#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Gene delivery of a modified antibody to Aβ reduces progression of murine Alzheimer’s disease


Autoři: Bradford M. Elmer aff001;  Kurt A. Swanson aff001;  Dinesh S. Bangari aff002;  Peter A. Piepenhagen aff002;  Errin Roberts aff002;  Tatyana Taksir aff002;  Lei Guo aff003;  Maria-Carmen Obinu aff004;  Pascal Barneoud aff004;  Susan Ryan aff002;  Bailin Zhang aff003;  Laurent Pradier aff004;  Zhi-Yong Yang aff001;  Gary J. Nabel aff001
Působiště autorů: Breakthrough Lab, Sanofi, Cambridge, Massachusetts, United States of America aff001;  Global Discovery Pathology, Sanofi, Framingham, Massachusetts, United States of America aff002;  Translational Sciences, Sanofi, Cambridge, Massachusetts, United States of America aff003;  R&D Neuroscience Unit, Sanofi, Chilly-Mazarin, France aff004
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0226245

Souhrn

Antibody therapies for Alzheimer’s Disease (AD) hold promise but have been limited by the inability of these proteins to migrate efficiently across the blood brain barrier (BBB). Central nervous system (CNS) gene transfer by vectors like adeno-associated virus (AAV) overcome this barrier by allowing the bodies’ own cells to produce the therapeutic protein, but previous studies using this method to target amyloid-β have shown success only with truncated single chain antibodies (Abs) lacking an Fc domain. The Fc region mediates effector function and enhances antigen clearance from the brain by neonatal Fc receptor (FcRn)-mediated reverse transcytosis and is therefore desirable to include for such treatments. Here, we show that single chain Abs fused to an Fc domain retaining FcRn binding, but lacking Fc gamma receptor (FcγR) binding, termed a silent scFv-IgG, can be expressed and released into the CNS following gene transfer with AAV. While expression of canonical IgG in the brain led to signs of neurotoxicity, this modified Ab was efficiently secreted from neuronal cells and retained target specificity. Steady state levels in the brain exceeded peak levels obtained by intravenous injection of IgG. AAV-mediated expression of this scFv-IgG reduced cortical and hippocampal plaque load in a transgenic mouse model of progressive β-amyloid plaque accumulation. These findings suggest that CNS gene delivery of a silent anti-Aβ scFv-IgG was well-tolerated, durably expressed and functional in a relevant disease model, demonstrating the potential of this modality for the treatment of Alzheimer’s disease.

Klíčová slova:

Mouse models – Enzyme-linked immunoassays – Alzheimer's disease – Central nervous system – Immunohistochemistry techniques – Hippocampus – Intravenous injections – Amyloid plaques


Zdroje

1. Tcw J, Goate AM. Genetics of beta-Amyloid Precursor Protein in Alzheimer's Disease. Cold Spring Harbor perspectives in medicine. 2017;7(6). doi: 10.1101/cshperspect.a024539 28003277.

2. Benilova I, Karran E, De Strooper B. The toxic Abeta oligomer and Alzheimer's disease: an emperor in need of clothes. Nature neuroscience. 2012;15(3):349–57. doi: 10.1038/nn.3028 22286176.

3. Mo JJ, Li JY, Yang Z, Liu Z, Feng JS. Efficacy and safety of anti-amyloid-beta immunotherapy for Alzheimer's disease: a systematic review and network meta-analysis. Annals of clinical and translational neurology. 2017;4(12):931–42. doi: 10.1002/acn3.469 29296624; PubMed Central PMCID: PMC5740249.

4. Clark KR, Penaud-Budloo M. Evaluation of the fate of rAAV genomes following in vivo administration. Methods Mol Biol. 2011;807:239–58. doi: 10.1007/978-1-61779-370-7_10 22034033.

5. Sehara Y, Fujimoto KI, Ikeguchi K, Katakai Y, Ono F, Takino N, et al. Persistent Expression of Dopamine-Synthesizing Enzymes 15 Years After Gene Transfer in a Primate Model of Parkinson's Disease. Hum Gene Ther Clin Dev. 2017;28(2):74–9. doi: 10.1089/humc.2017.010 28279081.

6. Marks WJ Jr., Baumann TL, Bartus RT. Long-Term Safety of Patients with Parkinson's Disease Receiving rAAV2-Neurturin (CERE-120) Gene Transfer. Human gene therapy. 2016;27(7):522–7. doi: 10.1089/hum.2015.134 26711317.

7. Hadaczek P, Eberling JL, Pivirotto P, Bringas J, Forsayeth J, Bankiewicz KS. Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC. Molecular therapy: the journal of the American Society of Gene Therapy. 2010;18(8):1458–61. doi: 10.1038/mt.2010.106 20531394; PubMed Central PMCID: PMC2927057.

8. Zaiss AK, Muruve DA. Immunity to adeno-associated virus vectors in animals and humans: a continued challenge. Gene therapy. 2008;15(11):808–16. doi: 10.1038/gt.2008.54 18385765.

9. Sudol KL, Mastrangelo MA, Narrow WC, Frazer ME, Levites YR, Golde TE, et al. Generating Differentially Targeted Amyloid-β Specific Intrabodies as a Passive Vaccination Strategy for Alzheimer's Disease. Molecular Therapy. 2009;17(12):2031–40. doi: https://doi.org/10.1038/mt.2009.174 19638957

10. Ryan DA, Mastrangelo MA, Narrow WC, Sullivan MA, Federoff HJ, Bowers WJ. Abeta-directed single-chain antibody delivery via a serotype-1 AAV vector improves learning behavior and pathology in Alzheimer's disease mice. Molecular therapy: the journal of the American Society of Gene Therapy. 2010;18(8):1471–81. doi: 10.1038/mt.2010.111 20551911; PubMed Central PMCID: PMC2927061.

11. Levites Y, Jansen K, Smithson LA, Dakin R, Holloway VM, Das P, et al. Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid beta, amyloid beta40, and amyloid beta42 single-chain variable fragments attenuates plaque pathology in amyloid precursor protein mice. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2006;26(46):11923–8. doi: 10.1523/JNEUROSCI.2795-06.2006 17108166.

12. Levites Y, O'Nuallain B, Puligedda RD, Ondrejcak T, Adekar SP, Chen C, et al. A human monoclonal IgG that binds abeta assemblies and diverse amyloids exhibits anti-amyloid activities in vitro and in vivo. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2015;35(16):6265–76. doi: 10.1523/JNEUROSCI.5109-14.2015 25904780; PubMed Central PMCID: PMC4405548.

13. Kou J, Kim H, Pattanayak A, Song M, Lim JE, Taguchi H, et al. Anti-Amyloid-beta Single-Chain Antibody Brain Delivery Via AAV Reduces Amyloid Load But May Increase Cerebral Hemorrhages in an Alzheimer's Disease Mouse Model. Journal of Alzheimer's disease: JAD. 2011;27(1):23–38. doi: 10.3233/JAD-2011-110230 21709371; PubMed Central PMCID: PMC3560395.

14. Fukuchi K, Tahara K, Kim HD, Maxwell JA, Lewis TL, Accavitti-Loper MA, et al. Anti-Abeta single-chain antibody delivery via adeno-associated virus for treatment of Alzheimer's disease. Neurobiology of disease. 2006;23(3):502–11. doi: 10.1016/j.nbd.2006.04.012 16766200; PubMed Central PMCID: PMC2459226.

15. Liu W, Zhao L, Blackman B, Parmar M, Wong MY, Woo T, et al. Vectored Intracerebral Immunization with the Anti-Tau Monoclonal Antibody PHF1 Markedly Reduces Tau Pathology in Mutant Tau Transgenic Mice. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2016;36(49):12425–35. doi: 10.1523/JNEUROSCI.2016-16.2016 27927959.

16. Saunders KO, Wang L, Joyce MG, Yang ZY, Balazs AB, Cheng C, et al. Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody Gene Transfer Protects Nonhuman Primates from Mucosal Simian-Human Immunodeficiency Virus Infection. Journal of virology. 2015;89(16):8334–45. doi: 10.1128/JVI.00908-15 26041300; PubMed Central PMCID: PMC4524228.

17. Deane R, Sagare A, Hamm K, Parisi M, LaRue B, Guo H, et al. IgG-assisted age-dependent clearance of Alzheimer's amyloid beta peptide by the blood-brain barrier neonatal Fc receptor. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2005;25(50):11495–503. doi: 10.1523/JNEUROSCI.3697-05.2005 16354907.

18. Boado RJ, Zhang Y, Zhang Y, Xia CF, Pardridge WM. Fusion antibody for Alzheimer's disease with bidirectional transport across the blood-brain barrier and abeta fibril disaggregation. Bioconjug Chem. 2007;18(2):447–55. doi: 10.1021/bc060349x 17315944; PubMed Central PMCID: PMC2596591.

19. Zhang Y, Pardridge WM. Mediated efflux of IgG molecules from brain to blood across the blood-brain barrier. Journal of neuroimmunology. 2001;114(1–2):168–72. doi: 10.1016/s0165-5728(01)00242-9 11240028.

20. Schlachetzki F, Zhu C, Pardridge WM. Expression of the neonatal Fc receptor (FcRn) at the blood-brain barrier. Journal of neurochemistry. 2002;81(1):203–6. doi: 10.1046/j.1471-4159.2002.00840.x 12067234.

21. Schupf N, Tang MX, Fukuyama H, Manly J, Andrews H, Mehta P, et al. Peripheral Abeta subspecies as risk biomarkers of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(37):14052–7. doi: 10.1073/pnas.0805902105 18779561; PubMed Central PMCID: PMC2544577.

22. Yang X, Ambrogelly A. Enlarging the repertoire of therapeutic monoclonal antibodies platforms: domesticating half molecule exchange to produce stable IgG4 and IgG1 bispecific antibodies. Curr Opin Biotechnol. 2014;30:225–9. doi: 10.1016/j.copbio.2014.09.001 25254943.

23. Reddy MP, Kinney CA, Chaikin MA, Payne A, Fishman-Lobell J, Tsui P, et al. Elimination of Fc receptor-dependent effector functions of a modified IgG4 monoclonal antibody to human CD4. Journal of immunology. 2000;164(4):1925–33. doi: 10.4049/jimmunol.164.4.1925 10657642.

24. Mizuguchi H, Xu Z, Ishii-Watabe A, Uchida E, Hayakawa T. IRES-dependent second gene expression is significantly lower than cap-dependent first gene expression in a bicistronic vector. Molecular therapy: the journal of the American Society of Gene Therapy. 2000;1(4):376–82. doi: 10.1006/mthe.2000.0050 10933956.

25. Blanchard V, Moussaoui S, Czech C, Touchet N, Bonici B, Planche M, et al. Time sequence of maturation of dystrophic neurites associated with Abeta deposits in APP/PS1 transgenic mice. Experimental neurology. 2003;184(1):247–63. doi: 10.1016/s0014-4886(03)00252-8 14637096.

26. Pradier L, Cohen C, Blanchard V, Debeir T, Barneoud P, Canton T, et al. SAR228810: An antiprotofibrillar beta-amyloid antibody designed to reduce risk of amyloid-related imaging abnormalities (ARIA). Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 2013;9(4):P808–P9. doi: 10.1016/j.jalz.2013.05.1678

27. Pradier L, Blanchard-Bregeon V, Bohme A, Debeir T, Menager J, Benoit P, et al. SAR228810: an antibody for protofibrillar amyloid beta peptide designed to reduce the risk of amyloid-related imaging abnormalities (ARIA). Alzheimer's research & therapy. 2018;10(1):117. Epub 2018/11/30. doi: 10.1186/s13195-018-0447-y 30486882; PubMed Central PMCID: PMC6264593.

28. Johnson PR, Schnepp BC, Zhang J, Connell MJ, Greene SM, Yuste E, et al. Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys. Nature medicine. 2009;15:901. doi: 10.1038/nm.1967 https://www.nature.com/articles/nm.1967#supplementary-information 19448633

29. Smith P, DiLillo DJ, Bournazos S, Li F, Ravetch JV. Mouse model recapitulating human Fcgamma receptor structural and functional diversity. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(16):6181–6. doi: 10.1073/pnas.1203954109 22474370; PubMed Central PMCID: PMC3341029.

30. Chao DT, Ma X, Li O, Park H, Law D. Functional characterization of N297A, a murine surrogate for low-Fc binding anti-human CD3 antibodies. Immunol Invest. 2009;38(1):76–92. doi: 10.1080/08820130802608238 19172487; PubMed Central PMCID: PMC2646398.

31. Shimada M, Abe S, Takahashi T, Shiozaki K, Okuda M, Mizukami H, et al. Prophylaxis and Treatment of Alzheimer's Disease by Delivery of an Adeno-Associated Virus Encoding a Monoclonal Antibody Targeting the Amyloid Beta Protein. PloS one. 2013;8(3):e57606. doi: 10.1371/journal.pone.0057606 23555563

32. Hicks MJ, Rosenberg JB, De BP, Pagovich OE, Young CN, Qiu JP, et al. AAV-directed persistent expression of a gene encoding anti-nicotine antibody for smoking cessation. Science translational medicine. 2012;4(140):140ra87. doi: 10.1126/scitranslmed.3003611 22745437; PubMed Central PMCID: PMC3622954.

33. Chen Y-H, Wu K-J, Wu K-L, Wu K-L, Tsai H-M, Chen M-L, et al. Recombinant Adeno-Associated Virus-Mediated Expression of Methamphetamine Antibody Attenuates Methamphetamine-Induced Hyperactivity in Mice. Scientific reports. 2017;7:46301. doi: 10.1038/srep46301 28387350

34. Balazs AB, Chen J, Hong CM, Rao DS, Yang L, Baltimore D. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature. 2011;481(7379):81–4. doi: 10.1038/nature10660 22139420; PubMed Central PMCID: PMC3253190.

35. Balazs AB, Bloom JD, Hong CM, Rao DS, Baltimore D. Broad protection against influenza infection by vectored immunoprophylaxis in mice. Nature biotechnology. 2013;31(7):647–52. doi: 10.1038/nbt.2618 23728362; PubMed Central PMCID: PMC4030719.

36. Balazs AB, Ouyang Y, Hong CM, Chen J, Nguyen SM, Rao DS, et al. Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission. Nature medicine. 2014;20(3):296–300. doi: 10.1038/nm.3471 24509526; PubMed Central PMCID: PMC3990417.

37. Penninkilampi R, Brothers HM, Eslick GD. Safety and Efficacy of Anti-Amyloid-beta Immunotherapy in Alzheimer's Disease: A Systematic Review and Meta-Analysis. Journal of neuroimmune pharmacology: the official journal of the Society on NeuroImmune Pharmacology. 2017;12(1):194–203. doi: 10.1007/s11481-016-9722-5 28025724.

38. Glockshuber R, Malia M, Pfitzinger I, Pluckthun A. A comparison of strategies to stabilize immunoglobulin Fv-fragments. Biochemistry. 1990;29(6):1362–7. Epub 1990/02/13. doi: 10.1021/bi00458a002 2110478.

39. Yamauchi S, Kobashigawa Y, Fukuda N, Teramoto M, Toyota Y, Liu C, et al. Cyclization of Single-Chain Fv Antibodies Markedly Suppressed Their Characteristic Aggregation Mediated by Inter-Chain VH-VL Interactions. Molecules. 2019;24(14). Epub 2019/07/22. doi: 10.3390/molecules24142620 31323851; PubMed Central PMCID: PMC6681014.

40. Vandenberghe ME, Herard AS, Souedet N, Sadouni E, Santin MD, Briet D, et al. High-throughput 3D whole-brain quantitative histopathology in rodents. Scientific reports. 2016;6:20958. doi: 10.1038/srep20958 26876372; PubMed Central PMCID: PMC4753455.

41. Esparza TJ, Wildburger NC, Jiang H, Gangolli M, Cairns NJ, Bateman RJ, et al. Soluble Amyloid-beta Aggregates from Human Alzheimer's Disease Brains. Scientific reports. 2016;6:38187. doi: 10.1038/srep38187 27917876; PubMed Central PMCID: PMC5137165.

42. Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, et al. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. The American journal of pathology. 1999;155(3):853–62. doi: 10.1016/s0002-9440(10)65184-x 10487842; PubMed Central PMCID: PMC1866907.

43. Wang Y-J, Gao C-Y, Yang M, Liu X-H, Sun Y, Pollard A, et al. Intramuscular delivery of a single chain antibody gene prevents brain Aβ deposition and cognitive impairment in a mouse model of Alzheimer’s disease. Brain, Behavior, and Immunity. 2010;24(8):1281–93. doi: 10.1016/j.bbi.2010.05.010 20595065

44. Hudry E, Vandenberghe LH. Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality. Neuron. 2019;101(5):839–62. Epub 2019/03/08. doi: 10.1016/j.neuron.2019.02.017 30844402.

45. Rafii MS, Baumann TL, Bakay RA, Ostrove JM, Siffert J, Fleisher AS, et al. A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease. Alzheimer's & dementia: the journal of the Alzheimer's Association. 2014;10(5):571–81. Epub 2014/01/15. doi: 10.1016/j.jalz.2013.09.004 24411134.

46. Jefferis R, Lund J, Pound JD. IgG-Fc-mediated effector functions: molecular definition of interaction sites for effector ligands and the role of glycosylation. Immunol Rev. 1998;163:59–76. doi: 10.1111/j.1600-065x.1998.tb01188.x 9700502.

47. Burnham B, Nass S, Kong E, Mattingly M, Woodcock D, Song A, et al. Analytical Ultracentrifugation as an Approach to Characterize Recombinant Adeno-Associated Viral Vectors. Hum Gene Ther Methods. 2015;26(6):228–42. doi: 10.1089/hgtb.2015.048 26414997.

48. Latta-Mahieu M, Elmer B, Bretteville A, Wang Y, Lopez-Grancha M, Goniot P, et al. Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-beta burden in several amyloid transgenic mouse models. Glia. 2018;66(3):492–504. Epub 2017/11/15. doi: 10.1002/glia.23260 29134678.


Článok vyšiel v časopise

PLOS One


2019 Číslo 12
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#