Product-related impurities in clinical-grade recombinant AAV vectors: Characterization and risk assessment

Biomedicines

Volumn 2, Issue 1, 2014, Pages 80-97

  Wright, J Fraser ^a,b  

^a CHILDREN S HOSPITAL OF PHILADELPHIA   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

AAV vectors; Clinical trials; Impurities

Indexed keywords

EID: 85014470228     PISSN: None     EISSN: 22279059     Source Type: Journal    
DOI: 10.3390/biomedicines2010080     Document Type: Review

References (65)

1. Carter, B.J. Adeno-associated virus vectors in clinical trials. Hum. Gene Ther. 2005, 16, 541-550
2. Warrington, K.H.; Herzog, R.W. Treatment of human disease by adeno-associated viral gene transfer. Hum. Genet. 2006, 119, 571-603
3. Mingozzi, F.; High, K.A. Therapeutic in vivo gene transfer for genetic disease using AAV: Progress and challenges. Nat. Rev. Genet. 2011, 12, 341-355
4. Maguire, A.M.; Simonelli, F.; Pierce, E.A.; Pugh, E.N.; Mingozzi, F.; Bennicelli, J.; Banfi, S.; Marshall, K.A.; Testa, F.; Surace, E.M.; et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N. Engl. J. Med. 2008, 358, 2240-2248
5. Bainbridge, J.W.; Smith, A.J.; Barker, S.S.; Robbie, S.; Henderson, R.; Balaggan, K.; Viswanathan, A.; Holder, G.E.; Stockman, A.; Tyler, N.; et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N. Engl. J. Med. 2008, 358, 2231-2239
6. Hauswirth, W.W.; Aleman, T.S.; Kaushal, S.; Cideciyan, A.V.; Schwartz, S.B.; Wang, L.; Conlon, T.J.; Boye, S.L.; Flotte, T.R.; Byrne, B.J.; et al. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: Short-term results of a phase I trial. Hum. Gene Ther. 2008, 19, 979-990
7. Maguire, A.M.; High, K.A.; Auricchio, A.; Wright, J.F.; Pierce, E.A.; Testa, F.; Mingozzi, F.; Bennicelli, J.L.; Ying, G.S.; Rossi, S.; et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: A phase 1 dose-escalation trial. Lancet 2009, 374, 1597-1605
8. Simonelli, F.; Maguire, A.M.; Testa, F.; Pierce, E.A.; Mingozzi, F.; Bennicelli, J.L.; Rossi, S.; Marshall, K.; Banfi, S.; Surace, E.M.; et al. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol. Ther. 2010, 18, 643-650
9. Bennett, J.; Ashtari, M.; Wellman, J.; Marshall, K.A.; Cyckowski, L.L.; Chung, D.C.; McCague, S.; Pierce, E.A.; Chen, Y.; Bennicelli, J.L.; et al. AAV2 gene therapy re-administration in three adults with congenital blindness. Sci. Transl. Med. 2012, 4, 120ra15
10. Testa, F.; Maguire, A.M.; Rossi, S.; Pierce, E.A.; Melillo, P.; Marshall, K.; Banfi, S.; Surace, E.M.; Sun, J.; Acerra, C.; et al. Three year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital amaurosis Type 2. Ophthalmology 2013, 120, 1283-1291
11. Nathwani, A.C.; Tuddenham, E.G.D.; Rangarajan, S.; Rosales, C.; McIntosh, J.; Linch, D.C.; Chowdary, P.; Riddell, A.; Jaquilmac Pie, A.; Harrington, C.; et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N. Engl. J. Med. 2011, 365, 2357-2365
12. Xie, Q.; Bu, W.; Bhatia, S.; Hare, J.; Somasundarm, T.; Azzi, A.; Chapman, M.S. The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy. Proc. Natl. Acad. Sci. USA 2002, 6, 10405-10410
13. European Medicines Agency. Assessment Report: Glybera. Available online: http://www.ema.europa. eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002145/WC500135476. pdf (accessed on 25 February 2014)
14. ICH harmonised tripartite guideline. Specification: Test procedures and acceptance criteria for biotechnological/biological product. Q6B Available online: http://www.ema.europa.eu/ docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002824.pdf (accessed on 25 February 2014)
15. US Department of Health Human Services, Food and Drug Administration. International conference on harmonisation; Guidance on viral safety evaluation of biotechnology products derived from cell lines of human or animal origin; availablility-FDA. Notice. Fed. Regist. 1998, 63, 51074-51084
16. PDA. Points to consider for aseptic processing. PDA J. Pharm. Sci. Technol. 2003, 57, 1-72
17. US Department of Health Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Office of Regulatory Affairs. Guidance for Industry: Sterile drug products produced by aseptic processing-Current good manufacturing practice. Available online: http://www.fda.gov/cber/guidelines.htm (accessed on 25 February 2014)
18. US Dept Health Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Guidance for Industry: INDs-Approaches to complying with CGMP during Phase 1. Available online: http://www.fda.gov/ohrms/ dockets/98fr/05d-0286-gdl0001.pdf (accessed on 25 February 2014)
19. Vaccines and related biological product advisory committee meeting. FDA Briefing Document. Cell lines derived from human tumors for vaccine manufacture. Available online: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOther Biologics/VaccinesandRelatedBiologicalProductsAdvisoryCommittee/ucm319554.htm (accessed on 25 February 2014)
20. Gombold, J.; Peden, K.; Gavin, D.; Wei, Z.; Baradaran, K.; Mire-Sluis, A.; Schenerman, M. Lot release and characterization testing of live-virus-based vaccines and gene therapy products, Part 1: Factors influencing assay choices. BioProcess Int. 2006, 4, 46-56
21. Clark, K.R.; Voulgaropoulou, F.; Fraley, D.M.; Johnson, P.R. Cell lines for the production of recombinant adeno-associated virus. Hum. Gene Ther. 1995, 6, 1329-1341
22. Conway, J.E.; Rhys, C.M.J.; Zolotukhin, I.; Zolotukhin, S.; Muzyczka, N.; Hayward, G.S.; Byrne, B.J. High-titer recombinant adeno-associated virus production utilizing a recombinant herpes simplex virus type 1 vector expressing AAV-2 Rep and Cap. Gene Ther. 1999, 6, 986-993
23. Xiao, X.; Li, J.; Samulski, R.J. Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. J. Virol. 1998, 72, 2224-2232
24. Matsushita, T.; Elliger, S.; Elliger, C.; Podsakoff, G.; Villarreal, L.; Kurtzman, G.J.; Iwaki, Y.; Colosi, P. Adeno-associated virus vectors can be efficiently produced without helper virus. Gene Ther. 1998, 5, 938-945
25. Urabe, M.; Ding, C.; Kotin, R.M. Insect cells as a factory to produce adeno-associated virus type 2 vectors. Hum. Gene Ther. 2002, 13, 1935-1943
26. Smith, R.H.; Ding, C.; Kotin, R.M. Serum-free production and column purification of adeno-asssociated virus type 5. J. Virol. Meth. 2003, 114, 115-124
27. Negrete, A.; Yang, L.C.; Mendez, A.F.; Levy, J.R.; Kotin, R.M. Economized large-scale production of high yield of rAAV for gene therapy applications exploiting baculovirus expression system. J. Gene Med. 2007, 9, 938-948
28. Belter, P.A.; Cussler, C.L.; Hu, W.S. Bioseparations; John Wiley and Sons: New York, NY, USA, 1988
29. Sadana, A. Bioseparation of Proteins; Academic Press: New York, NY, USA, 1998
30. Wang, X.; Hunter, A.K.; Mozier, N.M. Host cell proteins in biologics development: Identification, quantitation, and risk assessment. Biotechnol. Bioeng. 2009, 103, 446-458
31. Kapranov, P.; Chen, L.; Dederich, D.; Dong, B.; He, J.; Steinmann, K.E.; Moore, A.R.; Thompson, J.F.; Milos, P.M.; Xiao, W. Native molecular state of adeno-associated viral vectors revealed by singe-molecule sequencing. Hum. Gene Ther. 2012, 23, 46-56
32. Sommer, J.M.; Smith, P.H.; Parthasarathy, S.; Isaacs, J.; Vijay, S.; Kieran, J.; Powell, S.K.; McClelland, A.; Wright, J.F. Quantification of adeno-associated virus particles and empty capsids by optical density measurement. Mol. Ther. 2003, 7, 122-128
33. Lock, M.; Alvira, M.R.; Wilson, J.M. Analysis of particle content of recombinant adeno-associated virus serotype 8 vectors by ion-exchange chromatography. Hum. Gene Ther. Meth. 2012, 23, 56-64
34. Allay, J.M.; Sleep, S.; Long, S.; Tillman, D.M.; Clark, R.; Carney, G.; Fagone, P.; McIntosh, J.H.; Nienhuis, A.W.; Davidoff, A.M.; et al. Good manufacturing practice production of self-complementary serotype 8 adeno-associated viral vector for a haemophilia B clinical trial. Hum. Gene Ther. 2011, 22, 595-604
35. Manno, C.S.; Pierce, G.F.; Arruda, V.R.; Glader, B.; Ragni, M.; Rasko, J.J.; Ozelo, M.C.; Hoots, K.; Blatt, P.; Konkle, B.; et al. Successful transduction of liver in hemophilia by AAV-factor IX and limitations imposed by the host immune response. Nat. Med. 2006, 12, 342-347
36. Mingozzi, F.; Maus, M.V.; Hui, D.J.; Sabatino, D.E.; Murphy, S.L.; Rasko, J.E.; Ragni, M.V.; Manno, C.S.; Sommer, J.; Jiang, H.; et al. CD8+ T-cell responses to adeno-associated virus capsid in humans. Nat. Med. 2007, 13, 419-422
37. Pien, G.C.; Hasbrouck, N.C.; Maus, M.V.; Mingozzi, F.; High, K.A. Quantifying capsid peptide:MHC I complexes following adeno-associated virus (AAV) transduction. Blood 2007, 110, 1090A
38. Parker, A.; Nagy, D.; Vargas, J.; Anand, V.; Qu, G.; Wright, J.F.; Couto, L. In vivo performance of AAV2 vectors purified by CsCl gradient centrifugation or column chromatography. Mol. Ther. 2003, 7, S390
39. Mingozzi, F.; Anguela, X.M.; Pavani, G.; Chen, Y.; Davidson, R.J.; Hui, D.J.; Yazicioglu, M.; Elkouby, L.; Hinderer, C.J.; Faella, A.; et al. Overcoming pre-existing humoral immunity to AAV using capsid decoys. Science Trans. Med. 2013, 5, 194ra92
40. Ayuso, E.; Mingozzi, F.; Montane, J.; Leon, X.; Anguela, X.M.; Haurigot, V.; Edmonson, S.A.; Africa, L.; Zhou, S.; High, K.A.; et al. High AAV vector purity results in serotype-and tissueindependent enhancement of transduction efficiency. Gene Ther. 2010, 17, 503-510
41. Wright, J.F.; Wellman, J.; High, K.A. Manufacturing and regulatory strategies for clinical AAV2-hRPE65. Curr. Gene Ther. 2011, 12, 341-349
42. Zolotukhin, S.; Byrne, B.J.; Mason, E.; Zolotukhin, E.; Potter, M.; Chesnut, K.; Summerford, C.; Samulski, R.J.; Muzyczka, N. Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield. Gene Ther. 1999, 6, 973-985
43. Qu, G.; Bahr-Davidson, J.; Prado, J.; Tai, A.; Cataniag, F.; McDonnell, J.; Zhou, J.; Hauck, B.; Luna, J.; Sommer, J.M.; et al. Separation of adeno-associated virus type 2 empty particles from genome containing vector by anion-exchange column chromatography. J. Virol. Meth. 2007, 140, 183-192
44. Brument, N.; Morenweiser, R.; Blouin, V.; Toublance, E.; Raimbaud, I.; Chérel, Y.; Folliot, S.; Gaden, F.; Boulanger, P.; Kroner-Lux, G.; et al. A versatile and scalable two-step ion-exchange chromatography process for the purification of recombinant adeno-associated virus serotypes-2 and-5. Mol. Ther. 2002, 6, 678-686
45. Hauck, B.; Murphy, S.L.; Smith, P.H.; Liu, X.; Zelenaia, O.; Mingozzi, F.; Sommer, J.M.; High, K.A.; Wright, J.F. Undetectable transcription of cap in a clinical AAV vector: implications for pre-formed capsids in immune responses. Mol. Ther. 2009, 17, 144-152
46. Wistuba, A.; Kern, A.; Weger, S.; Grimm, D.; Kleinschmidt, J.A. Subcellular compartmentalization of adeno-associated virus type 2 assembly. J. Virol. 1997, 71, 1341-1352
47. Sonntag, F.; Schmidt, K.; Kleinschmidt, J.A. A viral assembly factor promotes AAV2 capsid formation in the nucleolus. Proc. Natl. Acad. Sci. USA 2010, 107, 10220-10225
48. Ledwith, B.J.; Manam, S.; Troilo, P.J.; Barnum, A.B.; Pauley, C.J.; Griffiths, T.G., 2nd; Harper, L.B.; Beare, C.M.; Bagdon, W.J.; Nichols, W.W. Plasmid DNA Vaccines: Investigation of integration into host cellular DNA following intramuscular injection in mice. Intervirology 2000, 43, 258-272
49. Wang, Z.; Troilo, P.H.J.; Wang, X.; Griffiths, T.G.; Pacchione, S.J.; Barnum, A.B.; Harper, L.B.; Pauley, C.J.; Niu, Z.; Denisova, L.; et al. Detection of integration of plasmid DNA into host genomic DNA following intramuscular injection and electroporation. Gene Ther. 2004, 11, 711-721
50. Sheng, L.; Cai, F.; Zhu, Y.; Pal, A.; Athanasiou, M.; Orrison, B.; Blair, D.G.; Hughes, S.H.; Coffin, J.M.; Lewis, A.M.; et al. Oncogenicity of DNA in vivo: Tumor induction with expression plasmids for activated H-ras and c-myc. Biologicals 2008, 36, 184-197
51. World Health Organization (WHO). Requirements for the Use of Animal Cells as in Vitro Substrates for the Production of Biologicals (Requirement for Biological Substance No. 50). WHO Technical Report Series, No. 878; WHO Expert Committee on Biological Standardization: Geneva, Swizerland, 1998; Annex 1
52. European Medicines Agency. Reflection paper on quality, non-clinical and clinical issues related to the development of recombinant adeno-associated viral vectors. Available online: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/07/WC500094345. pdf (accessed on 25 February 2014)
53. Chadeuf, G.; Ciron, C.; Moullier, P.; Salvetti, A. Evidence for encapsidation of prokaryotic sequences during recombinant adeno-associated virus production and their in vivo persistence after vector delivery. Mol. Ther. 2005, 12, 744-753
54. Dolgin, E. Gene therapies advance, but some see manufacturing challenges. Nat. Med. 2012, 18, 1718-1719
55. Samulski, R.J.; Shang, L.-S.; Shenk, T. Helper-free stocks of recombinant adeno-associated viruses: Normal integration does not require viral gene expression. J. Virol. 1989, 61, 3096-3101
56. Allen, J.M.; Debelak, D.J.; Reynolds, T.C.; Miller, A.D. Identification and elimination of replication-competent adeno-associated virus (AAV) that can arise by non-homologous recombination during AAV vector production. J. Virol. 1997, 71, 6816-6822
57. Clark, K.R.; Liu, X.; McGrath, J.P.; Johnson, P.R. Highly purified recombinant adeno-associated virus vectors are biologically active and free of detectable helper and wild-type virus. Hum. Gene Ther. 1999, 10, 1031-1039
58. Boutin, S.; Monteilhet, V.; Veron, P.; Leborgne, C.; Benveniste, O.; Montus, M.F.; Masurier, C. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) Types 1, 2, 5, 6, 8, and 9 in the healthy population: Implications for gene therapy using AAV vectors. Hum. Gene Ther. 2010, 21, 704-712
59. Maecker, H.T.; Ghanekar, S.A.; Suni, M.A.; He, X.S.; Picker, L.J.; Maino, V.C. Factors affecting the efficiency of CD8+ T cell cross-priming with exogenous antigens. J. Immunol. 2001, 166, 7268-7275
60. Grimm, D.; Kern, A.; Rittner, K.; Kleinschmidt, J.A. Novel tools for production and purification of recombinant adeno associated virus vectors. Hum. Gene Ther. 1998, 9, 2745-2760
61. Lu, H.; Qu, G.; Yang, X.; Xu, R.; Xiao, W. Systemic elimination of de novo capsid protein synthesis from replication-competent AAV contamination in the liver. Hum. Gene Ther. 2011, 22, 625-632
62. Dong, B.; Moore, A.R.; Dai, J.; Roberts, S.; Chu, K.; Kapranov, P.; Moss, B.; Xiao, W. A concept of eliminating nonhomologous recombinant for scalabe and safet AAV vector generation for human gene therapy. Nucleic Acids Res. 2013, 41, 6609-6617
63. Salvetti, A.; Oreve, S.; Chadeuf, G.; Favre, D.; Cherel, Y.; Champion-Arnaud, P.; David-Ameline, J.; Moullier, P. Factors influencing recombinant adeno-associated virus production. Hum. Gene Ther. 1998, 9, 695-706
64. Zhen, Z.; Espinoza, Y.; Bleu, T.; Sommer, J.M.; Wright, J.F. Infectious titer assay for adeno-associated virus vectors with sensitivity sufficient to detect single infectious events. Hum. Gene Ther. 2004, 15, 709-715
65. Mohiuddin, I.; Loiler, S.; Zolotukhin, I.; Byrne, B.J.; Flotte, T.R.; Snyder, R.O. Herpesvirus-based infectious titering of recombinant adeno-associated viral vectors. Mol. Ther. 2005, 11, 320-326