Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans

References

• Wang S, Mims PN, Roman RJ, Fan F. Is beta-amyloid accumulation a cause or consequence of Alzheimer’s disease? J Alzheimers Parkinsonism Dement. 2016;1:007.
   PubMedGoogle Scholar
• Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimer’s & Dementia. 2021;17(3):327–14. doi:10.1002/alz.12328.
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration (FDA). FDA’s decision to approve new treatment for Alzheimer’s disease [press release]; 2021 June 7 [accessed 2023 June 28]. https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease.
   Google Scholar
• US Food and Drug Administration (FDA). FDA grants accelerated approval for Alzheimer’s disease treatment [press release]; 2023 January 6 [accessed 2023 June 28]. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment.
   Google Scholar
• Aging NNIo. NIA statement on report of lecanemab reducing cognitive decline in Alzheimer’s clinical trial; 2023 [accessed 2023 March 16]. https://www.nia.nih.gov/news/nia-statement-report-lecanemab-reducing-cognitive-decline-alzheimers-clinical-trial
   Google Scholar
• van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21. doi:10.1056/NEJMoa2212948.
   PubMed Web of Science ®Google Scholar
• Grossberg GT, Tong G, Burke AD, Tariot PN, Fink A. Present algorithms and future treatments for Alzheimer’s disease. J Alzheimers Dis. 2019;67(4):1157–71. doi:10.3233/JAD-180903.
   PubMed Web of Science ®Google Scholar
• Yiannopoulou KG, Papageorgiou SG. Current and future treatments in Alzheimer disease: an update. J Cent Nerv Syst Dis. 2020;12:1179573520907397. doi:10.1177/1179573520907397.
   Web of Science ®Google Scholar
• Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537(7618):50–56. doi:10.1038/nature19323.
   PubMed Web of Science ®Google Scholar
• Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, Messer J, Oroszlan K, Rauchenberger R, Richter WF, et al. Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J Alzheimers Dis. 2012;28(1):49–69. doi:10.3233/JAD-2011-110977.
   PubMed Web of Science ®Google Scholar
• Saunders NR, Dreifuss JJ, Dziegielewska KM, Johansson PA, Habgood MD, Møllgård K, Bauer HC. The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history. Front Neurosci. 2014;8:404. doi:10.3389/fnins.2014.00404.
   PubMed Web of Science ®Google Scholar
• Bonkowski D, Katyshev V, Balabanov RD, Borisov A, Dore-Duffy P. The CNS microvascular pericyte: pericyte-astrocyte crosstalk in the regulation of tissue survival. Fluids Barriers CNS. 2011;8(1):8. doi:10.1186/2045-8118-8-8.
   PubMedGoogle Scholar
• Beshir SA, Aadithsoorya AM, Parveen A, Goh SSL, Hussain N, Menon VB, Abate G. Aducanumab therapy to treat Alzheimer’s disease: a narrative review. Int J Alzheimers Dis. 2022;2022:1–10. doi:10.1155/2022/9343514.
   Google Scholar
• Pardridge WM. Drug transport across the blood–brain barrier. J Cereb Blood Flow Metab. 2012;32(11):1959–72. doi:10.1038/jcbfm.2012.126.
   PubMed Web of Science ®Google Scholar
• Freskgård PO, Urich E. Antibody therapies in CNS diseases. Neuropharmacol. 2017;120:38–55. doi:10.1016/j.neuropharm.2016.03.014.
   PubMed Web of Science ®Google Scholar
• Johnsen KB, Burkhart A, Thomsen LB, Andresen TL, Moos T. Targeting the transferrin receptor for brain drug delivery. Prog Neurobiol. 2019;181:101665. doi:10.1016/j.pneurobio.2019.101665.
   PubMed Web of Science ®Google Scholar
• Pardridge WM, Kang YS, Buciak JL, Yang J. 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. Pharm Res. 1995;12(6):807–16. doi:10.1023/A:1016244500596.
   PubMed Web of Science ®Google Scholar
• Haqqani AS, Delaney CE, Brunette E, Baumann E, Farrington GK, Sisk W, Eldredge J, Ding W, Tremblay TL, Stanimirovic DB. Endosomal trafficking regulates receptor-mediated transcytosis of antibodies across the blood brain barrier. J Cereb Blood Flow Metab. 2018;38(4):727–40. doi:10.1177/0271678X17740031.
   PubMed Web of Science ®Google Scholar
• Zuchero YJ, Chen X, Bien-Ly N, Bumbaca D, Tong RK, Gao X, Zhang S, Hoyte K, Luk W, Huntley MA, et al. Discovery of novel blood–brain barrier targets to enhance brain uptake of therapeutic antibodies. Neuron. 2016;89(1):70–82. doi:10.1016/j.neuron.2015.11.024.
   PubMed Web of Science ®Google Scholar
• Yu YJ, Atwal JK, Zhang Y, Tong RK, Wildsmith KR, Tan C, Bien-Ly N, Hersom M, Maloney JA, Meilandt WJ, et al. Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates. Sci Transl Med. 2014;6(261):261ra154. doi:10.1126/scitranslmed.3009835.
   PubMed Web of Science ®Google Scholar
• Boado RJ, Pardridge WM. Brain and organ uptake in the rhesus monkey in vivo of recombinant iduronidase compared to an insulin receptor antibody–iduronidase fusion protein. Mol Pharmaceut. 2017;14(4):1271–77. doi:10.1021/acs.molpharmaceut.6b01166.
   PubMed Web of Science ®Google Scholar
• Gadkar K, Yadav D, Zuchero J, Couch J, Kanodia J, Kenrick M, Atwal J, Dennis M, Prabhu S, Watts R, et al. Mathematical PKPD and safety model of bispecific TfR/BACE1 antibodies for the optimization of antibody uptake in brain. Eur J Pharm Biopharm. 2016;101:53–61. doi:10.1016/j.ejpb.2016.01.009.
   PubMed Web of Science ®Google Scholar
• Kanodia JS, Gadkar K, Bumbaca D, Zhang Y, Tong RK, Luk W, Hoyte K, Lu Y, Wildsmith KR, Couch JA, et al. Prospective design of anti‐transferrin receptor bispecific antibodies for optimal delivery into the human brain. CPT Pharmacometrics Syst Pharmacol. 2016;5(5):283–91. doi:10.1002/psp4.12081.
   PubMedGoogle Scholar
• Couch JA, Yu YJ, Zhang Y, Tarrant JM, Fuji RN, Meilandt WJ, Solanoy H, Tong RK, Hoyte K, Luk W, et al. Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier. Sci Transl Med. 2013;5(183):183ra157. doi:10.1126/scitranslmed.3005338.
   Web of Science ®Google Scholar
• Niewoehner J, Bohrmann B, Collin L, Urich E, Sade H, Maier P, Rueger P, Stracke JO, Lau W, Tissot AC, et al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron. 2014;81(1):49–60. doi:10.1016/j.neuron.2013.10.061.
   PubMed Web of Science ®Google Scholar
• Weber F, Bohrmann B, Niewoehner J, Fischer JAA, Rueger P, Tiefenthaler G, Moelleken J, Bujotzek A, Brady K, Singer T, et al. Brain shuttle antibody for Alzheimer’s disease with attenuated peripheral effector function due to an inverted binding mode. Cell Rep. 2018;22(1):149–62. doi:10.1016/j.celrep.2017.12.019.
   PubMed Web of Science ®Google Scholar
• Klein G, Delmar P, Voyle N, Rehal S, Hofmann C, Abi-Saab D, Andjelkovic M, Ristic S, Wang G, Bateman R, et al. Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alz Res Therapy. 2019;11(1):101. doi:10.1186/s13195-019-0559-z.
   PubMed Web of Science ®Google Scholar
• Novakovic D, Feligioni M, Scaccianoce S, Caruso A, Piccinin S, Schepisi C, Errico F, Mercuri NB, Nicoletti F, Nisticò R. Profile of gantenerumab and its potential in the treatment of Alzheimer’s disease. Drug Des Devel Ther. 2013;7:1359–64. doi:10.2147/DDDT.S53401.
   PubMed Web of Science ®Google Scholar
• Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, Klunk WE, Ashford E, Yoo K, Xu ZX, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol. 2012;69(2):198–207. doi:10.1001/archneurol.2011.1538.
   PubMedGoogle Scholar
• Klein G, Delmar P, Kerchner G, Hofmann C, Abi-Saab D, Davis A, Voyle N, Baudler M, Fontoura P, Doody R. Thirty-six-month amyloid positron emission tomography results show continued reduction in amyloid burden with subcutaneous gantenerumab. J Prev Alzheimers Dis. 2021;8:1–4. doi:10.14283/jpad.2020.68.
   Web of Science ®Google Scholar
• Bateman R, Smith J, Donohue MC, Delmar P, Abbas R, Salloway S, Wojtowicz J, Blennow K, Bittner T, Black SE, et al. Topline results of phase III GRADUATE I & II pivotal trials with subcutaneous gantenerumab. J Prev Alzheimers Dis. 2022;9:S10.
   Google Scholar
• Ltd. FH-LR. [Ad Hoc Announcement Pursuant To Art. 53 LR] Roche Provides Update On Phase III GRADUATE Programme Evaluating Gantenerumab In Early Alzheimer’s Disease. 2022 [accessed 2023 March 16]. https://www.roche.com/media/releases/med-cor-2022-11-14.
   Google Scholar
• Madabushi R, Wang Y, Zineh I. A holistic and integrative approach for advancing model-informed drug development. CPT Pharmacom & Syst Pharma. 2019;8(1):9–11. doi:10.1002/psp4.12379.
   PubMedGoogle Scholar
• Retout S, Gieschke R, Serafin D, Weber C, Frey N, Hofmann C. Disease modeling and model-based meta-analyses to define a new direction for a phase III program of gantenerumab in Alzheimer’s disease. Clin Pharma And Therapeutics. 2022;111(4):857–66. doi:10.1002/cpt.2535.
   PubMed Web of Science ®Google Scholar
• Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S. Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: What have we learned? mAbs. 2011;3(1):61–66. doi:10.4161/mabs.3.1.13799.
   PubMed Web of Science ®Google Scholar
• ICH S6 (R1) Preclinical safety evaluation of biotechnology-derived pharmaceuticals. International Council For Harmonisation Of Technical Requirements For Pharmaceuticals For Human Use (ICH); 1997 [accessed 2023 14/08/2023]. https://www.ich.org/.
   Google Scholar
• Schlothauer T, Herter S, Koller CF, Grau-Richards S, Steinhart V, Spick C, Kubbies M, Klein C, Umaña P, Mössner E. Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions. Protein Eng Des Sel. 2016;29(10):457–66. doi:10.1093/protein/gzw040.
   PubMed Web of Science ®Google Scholar
• Kariolis MS, Wells RC, Getz JA, Kwan W, Mahon CS, Tong R, Kim DJ, Srivastava A, Bedard C, Henne KR, et al. Brain delivery of therapeutic proteins using an Fc fragment blood–brain barrier transport vehicle in mice and monkeys. Sci Transl Med. 2020;12(545):12. doi:10.1126/scitranslmed.aay1359.
   Web of Science ®Google Scholar
• Pardridge WM. CSF, blood–brain barrier, and brain drug delivery. Expert Opin Drug Deliv. 2016;13(7):963–75. doi:10.1517/17425247.2016.1171315.
   PubMed Web of Science ®Google Scholar
• Chiao P, Bedell BJ, Avants B, Zijdenbos AP, Grand’maison M, O’Neill P, O’Gorman J, Chen T, Koeppe R. Impact of reference and target region selection on amyloid PET SUV ratios in the phase 1b PRIME study of aducanumab. J Nucl Med. 2019;60(1):100–06. doi:10.2967/jnumed.118.209130.
   PubMed Web of Science ®Google Scholar
• Chang H, Morrow K, Bonacquisti E, Zhang W, Shah D. Antibody pharmacokinetics in rat brain determined using microdialysis. MAbs. 2018;10(6):843–53. doi:10.1080/19420862.2018.1473910.
   PubMed Web of Science ®Google Scholar
• Villaseñor R, Schilling M, Sundaresan J, Lutz Y, Collin L. Sorting tubules regulate blood–brain barrier transcytosis. Cell Rep. 2017;21(11):3256–70. doi:10.1016/j.celrep.2017.11.055.
   PubMed Web of Science ®Google Scholar
• Villaseñor R, Ozmen L, Messaddeq N, Grüninger F, Loetscher H, Keller A, Betsholtz C, Freskgård PO, Collin L. Trafficking of endogenous immunoglobulins by endothelial cells at the blood–brain barrier. Science Reports. 2016;6(1):25658. doi:10.1038/srep25658.
   PubMedGoogle Scholar
• Madabushi R, Benjamin JM, Grewal R, Pacanowski MA, Strauss DG, Wang Y, Zhu H, Zineh I. The US Food and drug administration’s model-informed drug development paired meeting pilot program: early experience and impact. Clin Pharma And Therapeutics. 2019;106(1):74–78. doi:10.1002/cpt.1457.
   PubMed Web of Science ®Google Scholar
• Ruderisch N, Schlatter D, Kuglstatter A, Guba W, Huber S, Cusulin C, Benz J, Rufer AC, Hoernschemeyer J, Schweitzer C, et al. Potent and selective BACE-1 peptide inhibitors lower brain Aβ levels mediated by brain shuttle transport. EBioMedicine. 2017;24:76–92. doi:10.1016/j.ebiom.2017.09.004.
   PubMed Web of Science ®Google Scholar
• Campos CR, Kemble AM, Niewoehner J, Freskgård PO, Urich E, Ginsberg SD. Brain shuttle neprilysin reduces central amyloid-β levels. PloS One. 2020;15(3):e0229850. doi:10.1371/journal.pone.0229850.
   PubMed Web of Science ®Google Scholar
• Monolix. Ver. 4.3.3 [software]. Antony (France): Lixoft; 2014 September.
   Google Scholar
• Wang J, Iyer S, Fielder PJ, Davis JD, Deng R. Projecting human pharmacokinetics of monoclonal antibodies from nonclinical data: comparative evaluation of prediction approaches in early drug development. Biopharm & Drug Disp. 2016;37(2):51–65. doi:10.1002/bdd.1952.
   PubMed Web of Science ®Google Scholar
• Valentin J. Basic anatomical and physiological data for use in radiological protection: reference values: ICRP publication 89. Ann ICRP. 2002;32(3–4):1–277. doi:10.1016/S0146-6453(03)00002-2.
   Google Scholar