain Shuttle Lift-Off. Available online: https:\/\/www.alzforum.org\/news\/conference-coverage\/trontinemab-fuels-hope-brain-shuttle-lift."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"eads3204","DOI":"10.1126\/science.ads3204","article-title":"Transferrin receptor-targeted anti-amyloid antibody enhances brain delivery and mitigates ARIA","volume":"389","author":"Pizzo","year":"2025","journal-title":"Science"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"e21172","DOI":"10.1096\/fj.202001787R","article-title":"Blood-brain barrier transport using a high affinity, brain-selective VNAR antibody targeting transferrin receptor 1","volume":"35","author":"Stocki","year":"2021","journal-title":"FASEB J."},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Clarke, E., Stocki, P., Sinclair, E.H., Gauhar, A., Fletcher, E.J.R., Krawczun-Rygmaczewska, A., Duty, S., Walsh, F.S., Doherty, P., and Rutkowski, J.L. (2022). A Single Domain Shark Antibody Targeting the Transferrin Receptor 1 Delivers a TrkB Agonist Antibody to the Brain and Provides Full Neuroprotection in a Mouse Model of Parkinson\u2019s Disease. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14071335"},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Sumbria, R.K., and Boado, R.J. (2026). Brain Delivery of Antibody-Derived Biologicals for Alzheimer\u2019s Disease: An Updated Narrative Review. Antibodies, 15.","DOI":"10.3390\/antib15020037"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1111\/j.1471-4159.2007.04759.x","article-title":"Sensitive ELISA detection of amyloid-beta protofibrils in biological samples","volume":"103","author":"Englund","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"100214","DOI":"10.1016\/j.tjpad.2025.100214","article-title":"Bispecific brain-penetrant antibodies for treatment of Alzheimer\u2019s disease","volume":"12","author":"Sehlin","year":"2025","journal-title":"J. Prev. Alzheimers Dis."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1007\/s11095-022-03282-2","article-title":"Transferrin Receptor Binding BBB-Shuttle Facilitates Brain Delivery of Anti-A\u03b2-Affibodies","volume":"39","author":"Lindberg","year":"2022","journal-title":"Pharm. Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.omtm.2020.08.014","article-title":"Tetravalent Bispecific Tandem Antibodies Improve Brain Exposure and Efficacy in an Amyloid Transgenic Mouse Model","volume":"19","author":"Do","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0304-3940(03)00898-X","article-title":"Human neprilysin is capable of degrading amyloid beta peptide not only in the monomeric form but also the pathological oligomeric form","volume":"350","author":"Kanemitsu","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Campos, C.R., Kemble, A.M., Niewoehner, J., Freskg\u00e5rd, P.O., and Urich, E. (2020). Brain Shuttle Neprilysin reduces central Amyloid-\u03b2 levels. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0229850"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"118325","DOI":"10.1016\/j.biopha.2025.118325","article-title":"Somatostatin therapy, neprilysin activation, and amyloid beta reduction: A novel approach for Alzheimer\u2019s treatment","volume":"189","author":"Metzendorf","year":"2025","journal-title":"Biomed. Pharmacother."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"e22208","DOI":"10.1096\/fj.202101644R","article-title":"Targeting insulin-like growth factor-1 receptor (IGF1R) for brain delivery of biologics","volume":"36","author":"Alata","year":"2022","journal-title":"FASEB J."},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Yogi, A., Hussack, G., van Faassen, H., Haqqani, A.S., Delaney, C.E., Brunette, E., Sandhu, J.K., Hewitt, M., Sulea, T., and Kemmerich, K. (2022). Brain Delivery of IGF1R5, a Single-Domain Antibody Targeting Insulin-like Growth Factor-1 Receptor. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14071452"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"14892","DOI":"10.1038\/ncomms14892","article-title":"Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression","volume":"8","author":"Cai","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/nrm1837","article-title":"Critical nodes in signalling pathways: Insights into insulin action","volume":"7","author":"Taniguchi","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.cytogfr.2005.04.004","article-title":"Molecular interactions of the IGF system","volume":"16","author":"Denley","year":"2005","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.neuroscience.2016.03.056","article-title":"The role of Insulin-Like Growth Factor 1 (IGF-1) in brain development, maturation and neuroplasticity","volume":"325","author":"Dyer","year":"2016","journal-title":"Neuroscience"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1007\/PL00000744","article-title":"Structure and function of the type 1 insulin-like growth factor receptor","volume":"57","author":"Adams","year":"2000","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"e03772","DOI":"10.7554\/eLife.03772","article-title":"How IGF-1 activates its receptor","volume":"3","author":"Kavran","year":"2014","journal-title":"Elife"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s12987-020-00209-0","article-title":"Differential expression of receptors mediating receptor-mediated transcytosis (RMT) in brain microvessels, brain parenchyma and peripheral tissues of the mouse and the human","volume":"17","author":"Zhang","year":"2020","journal-title":"Fluids Barriers CNS"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"4284","DOI":"10.1038\/s41598-021-83198-w","article-title":"Defining the epitope of a blood-brain barrier crossing single domain antibody specific for the type 1 insulin-like growth factor receptor","volume":"11","author":"Sheff","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/0306-4522(92)90193-6","article-title":"Cellular pattern of type-I insulin-like growth factor receptor gene expression during maturation of the rat brain: Comparison with insulin-like growth factors I and II","volume":"46","author":"Bondy","year":"1992","journal-title":"Neuroscience"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1007\/s12035-019-01827-y","article-title":"Adenovirus-Mediated Transduction of Insulin-Like Growth Factor 1 Protects Hippocampal Neurons from the Toxicity of A\u03b2 Oligomers and Prevents Memory Loss in an Alzheimer Mouse Model","volume":"57","author":"Selles","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1210\/er.2004-0024","article-title":"The insulin-like growth factor system and its pleiotropic functions in brain","volume":"26","author":"Russo","year":"2005","journal-title":"Endocr. Rev."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"384017","DOI":"10.1155\/2012\/384017","article-title":"Insulin in central nervous system: More than just a peripheral hormone","volume":"2012","author":"Duarte","year":"2012","journal-title":"J. Aging Res."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1016\/j.euroneuro.2014.01.020","article-title":"Insulin and insulin-like growth factor receptors in the brain: Physiological and pathological aspects","volume":"24","author":"Werner","year":"2014","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.neuron.2010.08.007","article-title":"Neuronal activity drives localized blood-brain-barrier transport of serum insulin-like growth factor-I into the CNS","volume":"67","author":"Nishijima","year":"2010","journal-title":"Neuron"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1073\/pnas.82.7.2153","article-title":"Insulin-like growth factor II (IGF II) in human brain: Regional distribution of IGF II and of higher molecular mass forms","volume":"82","author":"Haselbacher","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.str.2020.05.002","article-title":"How IGF-II Binds to the Human Type 1 Insulin-like Growth Factor Receptor","volume":"28","author":"Xu","year":"2020","journal-title":"Structure"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"116149","DOI":"10.1016\/j.celrep.2025.116149","article-title":"Viral insulin\/IGF-like peptides inhibit IGF-1 receptor signaling to enhance viral replication","volume":"44","author":"Chuard","year":"2025","journal-title":"Cell Rep."},{"key":"ref_159","doi-asserted-by":"crossref","unstructured":"Huttunen, J., Adla, S.K., Markowicz-Piasecka, M., and Huttunen, K.M. (2022). Increased\/Targeted Brain (Pro)Drug Delivery via Utilization of Solute Carriers (SLCs). Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14061234"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.cpet.2014.09.005","article-title":"18F-fluorodeoxyglucose PET\/computed tomography for primary brain tumors","volume":"10","author":"Segtnan","year":"2015","journal-title":"PET Clin."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"5221","DOI":"10.1007\/s11010-025-05324-w","article-title":"The role of L-DOPA in neurological and neurodegenerative complications: A review","volume":"480","author":"Kulkarni","year":"2025","journal-title":"Mol. Cell. Biochem."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"118382","DOI":"10.1016\/j.ejmech.2025.118382","article-title":"Advances in the development of large neutral amino acid transporter 1 (LAT1) substrate analogues and inhibitors for the delivery of drugs and radiopharmaceuticals","volume":"302","author":"Zhao","year":"2026","journal-title":"Eur. J. Med. Chem."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.neuron.2015.11.024","article-title":"Discovery of Novel Blood-Brain Barrier Targets to Enhance Brain Uptake of Therapeutic Antibodies","volume":"89","author":"Zuchero","year":"2016","journal-title":"Neuron"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"5053","DOI":"10.1038\/s41467-023-40681-4","article-title":"CD98hc is a target for brain delivery of biotherapeutics","volume":"14","author":"Chew","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1038\/s41467-025-57108-x","article-title":"Fc-engineered large molecules targeting blood-brain barrier transferrin receptor and CD98hc have distinct central nervous system and peripheral biodistribution","volume":"16","author":"Khoury","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1111\/j.1471-4159.2011.07208.x","article-title":"Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors","volume":"117","author":"Uchida","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.1002\/jps.23575","article-title":"Quantitative atlas of blood-brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset","volume":"102","author":"Hoshi","year":"2013","journal-title":"J. Pharm. Sci."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"183ra57","DOI":"10.1126\/scitranslmed.3005338","article-title":"Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier","volume":"5","author":"Couch","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_169","first-page":"1009","article-title":"Safety, tolerability, and pharmacokinetics of verenafusp alfa in healthy volunteers: Results of an open-label multicohort phase I study","volume":"97","author":"Smolyarchuk","year":"2025","journal-title":"Ter. Arkhiv"},{"key":"ref_170","unstructured":"(2026, August 30). DailyMed\u2014AVLAYAH-Tividenofusp Alfa-Eknm Injection, Powder, Lyophilized, for Solution, Available online: https:\/\/dailymed.nlm.nih.gov\/dailymed\/lookup.cfm?setid=014d92c1-b643-4680-8ca6-f0b3307da915."}],"container-title":["Antibodies"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4468\/15\/5\/86\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T04:34:08Z","timestamp":1789965248000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4468\/15\/5\/86"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,16]]},"references-count":170,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["antib15050086"],"URL":"https:\/\/doi.org\/10.3390\/antib15050086","relation":{},"ISSN":["2073-4468"],"issn-type":[{"value":"2073-4468","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,16]]}}}