{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T12:01:03Z","timestamp":1773144063960,"version":"3.50.1"},"reference-count":126,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,1,13]],"date-time":"2020-01-13T00:00:00Z","timestamp":1578873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PD\/BD\/128281\/2017, PTDC\/BBB-NAN\/1578\/2014, PTDC\/BIA-VIR\/29495\/2017"],"award-info":[{"award-number":["PD\/BD\/128281\/2017, PTDC\/BBB-NAN\/1578\/2014, PTDC\/BIA-VIR\/29495\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programme","award":["828774"],"award-info":[{"award-number":["828774"]}]},{"name":"\u201cla Caixa\u201d Banking Foundation","award":["HR17-00409"],"award-info":[{"award-number":["HR17-00409"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors due to their inherent targeting specificity. However, the use of mAbs in the treatment of CNS tumors is restricted by the blood\u2013brain barrier (BBB) that hinders the delivery of either small-molecules drugs (sMDs) or therapeutic proteins (TPs). To overcome this limitation, active research is focused on the development of strategies to deliver TPs and increase their concentration in the brain. Yet, their molecular weight and hydrophilic nature turn this task into a challenge. The use of BBB peptide shuttles is an elegant strategy. They explore either receptor-mediated transcytosis (RMT) or adsorptive-mediated transcytosis (AMT) to cross the BBB. The latter is preferable since it avoids enzymatic degradation, receptor saturation, and competition with natural receptor substrates, which reduces adverse events. Therefore, the combination of mAbs properties (e.g., selectivity and long half-life) with BBB peptide shuttles (e.g., BBB translocation and delivery into the brain) turns the therapeutic conjugate in a valid approach to safely overcome the BBB and efficiently eliminate metastatic brain cells.<\/jats:p>","DOI":"10.3390\/pharmaceutics12010062","type":"journal-article","created":{"date-parts":[[2020,1,13]],"date-time":"2020-01-13T04:05:51Z","timestamp":1578888351000},"page":"62","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0938-9038","authenticated-orcid":false,"given":"Marco","family":"Cavaco","sequence":"first","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal"}]},{"given":"Diana","family":"Gaspar","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal"}]},{"given":"Miguel","family":"ARB Castanho","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2989-7208","authenticated-orcid":false,"given":"Vera","family":"Neves","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3475","DOI":"10.1200\/JCO.2015.60.9503","article-title":"Treatment of Brain Metastases","volume":"33","author":"Lin","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1093\/neuonc\/nox077","article-title":"Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: A population-based study","volume":"19","author":"Cagney","year":"2017","journal-title":"Neuro-Oncology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1007\/s11912-011-0203-y","article-title":"Epidemiology of Brain Metastases","volume":"14","author":"Nayak","year":"2012","journal-title":"Curr. Oncol. Rep."},{"key":"ref_4","first-page":"4655","article-title":"Recent Trends in Epidemiology of Brain Metastases: An Overview","volume":"32","author":"Tabouret","year":"2012","journal-title":"Anticancer Res."},{"key":"ref_5","first-page":"884","article-title":"Multidisciplinary Management of Brain Metastases","volume":"12","author":"Eichler","year":"2007","journal-title":"Oncology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/nature17038","article-title":"Metastatic Colonization","volume":"529","author":"Obenauf","year":"2016","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1158\/0008-5472.CAN-17-2994","article-title":"Targeting Brain-Adaptive Cancer Stem Cells Prohibits Brain Metastatic Colonization of Triple-Negative Breast Cancer","volume":"78","author":"Ren","year":"2018","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.mrrev.2011.05.002","article-title":"Initial steps of metastasis: Cell invasion and endothelial transmigration","volume":"728","author":"Krupitza","year":"2011","journal-title":"Mutat. Res."},{"key":"ref_9","first-page":"523","article-title":"Molecular Pathways Mediating Metastases to the Brain via Epithelial-to-Mesenchymal Transition: Genes, Proteins, and Functional Analysis","volume":"36","author":"Jeevan","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/j.cell.2008.03.027","article-title":"The epithelial\u2013mesenchymal transition generates cells with properties of stem cells","volume":"133","author":"Mani","year":"2008","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1038\/s41556-018-0145-9","article-title":"Metastatic niche functions and therapeutic opportunities","volume":"20","author":"Kang","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.semcdb.2015.01.002","article-title":"Anatomy and Physiology of the Blood\u2013brain Barrier","volume":"38","author":"Serlin","year":"2015","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1021\/mp300518e","article-title":"Physiology of Blood\u2013Brain Interfaces in Relation to Brain Disposition of Small Compounds and Macromolecules","volume":"10","author":"Strazielle","year":"2013","journal-title":"Mol. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1002\/ca.23083","article-title":"Blood brain barrier: A review of its anatomy and physiology in health and disease","volume":"31","author":"Sharif","year":"2018","journal-title":"Clin. Anat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"a020412","DOI":"10.1101\/cshperspect.a020412","article-title":"The blood\u2013brain barrier","volume":"7","author":"Daneman","year":"2015","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/S0002-9440(10)61180-7","article-title":"Breast Cancer Metastasis to the Central Nervous System","volume":"167","author":"Weil","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nrd1414","article-title":"Targeted therapy for brain tumours","volume":"3","author":"Lesniak","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Green, C.E., Liu, T., Montel, V., Hsiao, G., Lester, R.D., Subramaniam, S., Gonias, S.L., and Klemke, R.L. (2009). Chemoattractant Signaling between Tumor Cells and Macrophages Regulates Cancer Cell Migration, Metastasis and Neovascularization. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0006713"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1101\/gad.314617.118","article-title":"Roles of the immune system in cancer: From tumor initiation to metastatic progression","volume":"32","author":"Gonzalez","year":"2018","journal-title":"Genes Dev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.3389\/fimmu.2019.01941","article-title":"Immune Microenvironment of Brain Metastases\u2014Are Microglia and Other Brain Macrophages Little Helpers?","volume":"10","author":"You","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_21","first-page":"33","article-title":"The role of the immune system in brain metastasis","volume":"10","author":"Leibold","year":"2019","journal-title":"Curr. Neurobiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1177\/1758834017736252","article-title":"Targeted therapy of brain metastases: Latest evidence and clinical implications","volume":"9","author":"Ahluwalia","year":"2017","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"161","DOI":"10.3389\/fonc.2018.00161","article-title":"Mechanisms and Therapy for Cancer Metastasis to the Brain","volume":"8","author":"Franchino","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.drudis.2006.10.013","article-title":"Blood\u2013brain barrier delivery","volume":"12","author":"Pardridge","year":"2007","journal-title":"Drug Discov. Today"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1158\/1078-0432.CCR-17-3351","article-title":"Drug Resistance in HER2-Positive Breast Cancer Brain Metastases: Blame the Barrier or the Brain?","volume":"24","author":"Kabraji","year":"2018","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.critrevonc.2019.07.010","article-title":"The evolving role of trastuzumab emtansine (T-DM1) in HER2-positive breast cancer with brain metastases","volume":"143","author":"Dong","year":"2019","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1186\/1748-717X-9-155","article-title":"Stereotactic radiosurgery (SRS) for brain metastases: A systematic review","volume":"9","author":"Nieder","year":"2014","journal-title":"Radiat. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1155\/2019\/3267409","article-title":"From Whole-Brain Radiotherapy to Immunotherapy: A Multidisciplinary Approach for Patients with Brain Metastases from NSCLC","volume":"2019","author":"Protopapa","year":"2019","journal-title":"J. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2923","DOI":"10.1093\/annonc\/mdx481","article-title":"Emerging treatment paradigms for brain metastasis in non-small-cell lung cancer: An overview of the current landscape and challenges ahead","volume":"28","author":"Ulahannan","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"30","DOI":"10.3389\/fsurg.2016.00030","article-title":"The Current and Future Treatment of Brain Metastases","volume":"3","author":"Hardesty","year":"2016","journal-title":"Front. Surg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"989","DOI":"10.4155\/tde.15.48","article-title":"Promising approaches to circumvent the blood\u2013brain barrier: Progress, pitfalls and clinical prospects in brain cancer","volume":"6","author":"Papademetriou","year":"2015","journal-title":"Ther. Deliv."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Teleanu, D.M., Chircov, C., Grumezescu, A.M., Volceanov, A., and Teleanu, R.I. (2018). Blood\u2013brain Delivery Methods Using Nanotechnology. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10040269"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.7150\/thno.21254","article-title":"Current Strategies for Brain Drug Delivery","volume":"8","author":"Dong","year":"2018","journal-title":"Theranostics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.nbd.2009.07.028","article-title":"Approaches to transport therapeutic drugs across the blood\u2013brain barrier to treat brain diseases","volume":"37","author":"Gabathuler","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s13052-018-0563-0","article-title":"Possible strategies to cross the blood\u2013brain barrier","volume":"44","author":"Bellettato","year":"2018","journal-title":"Ital. J. Pediatrics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e1129476","DOI":"10.1080\/21688370.2015.1129476","article-title":"Blood brain barrier: An overview on strategies in drug delivery, realistic in vitro modeling and in vivo live tracking","volume":"4","author":"Pandey","year":"2015","journal-title":"Tissue Barriers"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1002\/cncr.22450","article-title":"Enhanced chemotherapy delivery by intraarterial infusion and blood\u2013brain barrier disruption in the treatment of cerebral metastasis","volume":"109","author":"Fortin","year":"2007","journal-title":"Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/j.bbrc.2005.12.112","article-title":"Targeted delivery of antibodies through the blood\u2013brain barrier by MRI-guided focused ultrasound","volume":"340","author":"Kinoshita","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0361-9230(03)00043-1","article-title":"Facilitation of drug entry into the CNS via transient permeation of blood brain barrier: Laboratory and preliminary clinical evidence from bradykinin receptor agonist, Cereport","volume":"60","author":"Borlongan","year":"2003","journal-title":"Brain Res. Bull."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3\u201325.1","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"152","DOI":"10.3109\/09687688.2014.937468","article-title":"The blood\u2013brain barrier: Structure, function and therapeutic approaches to cross it","volume":"31","author":"Tajes","year":"2014","journal-title":"Molec. Membr. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Parodi, A., Rudzi\u0144ska, M., Deviatkin, A.A., Soond, S.M., Baldin, A.V., and Zamyatnin, A.A. (2019). Established and Emerging Strategies for Drug Delivery Across the Blood\u2013brain Barrier in Brain Cancer. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11050245"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.3389\/fnins.2018.01019","article-title":"Transcytosis to Cross the Blood Brain Barrier, New Advancements and Challenges","volume":"12","author":"Pulgar","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.tibtech.2015.10.005","article-title":"Antibody Approaches To Treat Brain Diseases","volume":"34","author":"Neves","year":"2015","journal-title":"Trends Biotechnol."},{"key":"ref_45","unstructured":"Gao, H., and Gao, X. (2019). 6\u2014Carrier-Mediated Transportation through BBB. Brain Targeted Drug Delivery System, Academic Press."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.3390\/molecules13051035","article-title":"Progress in Drug Delivery to the Central Nervous System by the Prodrug Approach","volume":"13","author":"Pavan","year":"2008","journal-title":"Molecules"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1016\/S0196-9781(01)00537-X","article-title":"Peptide drug modifications to enhance bioavailability and blood\u2013brain barrier permeability","volume":"22","author":"Witt","year":"2001","journal-title":"Peptides"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1038\/jcbfm.2012.126","article-title":"Drug transport across the blood\u2013brain barrier","volume":"32","author":"Pardridge","year":"2012","journal-title":"J. Cereb Blood Flow. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1023\/A:1007592720793","article-title":"Transport Across the Primate Blood\u2013brain 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_50","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1124\/mi.3.2.90","article-title":"Blood\u2013brain barrier drug targeting: The future of brain drug development","volume":"3","author":"Pardridge","year":"2003","journal-title":"Mol. Interv."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.brainres.2006.07.005","article-title":"Blood\u2013brain barrier targeting of BDNF improves motor function in rats with middle cerebral artery occlusion","volume":"1111","author":"Zhang","year":"2006","journal-title":"Brain Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"233","DOI":"10.3892\/etm.2014.1727","article-title":"Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants","volume":"211","author":"Yu","year":"2014","journal-title":"J. Exp. Med."},{"key":"ref_53","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_54","doi-asserted-by":"crossref","first-page":"261ra154","DOI":"10.1126\/scitranslmed.3009835","article-title":"Therapeutic bispecific antibodies cross the blood\u2013brain barrier in nonhuman primates","volume":"6","author":"Yu","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_55","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\u2013brain barrier","volume":"96","author":"Boado","year":"2007","journal-title":"Biotechnol. Bioeng."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Vieira, D.B., and Gamarra, L.F. (2018). Multifunctional Nanoparticles for Successful Targeted Drug Delivery across the Blood\u2013brain Barrier, Molecular Insight of Drug Design. IntechOpen.","DOI":"10.5772\/intechopen.76922"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2967","DOI":"10.1039\/C8CS00805A","article-title":"Emerging blood\u2013brain-barrier-crossing nanotechnology for brain cancer theranostics","volume":"48","author":"Tang","year":"2019","journal-title":"Chem. Soc. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.jconrel.2016.05.044","article-title":"Nanoparticle-mediated brain drug delivery: Overcoming blood\u2013brain barrier to treat neurodegenerative diseases","volume":"235","author":"Saraiva","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"709","DOI":"10.2217\/nnm.14.27","article-title":"Targeting nanoparticles across the blood\u2013brain barrier with monoclonal antibodies","volume":"9","author":"Loureiro","year":"2014","journal-title":"Nanomedicine"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1801362","DOI":"10.1002\/adma.201801362","article-title":"Overcoming the Blood\u2013Brain Barrier: The Role of Nanomaterials in Treating Neurological Diseases","volume":"30","author":"Furtado","year":"2018","journal-title":"Adv. Mater."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Abdul Razzak, R., Florence, G.J., and Gunn-Moore, F.J. (2019). Approaches to CNS Drug Delivery with a Focus on Transporter-Mediated Transcytosis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20123108"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.neuropharm.2016.08.025","article-title":"Targeting blood\u2013brain-barrier transcytosis\u2014Perspectives for drug delivery","volume":"120","author":"Meyer","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0169-409X(95)00005-R","article-title":"Antibody delivery through the blood\u2013brain barrier","volume":"15","author":"Bickel","year":"1995","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"15414","DOI":"10.1016\/S0021-9258(18)48160-4","article-title":"Adsorptive-mediated transcytosis of cationized albumin and a beta-endorphin-cationized albumin chimeric peptide by isolated brain capillaries. Model system of blood\u2013brain barrier transport","volume":"262","author":"Kumagai","year":"1987","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1208\/s12248-008-9055-2","article-title":"CNS Delivery Via Adsorptive Transcytosis","volume":"10","author":"Ghinea","year":"2008","journal-title":"AAPS J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4690","DOI":"10.1039\/C6CS00076B","article-title":"Blood\u2013brain barrier shuttle peptides: An emerging paradigm for brain delivery","volume":"45","author":"Giralt","year":"2016","journal-title":"Chem. Soc. Rev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.2174\/1381612824666171201115126","article-title":"Peptide Mediated Brain Delivery of Nano- and Submicroparticles: A Synergistic Approach","volume":"24","author":"McCully","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"113","DOI":"10.12688\/f1000research.9970.1","article-title":"Recent advances in (therapeutic protein) drug development","volume":"6","author":"Alexaki","year":"2017","journal-title":"F1000Research"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"295","DOI":"10.2165\/11319980-000000000-00000","article-title":"CYP-Mediated Therapeutic Protein-Drug Interactions","volume":"49","author":"Lee","year":"2010","journal-title":"Clin. Pharm."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1002\/cpt.605","article-title":"Interactions between therapeutic proteins and small molecules: The shared role of perpetrators and victims","volume":"102","author":"Cavaco","year":"2016","journal-title":"Clin. Pharm. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Rosenberg, A., and Demeule, B. (2015). Structure of Monoclonal Antibodies. Biobetters: Protein Engineering to Approach the Curative, Springer.","DOI":"10.1007\/978-1-4939-2543-8"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/nri2155","article-title":"FcRn: The neonatal Fc receptor comes of age","volume":"7","author":"Roopenian","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nri2744","article-title":"Antibodies and cancer therapy: Versatile platforms for cancer immunotherapy","volume":"10","author":"Weiner","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"38644","DOI":"10.1038\/srep38644","article-title":"Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo","volume":"6","author":"Dobson","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/j.biotechadv.2016.07.004","article-title":"Therapeutic monoclonal antibodies and derivatives: Historical perspectives and future directions","volume":"34","author":"Rodgers","year":"2016","journal-title":"Biotechnol. Adv."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.semcancer.2011.12.009","article-title":"Monoclonal Antibodies for the Treatment of Cancer","volume":"22","author":"Shuptrine","year":"2012","journal-title":"Semin. Cancer Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.virol.2010.12.045","article-title":"Complement and Viral Pathogenesis","volume":"411","author":"Stoermer","year":"2011","journal-title":"Virology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1111\/j.1349-7006.2009.01222.x","article-title":"Engineered therapeutic antibodies with improved effector functions","volume":"100","author":"Kubota","year":"2009","journal-title":"Cancer Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.molimm.2015.03.255","article-title":"Molecular properties of human IgG subclasses and their implications for designing therapeutic monoclonal antibodies against infectious diseases","volume":"67","author":"Irani","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1111\/j.1476-5381.2009.00190.x","article-title":"Therapeutic antibodies: Successes, limitations and hopes for the future","volume":"157","author":"Chames","year":"2009","journal-title":"Br. J. Pharm."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.3389\/fimmu.2017.01287","article-title":"Antibody or Antibody Fragments: Implications for Molecular Imaging and Targeted Therapy of Solid Tumors","volume":"8","author":"Xenaki","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Bates, A., and Power, C.A. (2019). David vs. Goliath: The Structure, Function, and Clinical Prospects of Antibody Fragments. Antibodies, 8.","DOI":"10.3390\/antib8020028"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.2147\/NDT.S114636","article-title":"The use of natalizumab for multiple sclerosis","volume":"13","author":"Brandstadter","year":"2017","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e2250","DOI":"10.1212\/WNL.0000000000007452","article-title":"Erenumab in chronic migraine","volume":"92","author":"Lipton","year":"2019","journal-title":"Neurology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/j.1527-3458.2007.00003.x","article-title":"Pharmacological Properties, Toxicology and Scientific Rationale for the use of Natalizumab (Tysabri\u00ae) in Inflammatory Diseases","volume":"13","author":"Bennett","year":"2007","journal-title":"CNS Drug Rev."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1177\/1756285608101861","article-title":"Natalizumab in the Treatment of Multiple Sclerosis","volume":"2","author":"Yaldizli","year":"2009","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1177\/0333102419867282","article-title":"Erenumab (AMG 334), a monoclonal antagonist antibody against the canonical CGRP receptor, does not impair vasodilatory or contractile responses to other vasoactive agents in human isolated cranial arteries","volume":"39","author":"Ohlsson","year":"2019","journal-title":"Cephalalgia"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1056\/NEJMoa1705848","article-title":"A Controlled Trial of Erenumab for Episodic Migraine","volume":"377","author":"Goadsby","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_89","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_90","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.neuron.2015.11.024","article-title":"Discovery of Novel Blood\u2013brain Barrier Targets to Enhance Brain Uptake of Therapeutic Antibodies","volume":"89","author":"Zuchero","year":"2016","journal-title":"Neuron"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Sehlin, D., Syv\u00e4nen, S., Ballanger, B., Barthel, H., Bischof, G.N., Boche, D., Boecker, H., Bohn, K.P., Borghammer, P., and Cross, D. (2019). Engineered antibodies: New possibilities for brain PET?. Eur. J. Nucl. Med. Mol. Imaging.","DOI":"10.1007\/s00259-019-04426-0"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.1016\/S1470-2045(17)30693-9","article-title":"Clinical trial design for systemic agents in patients with brain metastases from solid tumours: A guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group","volume":"19","author":"Camidge","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1007\/s00432-019-03034-7","article-title":"Brain metastasis as exclusion criteria in clinical trials involving extensive-stage small cell lung cancer","volume":"145","author":"Wang","year":"2019","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1097\/JTO.0000000000000615","article-title":"Targeted Therapy for Brain Metastases in EGFR-Mutated and ALK-Rearranged Non-Small-Cell Lung Cancer","volume":"10","author":"Baik","year":"2015","journal-title":"J. Thorac. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2217\/cns-2016-0038","article-title":"Immunotherapy and targeted therapy in brain metastases: Emerging options in precision medicine","volume":"6","author":"Lazaro","year":"2017","journal-title":"CNS Oncol."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Puttemans, J., Lahoutte, T., D\u2019Huyvetter, M., and Devoogdt, N. (2019). Beyond the Barrier: Targeted Radionuclide Therapy in Brain Tumors and Metastases. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11080376"},{"key":"ref_97","first-page":"2344","article-title":"Development of anticancer agents targeting the Wnt\/\u03b2-catenin signaling","volume":"5","author":"Zhang","year":"2015","journal-title":"Am. J. Cancer Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.pharmthera.2016.03.003","article-title":"Emerging therapeutic targets in metastatic progression: A focus on breast cancer","volume":"161","author":"Li","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Stalmans, S., Bracke, N., Wynendaele, E., Gevaert, B., Peremans, K., Burvenich, C., Polis, I., and De Spiegeleer, B. (2015). Cell-Penetrating Peptides Selectively Cross the Blood\u2013brain Barrier In Vivo. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0139652"},{"key":"ref_100","unstructured":"AntibodySociety (2019, December 05). Therapeutic Monoclonal Antibodies Approved or in Review in the EU or the US. Available online: https:\/\/www.antibodysociety.org\/resources\/approved-antibodies\/."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1002\/cpt.1412","article-title":"Novel Multiple Sclerosis Drugs in the Pipeline","volume":"105","author":"Chataway","year":"2019","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Jov\u010devska, I., and Muyldermans, S. (2019). The Therapeutic Potential of Nanobodies. BioDrugs.","DOI":"10.1007\/s40259-019-00392-z"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.trci.2019.05.008","article-title":"Alzheimer\u2019s disease drug development pipeline: 2019","volume":"5","author":"Cummings","year":"2019","journal-title":"Alzheimer\u2019s Dement. (N.Y.)"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1080\/19420862.2018.1556465","article-title":"Antibodies to watch in 2019","volume":"11","author":"Kaplon","year":"2019","journal-title":"mAbs"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"528","DOI":"10.3892\/br.2016.639","article-title":"Cell-penetrating peptides: Possible transduction mechanisms and therapeutic applications","volume":"4","author":"Guo","year":"2016","journal-title":"Biomed. Rep."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Avci, F.G., Akbulut, B.S., and Ozkirimli, E. (2018). Membrane Active Peptides and Their Biophysical Characterization. Biomolecules, 8.","DOI":"10.20944\/preprints201807.0008.v1"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.peptides.2010.10.006","article-title":"Computational studies of protegrin antimicrobial peptides: A review","volume":"32","author":"Bolintineanu","year":"2011","journal-title":"Peptides"},{"key":"ref_108","first-page":"414729","article-title":"Mechanisms of cellular uptake of cell-penetrating peptides","volume":"2011","author":"Madani","year":"2011","journal-title":"J. Biophys. (Hindawi Publ. Corp. Online)"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1016\/j.biopha.2018.09.097","article-title":"Cell penetrating peptides: A concise review with emphasis on biomedical applications","volume":"108","author":"Derakhshankhah","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1039\/C5BM00383K","article-title":"Strategies for transporting nanoparticles across the blood\u2013brain barrier","volume":"4","author":"Zhang","year":"2016","journal-title":"J. Biomater. Sci."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/0092-8674(88)90263-2","article-title":"Cellular uptake of the tat protein from human immunodeficiency virus","volume":"55","author":"Frankel","year":"1988","journal-title":"Cell"},{"key":"ref_112","first-page":"30361","article-title":"Routes for drug translocation across the blood\u2013brain barrier: Exploiting peptides as delivery vectors","volume":"S0022-3549","author":"Kristensen","year":"2017","journal-title":"J. Pharm. Sci."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1111\/j.1600-0854.2007.00572.x","article-title":"A Comprehensive Model for the Cellular Uptake of Cationic Cell-penetrating Peptides","volume":"8","author":"Duchardt","year":"2007","journal-title":"Traffic"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1126\/science.285.5433.1569","article-title":"In Vivo Protein Transduction: Delivery of a Biologically Active Protein into the Mouse","volume":"285","author":"Schwarze","year":"1999","journal-title":"Science"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"379","DOI":"10.3390\/ph3020379","article-title":"Cell Permeable Peptides: A Promising Tool to Deliver Neuroprotective Agents in the Brain","volume":"3","author":"Antoniou","year":"2010","journal-title":"Pharmaceutics"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"197","DOI":"10.2174\/1570159X11311020006","article-title":"Cell-Penetrating Peptide-Mediated Therapeutic Molecule Delivery into the Central Nervous System","volume":"11","author":"Zou","year":"2013","journal-title":"Curr. Neuropharmacol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1242\/jcs.02740","article-title":"Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling","volume":"119","author":"Yayon","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1124\/jpet.107.131318","article-title":"Identification and Design of Peptides as a New Drug Delivery System for the Brain","volume":"324","author":"Demeule","year":"2008","journal-title":"J. Pharm. Exp."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1158\/1535-7163.MCT-14-0399","article-title":"ANG4043, a Novel Brain-Penetrant Peptide-mAb Conjugate, Is Efficacious against HER2-Positive Intracranial Tumors in Mice","volume":"14","author":"Regina","year":"2015","journal-title":"Mol. Cancer"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"8244","DOI":"10.1038\/ncomms9244","article-title":"dNP2 is a blood\u2013brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis","volume":"6","author":"Lim","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Neves, V., Aires-da-Silva, F., Morais, M., Gano, L., Ribeiro, E., Pinto, A., Aguiar, S., Gaspar, D., Fernandes, C., and Correia, J.D.G. (2017). Novel peptides derived from Dengue virus capsid protein translocate reversibly the blood\u2013brain barrier through a receptor-free mechanism. ACS Chem. Biol.","DOI":"10.1021\/acschembio.7b00087"},{"key":"ref_122","unstructured":"C\u00f4rte-Real, S., Neves, V., Oliveira, S., Canh\u00e3o, P., Outeiro, T., Castanho, M., and Aires da Silva, F. (2016). Antibody Molecules and Peptide Delivery Systems for Use in Alzheimer\u2019S Disease and Related Disorders. (WO2016120843A1)."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"e23095","DOI":"10.1002\/bip.23095","article-title":"Peptibodies: An elegant solution for a long-standing problem","volume":"110","author":"Cavaco","year":"2018","journal-title":"Pept. Sci."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"4595","DOI":"10.4049\/jimmunol.1403014","article-title":"FcRn: The Architect Behind the Immune and Nonimmune Functions of IgG and Albumin","volume":"194","author":"Pyzik","year":"2015","journal-title":"J. Immunol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"17282","DOI":"10.18632\/oncotarget.24629","article-title":"Glioblastoma-specific anti-TUFM nanobody for in-vitro immunoimaging and cancer stem cell targeting","volume":"9","author":"Samec","year":"2018","journal-title":"Oncotarget"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.3389\/fimmu.2017.01442","article-title":"Nanobody-Based Delivery Systems for Diagnosis and Targeted Tumor Therapy","volume":"8","author":"Hu","year":"2017","journal-title":"Front. Immunol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/1\/62\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:42:52Z","timestamp":1760362972000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/1\/62"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,13]]},"references-count":126,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["pharmaceutics12010062"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics12010062","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,13]]}}}