Immunogenicity assessment of AAV-based gene therapies: An IQ consortium industry white paper

Yang, Tong‐Yuan; Braun, Manuela; Lembke, Wibke; McBlane, Fraser; Kamerud, John; DeWall, Stephen; Tarcsa, Edit; Fang, Xiaodong; Hofer, Lena; Kavita, Uma; Upreti, Vijay V.; Gupta, Swati; Loo, Lina; Johnson, Alison J.; Chandode, Rakesh Kantilal; Stubenrauch, Kay-Gunnar; Vinzing, Maya; Xia, Cindy Q.; Jawa, Vibha

doi:10.1016/j.omtm.2022.07.018

Cited by 33 publications

(36 citation statements)

References 197 publications

(367 reference statements)

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“…The introduction of various standardized quality measures for a catheter-based clinically applicable ROA and a meaningful clinical endpoint design by our CMR study enabled a first proof-of-concept study already demonstrating therapeutic efficacy of the vector-target system with a dosage ranging at the lower end of approved dose margins in current early rAAV-based CHF gene therapy trials. This corroborates the therapeutic efficacy of our GTMP candidate rAAV5 -hS100A1 and provides the rationale for further pre-clinical dose-escalating studies leveraging the full dose range of up to 3×10 14 vgcs per patient being approved for AAV-based CHF GTMPs in ongoing FiH studies (NCT04179643). The favorable clinical safety profile of rAAV5, its high production yield and experience of regulatory bodies with this serotype, render the vector a promising candidate for expedited cardiac GTMP developmental programs using S100A1 as a therapeutic target.…”

Section: Conclusion and Clinical Perspectivesupporting

confidence: 73%

“…Hence, conclusions drawn from these clinical programs should advice the selection of appropriate AAV vector types for cardiac GTMP programs to mitigate the risk of failure throughout pre-clinical and clinical development. [12][13][14] Of note, rAAV9, which engendered considerable interest as a vector for treating hereditary and common cardiac disorders 1,3 , provoked numerous serious (SAEs) and fatal adverse events (FAEs) in clinical studies for spinal muscular atrophy or Duchenne muscular dystrophy (rAAV9-miniDMD) 15,16 . To this rAAV5 contrasts with proven long-term clinical safety and efficacy in patients, such as for hemophilia A or B.…”

Section: Introductionmentioning

confidence: 99%

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Cardiac-targeted rAAV5-S100A1 gene therapy protects against adverse remodeling and contractile dysfunction in post-ischemic hearts

Kehr

Salatzki

Krautz

et al. 2023

Preprint

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SummaryToxicity by recombinant adeno-associated viruses (rAAV) in clinical gene therapy trials (e.g., by rAAV9-mediated fatal liver failure) significantly impairs translation of preclinical rAAV-based cardiac gene therapies employing these vectors. For rAAV5 - a capsid that has shown long-term safety in clinical trials - our translational study demonstrates effective transduction of the left ventricle (LV) of healthy pigs via catheter-based retrograde intravenous delivery (CRID) by means of luciferase reporter gene biodistribution analyses. Combination of rAAV5 with the cardioprotective human geneS100A1(hS100A1) prevents LV myocardial infarct (MI) enlargement and improves LV systolic contractile performance in a porcine model of post-MI chronic cardiac dysfunction. Use of a cardiac-biased promoter ensured the cardiac-directed expression of the therapeutic human transgene without signs of clinical toxicity. The beneficial effects of rAAV5-hS100A1were linked to an attenuated activity of post-MI inflammatory gene networks and this was further validated in a murine model. These novel data together with proven scalable producibility and low pre-existing immunity against rAAV5 in humans may collectively advance clinical translation of rAAV5-hS100A1as a gene therapy medicinal product (GTMP) for a common cardiovascular disease, such as chronic heart failure (CHF).HighlightsRecent fatal adverse events in recombinant adeno-associated virus (AAV)-based clinical gene therapy trials advise the use of rAAV serotypes with proven long-term clinical safety, such as rAAV5, for the pre-clinical development and clinical translation of rAAV-based cardiac gene therapy medicinal products.In a biodistribution and therapeutic proof-of-concept study in farm pigs, rAAV5 was identified as an effective viral vector for cardiac gene transfer and gene therapy for post-ischemic cardiac dysfunction when applied by a standardized cardiac-targeted catheter-based route of administration with the luciferase reporter and cardioprotective human gene S100A1 (hS100A1), respectively.A systems biology analysis linked the novel finding of mitigated inflammatory and activated cardioprotective gene network activities in rAAV5-hS100A1treated postischemic myocardium with improved study left ventricular ejection fraction and prevention of myocardial infarct extension, respectively, which warrants further mechanistic molecular studies.Since rAAV5 has been recently approved for clinical use in a non-cardiac indication and cardiac-targeted S100A1 gene therapy has been effective in numerous pre-clinical animal models of acute and chronic cardiac dysfunction, our translational data support an expedited developmental path for rAAV5-hS100A1throughout investigational new drug-enabling studies towards a first-in-human clinical trial for post-myocardial infarction heart failure.

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Section: Conclusion and Clinical Perspectivesupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Cardiac-targeted rAAV5-S100A1 gene therapy protects against adverse remodeling and contractile dysfunction in post-ischemic hearts

Kehr

Salatzki

Krautz

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…A possible interpretation of this might be related to repeated exposure to the living environment and latent AAVs, integrated into the chromosome and re-activated with the infection of helper virus, including adenovirus. 14,33 Indeed, our data suggest that the second challenge with AAV induced high titer of NAbs which cross-reacted with many AAV serotypes.…”

Section: Discussionmentioning

confidence: 71%

“…[9][10][11] Hence, most clinical trials of systemic administration of AAV vector have targeted only patients without NAbs against the AAV. [12][13][14] We have recently reported the prevalence of NAbs against several AAV serotypes in Japanese hemophiliacs and healthy individuals and found the prevalence to range from 20% to 30% in the parent population. 15 The administration of AAV vectors, in addition to natural infection with AAV, correspondingly induces a high titer of NAbs against the AAV vector.…”

Section: Introductionmentioning

confidence: 99%

Successful Liver transduction by Re-administration of Different Adeno-Associated Virus Vector Serotypes in Mice

Baatartsogt

Kashiwakura

Hiramoto

et al. 2022

Preprint

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Intravenous administration of adeno-associated virus (AAV) vector is a promising gene therapy approach for monogenic diseases. However, re-administration of the same AAV serotype is impossible due to the induction of anti-AAV neutralizing antibodies (NAbs). Here we examined the feasibility of re-administration of AAV vectors to change the serotypes. We administered AAV3B, AAV5, or AAV8 vectors targeting the liver of C57BL/6 mice intravenously, and then assessed the emergence of NAbs and the transduction efficacy with a second administration. For all serotypes, we confirmed that re-administration with the same serotype was not possible. Although the highest neutralizing activity of NAb was induced by AAV5; however, the NAbs elicited by AAV5 did not react with any other serotypes, resulting in success in re-administration with the other serotypes. The re-administration of AAV5 was also successful in all mice treated with AAV3B and AAV8. The effective secondary administration of AAV3B and AAV8 was observed in most mice treated with AAV8 and AAV3B, respectively. However, few mice developed NAbs cross-reactive with the other serotypes, especially the serotypes with close sequence homology. In summary, AAV vector administration induced NAbs relatively specific to the serotype administrated. Secondary administration of AAVs targeting liver transduction could be successfully achieved by switching AAV serotypes in mice.

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“…Thus, reducing the vector dose is one important aspect of ensuring the safety of AAV-based gene therapy. [11][12][13] Another problem with AAV vectors is the patient's immune status against AAV. Like the naturally occurring anti-AAV-neutralizing antibodies (NAbs) attenuates AAV-mediated gene therapy, 14,15 induction of NAbs after an AAV vector administration deprives a chance to re-administrate the same serotype of the AAV vector.…”

Section: Introductionmentioning

confidence: 99%

Efficient Gene Transduction in Pigs and Macaques with the Engineered AAV Vector AAV.GT5 for Hemophilia B Gene Therapy

Kashiwakura

Endo

Ugajin

et al. 2022

Preprint

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Gene therapy for hemophilia using adeno-associated virus (AAV) vectors allows long-term coagulation factor expression. We examined the potential of a novel engineered liver-tropic AAV3B-based vector AAV.GT5 for hemophilia B gene therapy. In vitro transduction with AAV.GT5 in human hepatocytes was more than 100 times higher than with AAV-Spark100, while in vivo transduction efficacy into the liver and the increase in coagulation factor IX (FIX) antigen following intravenous injection of these vectors were similar in PXB mice (chimeric mice with a humanized liver) and macaques. The discrepancy was due to the low recovery and short half-life of AAV.GT5 in blood, depending on the positive charge of the heparin-binding site in the original AAV3B. The intra-hepatic vascular administration of AAV.GT5, but not AAV-Spark100, enhanced vector transduction into the liver and reduced vector distribution to the kidney in pigs. In macaques, the intra-hepatic artery injection of AAV.GT5 yielded a comparable increase in FIX antigen with a one-third dosage of peripheral venous administration. Two of four macaques who received AAV.GT5 intravenously did not develop neutralizing antibodies (NAbs) against AAV.GT5, while AAV-Spark100 induced serotype-specific NAbs in all four macaques. The NAb produced after the administration was relatively specific to the serotype and less responsive to the other serotype. As a result, the administration of AAV.GT5 successfully boosted FIX expression in one animal previously given AAV-Spark100. Thus, AAV.GT5 has different biodistribution and immunogenic characteristics compared with AAV-Spark100, and the intra-hepatic vascular administration may lessen the vector dose and avoid vector distribution to other organs.

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Immunogenicity assessment of AAV-based gene therapies: An IQ consortium industry white paper

Cited by 33 publications

References 197 publications

Cardiac-targeted rAAV5-S100A1 gene therapy protects against adverse remodeling and contractile dysfunction in post-ischemic hearts

Cardiac-targeted rAAV5-S100A1 gene therapy protects against adverse remodeling and contractile dysfunction in post-ischemic hearts

Successful Liver transduction by Re-administration of Different Adeno-Associated Virus Vector Serotypes in Mice

Efficient Gene Transduction in Pigs and Macaques with the Engineered AAV Vector AAV.GT5 for Hemophilia B Gene Therapy

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