{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T00:18:36Z","timestamp":1793837916663,"version":"4.6.1"},"reference-count":100,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Aging of the National Institutes of Health","award":["R01AG062840"],"award-info":[{"award-number":["R01AG062840"]}]},{"name":"National Institute of Aging of the National Institutes of Health","award":["R01AG085724"],"award-info":[{"award-number":["R01AG085724"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibodies"],"abstract":"<jats:p>Antibodies directed against \u03b2-amyloid (A\u03b2) have been developed for the treatment of Alzheimer\u2019s disease (AD). However, the in vivo central efficacy is reduced by the poor penetration of antibodies across the blood\u2013brain barrier (BBB). In addition, these antibodies have been associated with adverse effects like amyloid-related imaging abnormalities. Thus, the development of new antibody-based therapies for AD with improved transport across the BBB may improve efficacy and reduce adverse effects. Antibodies targeting the BBB transferrin receptor (TfR) are able to cross the BBB through receptor-mediated transcytosis, producing a global distribution throughout the brain. Along the same line, bispecific antibodies directed to both the BBB TfR and A\u03b2 showed enhanced brain uptake and pharmacological effects with diminished adverse side effects in experimental animal models of AD and in clinical trials. A generation of brain-penetrating fusion proteins targeting the BBB-TfR has been shown to represent novel treatments for AD, and this includes erythropoietin, tumor necrosis factor alpha inhibitors, neprilysin, somatostatin, oligonucleotides, and an antibody activating TREM2. The aim of this article is to review the progress made in the delivery of antibody-derived biologicals to the brain for AD, targeting the BBB-TfR.<\/jats:p>","DOI":"10.3390\/antib15020037","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T10:11:04Z","timestamp":1776420664000},"page":"37","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Brain Delivery of Antibody-Derived Biologicals for Alzheimer\u2019s Disease: An Updated Narrative Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7459-0723","authenticated-orcid":false,"given":"Rachita K.","family":"Sumbria","sequence":"first","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences and Center for Targeted Drug Delivery (CTDD), School of Pharmacy, Chapman University, Irvine, CA 92618, USA"},{"name":"Department of Neurology, University of California, Irvine, CA 92697, 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":[[2026,4,17]]},"reference":[{"key":"ref_1","unstructured":"(2021, June 25). LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Aducanumab, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK571858\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1111\/psyg.12944","article-title":"Aducanumab for the treatment of Alzheimer\u2019s disease: A systematic review","volume":"23","author":"Rahman","year":"2023","journal-title":"Psychogeriatrics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1007\/s40265-024-02087-4","article-title":"Donanemab: First Approval","volume":"84","author":"Kang","year":"2024","journal-title":"Drugs"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1001\/jama.2023.13239","article-title":"Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial","volume":"330","author":"Sims","year":"2023","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/s40265-023-01851-2","article-title":"Lecanemab: First Approval","volume":"83","author":"Hoy","year":"2023","journal-title":"Drugs"},{"key":"ref_6","unstructured":"(2023, February 10). LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Lecanemab, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK589468\/."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Doran, S.J., and Sawyer, R.P. (2024). Risk factors in developing amyloid related imaging abnormalities (ARIA) and clinical implications. Front. Neurosci., 18.","DOI":"10.3389\/fnins.2024.1326784"},{"key":"ref_8","first-page":"281","article-title":"Blood-brain barrier and new approaches to brain drug delivery","volume":"156","author":"Pardridge","year":"1992","journal-title":"West. J. Med."},{"key":"ref_9","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_10","doi-asserted-by":"crossref","unstructured":"Pardridge, W.M. (2022). A Historical Review of Brain Drug Delivery. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14061283"},{"key":"ref_11","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_12","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_13","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_14","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1159\/000356193","article-title":"Physiology and pharmacology of erythropoietin","volume":"40","author":"Jelkmann","year":"2013","journal-title":"Transfus. Med. Hemother"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nrn1687","article-title":"Emerging biological roles for erythropoietin in the nervous system","volume":"6","author":"Brines","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"387","DOI":"10.2174\/156720205774962683","article-title":"Erythropoietin requires NF-kappaB and its nuclear translocation to prevent early and late apoptotic neuronal injury during beta-amyloid toxicity","volume":"2","author":"Chong","year":"2005","journal-title":"Curr. Neurovasc Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/2047-9158-1-7","article-title":"Erythropoietin prevents PC12 cells from beta-amyloid-induced apoptosis via PI3K\u2044Akt pathway","volume":"1","author":"Jing","year":"2012","journal-title":"Transl. Neurodegener."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.neulet.2008.07.007","article-title":"Protective effect of erythropoietin on beta-amyloid-induced PC12 cell death through antioxidant mechanisms","volume":"442","author":"Li","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3234","DOI":"10.1111\/bph.12672","article-title":"JAK2\/STAT5\/Bcl-xL signalling is essential for erythropoietin-mediated protection against apoptosis induced in PC12 cells by the amyloid \u03b2-peptide A\u03b225-35","volume":"171","author":"Ma","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.brainres.2015.05.031","article-title":"Erythropoietin attenuates Alzheimer-like memory impairments and pathological changes induced by amyloid \u03b242 in mice","volume":"1618","author":"Li","year":"2015","journal-title":"Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/j.1471-4159.2011.07534.x","article-title":"Erythropoietin improves memory function with reducing endothelial dysfunction and amyloid-beta burden in Alzheimer\u2019s disease models","volume":"120","author":"Lee","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.ejphar.2015.11.046","article-title":"Downstream modulation of extrinsic apoptotic pathway in streptozotocin-induced Alzheimer\u2019s dementia in rats: Erythropoietin versus curcumin","volume":"770","author":"Samy","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3233\/JAD-141389","article-title":"Memory Improvement in the A\u03b2PP\/PS1 Mouse Model of Familial Alzheimer\u2019s Disease Induced by Carbamylated-Erythropoietin is Accompanied by Modulation of Synaptic Genes","volume":"45","author":"Aso","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13195-020-00766-4","article-title":"Erythropoietin-derived peptide treatment reduced neurological deficit and neuropathological changes in a mouse model of tauopathy","volume":"13","author":"Choi","year":"2021","journal-title":"Alzheimers Res. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"23","DOI":"10.17219\/acem\/61044","article-title":"Neuroprotective effects of erythropoietin on Alzheimer\u2019s dementia model in rats","volume":"26","author":"Cevik","year":"2017","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Shim, K.H., Ha, S., Choung, J.S., Choi, J.I., Kim, D.Y., Kim, J.M., and Kim, M. (2022). Therapeutic Effect of Erythropoietin on Alzheimer\u2019s Disease by Activating the Serotonin Pathway. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158144"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"50","DOI":"10.4103\/2277-9175.100157","article-title":"Erythropoietin improves neuronal proliferation in dentate gyrus of hippocampal formation in an animal model of Alzheimer\u2019s disease","volume":"1","author":"Arabpoor","year":"2012","journal-title":"Adv. Biomed. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lourhmati, A., Buniatian, G.H., Paul, C., Verleysdonk, S., Buecheler, R., Buadze, M., Proksch, B., Schwab, M., Gleiter, C.H., and Danielyan, L. (2013). Age-dependent astroglial vulnerability to hypoxia and glutamate: The role for erythropoietin. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0077182"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1097\/nen.0b013e3180517b28","article-title":"Brain erythropoietin receptor expression in Alzheimer disease and mild cognitive impairment","volume":"66","author":"Assaraf","year":"2007","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9848","DOI":"10.1073\/pnas.0901840106","article-title":"Optimal neuroprotection by erythropoietin requires elevated expression of its receptor in neurons","volume":"106","author":"Sanchez","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","first-page":"100459","article-title":"Longitudinal pharmacokinetic and safety studies of an antibody-erythropoietin fusion protein for Alzheimer\u2019s disease","volume":"10","author":"Chang","year":"2025","journal-title":"Int. J. Pharm. X"},{"key":"ref_32","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_33","doi-asserted-by":"crossref","first-page":"10526","DOI":"10.1073\/pnas.97.19.10526","article-title":"Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury","volume":"97","author":"Brines","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1111\/j.1471-4159.1987.tb04107.x","article-title":"Biotin transport through the blood-brain barrier","volume":"48","author":"Spector","year":"1987","journal-title":"J. Neurochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ejphar.2004.10.035","article-title":"Passage of erythropoietic agents across the blood-brain barrier: A comparison of human and murine erythropoietin and the analog darbepoetin alfa","volume":"505","author":"Banks","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1038\/ki.1997.55","article-title":"Detection of erythropoietin in human liquor: Intrinsic erythropoietin production in the brain","volume":"51","author":"Marti","year":"1997","journal-title":"Kidney Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e12782","DOI":"10.1111\/nan.12782","article-title":"Dysfunction of the blood-brain barrier in Alzheimer\u2019s disease: Evidence from human studies","volume":"48","author":"Kurz","year":"2022","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Wu, S.K., Yang, M.T., Kang, K.H., Liou, H.C., Lu, D.H., Fu, W.M., and Lin, W.L. (2014). Targeted delivery of erythropoietin by transcranial focused ultrasound for neuroprotection against ischemia\/reperfusion-induced neuronal injury: A long-term and short-term study. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090107"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1093\/brain\/awm203","article-title":"Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis","volume":"130","author":"Ehrenreich","year":"2007","journal-title":"Brain"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"171","DOI":"10.3171\/2009.3.JNS081332","article-title":"Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: A Phase II randomized, double-blind, placebo-controlled trial. Clinical article","volume":"111","author":"Tseng","year":"2009","journal-title":"J. Neurosurg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1001\/jama.2014.6490","article-title":"Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: A randomized clinical trial","volume":"312","author":"Robertson","year":"2014","journal-title":"JAMA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1161\/STROKEAHA.122.038650","article-title":"Transdural Revascularization by Multiple Burrhole After Erythropoietin in Stroke Patients With Cerebral Hypoperfusion: A Randomized Controlled Trial","volume":"53","author":"Hong","year":"2022","journal-title":"Stroke"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e647","DOI":"10.1161\/STROKEAHA.109.564872","article-title":"Recombinant human erythropoietin in the treatment of acute ischemic stroke","volume":"40","author":"Ehrenreich","year":"2009","journal-title":"Stroke"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1113\/jphysiol.2006.122689","article-title":"Erythropoietin treatment elevates haemoglobin concentration by increasing red cell volume and depressing plasma volume","volume":"578","author":"Lundby","year":"2007","journal-title":"J. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1517\/13543784.2010.517954","article-title":"Erythropoietin molecules to treat acute ischemic stroke: A translational dilemma!","volume":"19","author":"Lapchak","year":"2010","journal-title":"Expert. Opin. Investig. Drugs"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.2119\/molmed.2011.00259","article-title":"Circulating damage marker profiles support a neuroprotective effect of erythropoietin in ischemic stroke patients","volume":"17","author":"Ehrenreich","year":"2011","journal-title":"Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1177\/0269881113494939","article-title":"Intranasal formulation of erythropoietin (EPO) showed potent protective activity against amyloid toxicity in the A\u03b225\u201335 non-transgenic mouse model of Alzheimer\u2019s disease","volume":"27","author":"Maurice","year":"2013","journal-title":"J. Psychopharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.pbb.2014.12.011","article-title":"Erythropoietin improves synaptic plasticity and memory deficits by decrease of the neurotransmitter release probability in the rat model of Alzheimer\u2019s disease","volume":"130","author":"Moosavi","year":"2015","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.pathophys.2013.01.001","article-title":"Erythropoietin improves spatial learning and memory in streptozotocin model of dementia","volume":"20","author":"Hamidi","year":"2013","journal-title":"Pathophysiology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1080\/17482960600783456","article-title":"Erythropoietin does not preserve motor neurons in a mouse model of familial ALS","volume":"8","author":"Grignaschi","year":"2007","journal-title":"Amyotroph. Lateral Scler."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s12017-019-08524-y","article-title":"The Promises and Challenges of Erythropoietin for Treatment of Alzheimer\u2019s Disease","volume":"21","author":"Sun","year":"2019","journal-title":"Neuromolecular Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1177\/13872877251386885","article-title":"NeuroEPO plus (NeuralCIM(\u00ae)) in Alzheimer\u2019s disease: Post-trial observational follow-up study","volume":"108","year":"2025","journal-title":"J. Alzheimers Dis."},{"key":"ref_53","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_54","doi-asserted-by":"crossref","first-page":"6741","DOI":"10.1073\/pnas.1031753100","article-title":"Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo","volume":"100","author":"Erbayraktar","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"H\u00f6ke, A. (2006). Development of Non-Erythropoietic Erythropoietin Variants for Neuroprotection. Erythropoietin and the Nervous System: Novel Therapeutic Options for Neuroprotection, Springer US.","DOI":"10.1007\/978-0-387-30011-5"},{"key":"ref_56","first-page":"126","article-title":"Pharmacokinetics of erythropoietin in genetically anemic mice","volume":"26","author":"Kato","year":"1998","journal-title":"Drug Metab. Dispos."},{"key":"ref_57","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_58","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_59","doi-asserted-by":"crossref","first-page":"4963","DOI":"10.1021\/acs.molpharmaceut.8b00594","article-title":"Brain Penetrating Bifunctional Erythropoietin-Transferrin Receptor Antibody Fusion Protein for Alzheimer\u2019s Disease","volume":"15","author":"Chang","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_60","first-page":"627","article-title":"Hematologic safety of chronic brain-penetrating erythropoietin dosing in APP\/PS1 mice","volume":"5","author":"Sun","year":"2019","journal-title":"Alzheimers Dement"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Yang, J., Ou, W., Jagadeesan, N., Simanauskaite, J., Sun, J., Castellanos, D., Cribbs, D.H., and Sumbria, R.K. (2023). The Effects of a Blood-Brain Barrier Penetrating Erythropoietin in a Mouse Model of Tauopathy. Pharmaceuticals, 16.","DOI":"10.3390\/ph16040558"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.brainres.2011.01.061","article-title":"Brain penetrating IgG-erythropoietin fusion protein is neuroprotective following intravenous treatment in Parkinson\u2019s disease in the mouse","volume":"1382","author":"Zhou","year":"2011","journal-title":"Brain Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/s41582-025-01123-5","article-title":"Amyloid-lowering immunotherapies for Alzheimer disease: Current status and future directions","volume":"21","author":"Rafii","year":"2025","journal-title":"Nat. Rev. Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.nbd.2018.06.004","article-title":"Does inflammation precede tau aggregation in early Alzheimer\u2019s disease? A PET study","volume":"117","author":"Parbo","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/s41582-021-00549-x","article-title":"Peripheral and central immune system crosstalk in Alzheimer disease\u2014A research prospectus","volume":"17","author":"Bettcher","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/s41577-024-01104-7","article-title":"Neuroinflammation in Alzheimer disease","volume":"25","author":"Heneka","year":"2025","journal-title":"Nat. Rev. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1111\/j.1752-8062.2009.00121.x","article-title":"Translational medicine lessons from flurizan\u2019s failure in Alzheimer\u2019s disease (AD) trial: Implication for future drug discovery and development for AD","volume":"2","author":"Wan","year":"2009","journal-title":"Clin. Transl. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5155","DOI":"10.1523\/JNEUROSCI.2484-16.2017","article-title":"Peripheral Tumor Necrosis Factor-Alpha (TNF-\u03b1) Modulates Amyloid Pathology by Regulating Blood-Derived Immune Cells and Glial Response in the Brain of AD\/TNF Transgenic Mice","volume":"37","author":"Paouri","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1212\/WNL.0000000000001617","article-title":"Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial","volume":"84","author":"Butchart","year":"2015","journal-title":"Neurology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1179573517709278","DOI":"10.1177\/1179573517709278","article-title":"Tumor necrosis factor \u03b1 Inhibition for Alzheimer\u2019s Disease","volume":"9","author":"Chang","year":"2017","journal-title":"J. Cent. Nerv. Syst. Dis."},{"key":"ref_71","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_72","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.brainres.2010.10.053","article-title":"Anti-TNF-\u03b1 reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP\/PS1 transgenic mouse brains","volume":"1368","author":"Shi","year":"2011","journal-title":"Brain Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"713","DOI":"10.2165\/11310810-000000000-00000","article-title":"Tumour necrosis factor modulation for treatment of Alzheimer\u2019s disease: Rationale and current evidence","volume":"23","author":"Tobinick","year":"2009","journal-title":"CNS Drugs"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1111\/j.1532-5415.2011.03445.x","article-title":"Cognitive improvement with intrathecal administration of infliximab in a woman with Alzheimer\u2019s disease","volume":"59","author":"Shi","year":"2011","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.nbd.2017.02.010","article-title":"Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice","volume":"102","author":"MacPherson","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_76","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_77","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1124\/jpet.111.185876","article-title":"Neuroprotection with a brain-penetrating biologic tumor necrosis factor inhibitor","volume":"339","author":"Zhou","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1021\/mp400004a","article-title":"Pharmacokinetics and brain uptake of an IgG-TNF decoy receptor fusion protein following intravenous, intraperitoneal, and subcutaneous administration in mice","volume":"10","author":"Sumbria","year":"2013","journal-title":"Mol. Pharm."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1136\/jnnp.74.9.1200","article-title":"Intrathecal inflammation precedes development of Alzheimer\u2019s disease","volume":"74","author":"Tarkowski","year":"2003","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1186\/s12974-021-02332-7","article-title":"Biologic TNF-\u03b1 inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy","volume":"18","author":"Ou","year":"2021","journal-title":"J. Neuroinflamm."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1021\/acs.molpharmaceut.7b00200","article-title":"Blood-Brain Barrier Penetrating Biologic TNF-\u03b1 Inhibitor for Alzheimer\u2019s Disease","volume":"14","author":"Chang","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Ou, W., Ohno, Y., Yang, J., Chandrashekar, D.V., Abdullah, T., Sun, J., Murphy, R., Roules, C., Jagadeesan, N., and Cribbs, D.H. (2022). Efficacy and Safety of a Brain-Penetrant Biologic TNF-\u03b1 Inhibitor in Aged APP\/PS1 Mice. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14102200"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1186\/s12967-024-05008-x","article-title":"Modulation of hippocampal protein expression by a brain penetrant biologic TNF-\u03b1 inhibitor in the 3xTg Alzheimer\u2019s disease mice","volume":"22","author":"Jagadeesan","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_84","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_85","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1021\/mp1003515","article-title":"Receptor-mediated abeta amyloid antibody targeting to Alzheimer\u2019s disease mouse brain","volume":"8","author":"Zhou","year":"2011","journal-title":"Mol. Pharm."},{"key":"ref_86","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_87","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_88","doi-asserted-by":"crossref","first-page":"3507","DOI":"10.1021\/mp400348n","article-title":"Disaggregation of amyloid plaque in brain of Alzheimer\u2019s disease transgenic mice with daily subcutaneous administration of a tetravalent bispecific antibody that targets the transferrin receptor and the Abeta amyloid peptide","volume":"10","author":"Sumbria","year":"2013","journal-title":"Mol. Pharm."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1186\/s13195-022-01110-8","article-title":"Gantenerumab: An anti-amyloid monoclonal antibody with potential disease-modifying effects in early Alzheimer\u2019s disease","volume":"14","author":"Bateman","year":"2022","journal-title":"Alzheimers Res. Ther."},{"key":"ref_90","unstructured":"Kulic, L. (2025, January 1\u20135). Trontinemab Fuels Hope for Brain Shuttle Lift-Off. Proceedings of the AD\/PD\u2122 2025: Advances in Science & Therapy, Vienna, Austria."},{"key":"ref_91","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_92","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_93","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_94","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_95","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_96","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_97","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s13195-022-01132-2","article-title":"Blood-brain barrier penetrating neprilysin degrades monomeric amyloid-beta in a mouse model of Alzheimer\u2019s disease","volume":"14","author":"Rofo","year":"2022","journal-title":"Alzheimers Res. Ther."},{"key":"ref_98","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_99","first-page":"416","article-title":"A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer\u2019s disease models","volume":"26","author":"Zhan","year":"2023","journal-title":"Nat. Neurosci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1136\/jnnp-2025-337198","article-title":"Amyloid-related imaging abnormalities (ARIA) in Alzheimer\u2019s immunotherapy: A framework and challenges for global surveillance strategies","volume":"97","author":"Hu","year":"2026","journal-title":"J. Neurol. Neurosurg. Psychiatry"}],"container-title":["Antibodies"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4468\/15\/2\/37\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T10:28:30Z","timestamp":1776421710000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4468\/15\/2\/37"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,17]]},"references-count":100,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["antib15020037"],"URL":"https:\/\/doi.org\/10.3390\/antib15020037","relation":{},"ISSN":["2073-4468"],"issn-type":[{"value":"2073-4468","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,17]]}}}