Boutin S, Monteilhet V, Veron P, Leborgne C, Benveniste O, Montus MF, 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;21:704–12.

Article  CAS  PubMed  Google Scholar 

Calcedo R, Franco J, Qin Q, Richardson DW, Mason JB, Boyd S, Wilson JM. Preexisting neutralizing antibodies to adeno-associated virus capsids in large animals other than monkeys may confound in vivo gene therapy studies. Hum Gene Ther Methods. 2015;26:103–5.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Calcedo R, Morizono H, Wang L, McCarter R, He J, Jones D, Batshaw ML, Wilson JM. Adeno-associated virus antibody profiles in newborns, children, and adolescents. Clin Vaccine Immunol. 2011;18:1586–8.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJE, Ozelo MC, Hoots K, Blatt P, Konkle B, Dake M, Kaye R, Razavi M, Zajko A, Zehnder J, Rustagi P, Nakai H, Chew A, Leonard D, Wright JF, Lessard RR, Sommer JM, Tigges M, Sabatino D, Luk A, Jiang H, Mingozzi F, Couto L, Ertl HC, High KA, Kay MA. Successful transduction of liver in hemophilia by AAV-factor IX and limitations imposed by the host immune response. Nat Med. 2006;12:342–7.

Article  CAS  PubMed  Google Scholar 

Mingozzi F, Chen Y, Edmonson SC, Zhou S, Thurlings RM, Tak PP, High KA, Vervoordeldonk MJ. Prevalence and pharmacological modulation of humoral immunity to AAV vectors in gene transfer to synovial tissue. Gene Ther. 2013;20:417–24.

Article  CAS  PubMed  Google Scholar 

Mingozzi F, High KA. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood. 2013;122:23–36.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Weber T. Anti-AAV antibodies in AAV gene therapy: current challenges and possible solutions. Front Immunol. 2021;12. https://doi.org/10.3389/fimmu.2021.658399

Calcedo R, Wilson JM. AAV natural infection induces broad cross-neutralizing antibody responses to multiple AAV serotypes in chimpanzees. Hum Gene Ther Clin Dev. 2016;27:79–82.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dai Y, Kavita U, Lampen MH, Gielen S, Banks G, Levesque P, Kozhich A, Pillutla R, Zhang Y, Jawa V, Adam L. Prevalence of pre-existing neutralizing antibodies against adeno-associated virus serotypes 1, 2, 5, 6, 8, and 9 in sera of different pig strains. Hum Gene Ther. 2022;33:451–9.

Article  CAS  PubMed  Google Scholar 

Fitzpatrick Z, Leborgne C, Barbon E, Masat E, Ronzitti G, van Wittenberghe L, Vignaud A, Collaud F, Charles S, Simon Sola M, Jouen F, Boyer O, Mingozzi F. Influence of pre-existing anti-capsid neutralizing and binding antibodies on AAV vector transduction. Mol Ther Methods Clin Dev. 2018;9:119–29.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cao L, Ledeboer A, Pan Y, Lu Y, Meyer K. Clinical enrollment assay to detect preexisting neutralizing antibodies to AAV6 with demonstrated transgene expression in gene therapy trials. Gene Ther. 2022;30(1–2):150–9.

PubMed  PubMed Central  Google Scholar 

Falese L, Sandza K, Yates B, Triffault S, Gangar S, Long B, Tsuruda L, Carter B, Vettermann C, Zoog SJ, Fong S. Strategy to detect pre-existing immunity to AAV gene therapy. Gene Ther. 2017;24:768–78.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kasprzyk T, Triffault S, Long BR, Zoog SJ, Vettermann C. Confirmatory detection of neutralizing antibodies to AAV gene therapy using a cell-based transduction inhibition assay. Mol Ther Methods Clin Dev. 2022;24:222–9.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Meliani A, Leborgne C, Triffault S, Jeanson-Leh L, Veron P, Mingozzi F. Determination of anti-adeno-associated virus vector neutralizing antibody titer with an in vitro reporter system. Hum Gene Ther Methods. 2015;26:45–53.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kavita U, Dai Y, Salvador L, Miller W, Adam LP, Levesque PC, Zhang YJ, Ji QC, Pillutla RC. Development of a chemiluminescent ELISA method for the detection of total anti-adeno associated virus serotype 9 (AAV9) antibodies. Hum Gene Ther Methods. 2018;29(6):237.

Article  CAS  PubMed  Google Scholar 

Simmons E, Wen Y, Li J, Qian YW, Wong LC, Konrad RJ, Bivi N. A sensitive and drug tolerant assay for detecting anti-AAV9 antibodies using affinity capture elution. J Immunol Methods. 2022;512:113397.

Article  PubMed  Google Scholar 

Haar J, Blazevic D, Strobel B, Kreuz S, Michelfelder S. MSD-based assays facilitate a rapid and quantitative serostatus profiling for the presence of anti-AAV antibodies. Mol Ther Methods Clin Dev. 2022;25:360–9.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jani D, Marsden R, Mikulskis A, Gleason C, Klem T, Krinos Fiorotti C, Myler H, Yang L, Fiscella M. Recommendations for the development and validation of confirmatory anti-drug antibody assays. Bioanalysis. 2015;7:1619–31.

Article  CAS  PubMed  Google Scholar 

Shankar G, Devanarayan V, Amaravadi L, Barrett YC, Bowsher R, Finco-Kent D, Fiscella M, Gorovits B, Kirschner S, Moxness M, Parish T, Quarmby V, Smith H, Smith W, Zuckerman LA, Koren E. Recommendations for the validation of immunoassays used for detection of host antibodies against biotechnology products. J Pharm Biomed Anal. 2008;48:1267–81.

Article  CAS  PubMed  Google Scholar 

Shen M, Dong X, Tsong Y. Statistical evaluation of several methods for cut-point determination of immunogenicity screening assay. J Biopharm Stat. 2015;25:269–79.

Article  PubMed  Google Scholar 

Lin LI. A concordance correlation coefficient to evaluate reproducibility. Biometrics. 1989;45:255–68.

Article  CAS  PubMed  Google Scholar 

Gorovits B, Azadeh M, Buchlis G, Harrison T, Havert M, Jawa V, Long B, McNally J, Milton M, Nelson R, O’Dell M, Richards K, Vettermann C, Wu B. Evaluation of the humoral response to adeno-associated virus-based gene therapy modalities using total antibody assays. AAPS J. 2021;23:108.

Article  CAS  PubMed  Google Scholar 

Gorovits B, Fiscella M, Havert M, Koren E, Long B, Milton M, Purushothama S. Recommendations for the development of cell-based anti-viral vector neutralizing antibody assays. AAPS J. 2020;22:24.

Article  PubMed  Google Scholar 

Devanarayan V, Smith WC, Brunelle RL, Seger ME, Krug K, Bowsher RR. Recommendations for systematic statistical computation of immunogenicity cut points. AAPS J. 2017;19:1487–98.

Article  CAS  PubMed  Google Scholar 

Kruzik A, Koppensteiner H, Fetahagic D, Hartlieb B, Dorn S, Romeder-Finger S, Coulibaly S, Weber A, Hoellriegl W, Horling FM, Scheiflinger F, Reipert BM, de la Rosa M. Detection of biologically relevant low-titer neutralizing antibodies against adeno-associated virus require sensitive in vitro assays. Hum Gene Ther Methods. 2019;30:35–43.

Article  CAS  PubMed  Google Scholar 

Wang L, Calcedo R, Bell P, Lin J, Grant RL, Siegel DL, Wilson JM. Impact of pre-existing immunity on gene transfer to nonhuman primate liver with adeno-associated virus 8 vectors. Hum Gene Ther. 2011;22:1389–401.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Long BR, Sandza K, Holcomb J, Crockett L, Hayes GM, Arens J, Fonck C, Tsuruda LS, Schweighardt B, O’Neill CA, Zoog S, Vettermann C. The impact of pre-existing immunity on the non-clinical pharmacodynamics of AAV5-based gene therapy. Mol Ther Methods Clin Dev. 2019;13:440–52.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yang T-Y, Braun M, Lembke W, McBlane F, Kamerud J, DeWall S, Tarcsa E, Fang X, Hofer L, Kavita U, Upreti VV, Gupta S, Loo L, Johnson AJ, Chandode RK, Stubenrauch K-G, Vinzing M, Xia CQ, Jawa V. Immunogenicity assessment of AAV-based gene therapies: An IQ consortium industry white paper. Mol Ther - Methods Clin Dev. 2022;26:471–94.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Food, U., and D. Administration. Immunogenicity testing of therapeutic protein products—developing and validating assays for anti-drug antibody detection. US Food and Drug Administration: Silver Spring; 2019.

Kruzik A, Fetahagic D, Hartlieb B, Dorn S, Koppensteiner H, Horling FM, Scheiflinger F, Reipert BM, de la Rosa M. Prevalence of anti-adeno-associated virus immune responses in international cohorts of healthy donors. Mol Ther - Methods Clin Dev. 2019;14:126–33.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mével M, Bouzelha M, Leray A, Pacouret S, Guilbaud M, Penaud-Budloo M, Alvarez-Dorta D, Dubreil L, Gouin SG, Combal JP, Hommel M, Gonzalez-Aseguinolaza G, Blouin V, Moullier P, Adjali O, Deniaud D, Ayuso E. Chemical modification of the adeno-associated virus capsid to improve gene delivery. Chem Sci. 2019;11:1122–31.

Article  PubMed  PubMed Central  Google Scholar 

Lee GK, Maheshri N, Kaspar B, Schaffer DV. PEG conjugation moderately protects adeno-associated viral vectors against antibody neutralization. Biotechnol Bioeng. 2005;92:24–34.

Article  CAS  PubMed  Google Scholar 

Verma S, Nwosu SN, Razdan R, Upadhyayula SR, Phan HC, Koroma AA, Leguizamo I, Correa NS, Kuipa M, Lee D, Vanderford TH, Gardner MR. Seroprevalence of adeno-associated virus neutralizing antibodies in males with Duchenne muscular dystrophy. Hum Gene Ther. 2022. https://doi.org/10.1089/hum.2022.081.

Article  PubMed  Google Scholar 

Leborgne C, Latournerie V, Boutin S, Desgue D, Quéré A, Pignot E, Collaud F, Charles S, Simon Sola M, Masat E, Jouen F, Boyer O, Masurier C, Mingozzi F, Veron P. Prevalence and long-term monitoring of humoral immunity against adeno-associated virus in Duchenne muscular dystrophy patients. Cell Immunol. 2019;342: 103780.