Structural and functional characterization of capsid binding by anti-AAV9 monoclonal antibodies from infants after SMA gene therapy

Logan, Grant J; Mietzsch, Mario; Khandekar, Neeta; D’Silva, Arlene M; Anderson, Daniel G.; Mandwie, Mawj; Hsi, Jane; Nelson, Austin R; Chipman, Paul R.; Jackson, Jennifer M.; Schofield, Peter R.; Christ, Daniel; Goodnow, Christopher C.; Reed, Joanne H.; Farrar, Michelle A.; McKenna, Robert; Alexander, Ian E.

doi:10.1016/j.ymthe.2023.03.032

Cited by 14 publications

(13 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is probably the result of the chain slightly shifting towards the 2/5-fold wall and the need to still enter the 2-fold depression. The remaining five CDRs of the Fab do not show significant length differences as previously reported 24 . The phylogenetic analysis of the V L chains showed a clustering of group B and most of group A Fabs (Fig.S1C) suggesting a potential role of the light chain for the binding mode of the Fab.…”

Section: Resultssupporting

confidence: 83%

“…Utilizing standard 3D-reconstruction protocols by imposing icosahedral symmetry using ∼43,000-366,000 particles resulted in cryo-EM maps at resolutions ranging from 1.88–3.27 Å (Tab.S1). For each map, the density contributed by the bound Fab was detected at the previously determined capsid regions 24 . At the 2/5-fold wall of the capsid Fab1-2 was resolved at a resolution of 2.61 Å (Fig.1A).…”

Section: Resultsmentioning

confidence: 99%

“…In the past 12 years, the antibody responses against the AAV capsids were primarily simulated with mouse mAbs 13,20,33,34 . However, our recent study characterizing 21 anti-AAV9 capsid mAbs from human patients indicated that human and mouse antibodies may exhibit differential binding characteristics to the AAV capsids 24 . Prior studies showed that 66% of mouse mAbs bound to the 3-fold region whereas 75% of human mAbs bound to the 2-fold region of the AAV9 capsid 19,33 .…”

Section: Discussionmentioning

confidence: 99%

“…Enzyme-linked immunosorbent assays (ELISA) were performed as previously described 24 . Briefly, sera were assayed for reactivity to AAV9 or hAEV6 by ELISA.…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Structural characterization of antibody-responses from Zolgensma treatment provides the blueprint for the engineering of an AAV capsid suitable for redosing

Mietzsch,

Nelson,

Hsi

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Monoclonal antibodies (mAbs) are useful tools to dissect the neutralizing antibody response against the adeno-associated virus (AAV) capsids used as gene therapy delivery vectors. This study structurally characterizes the interactions of 21 human-derived antibodies from patients treated with the AAV9 vector, Zolgensma®, utilizing high-resolution cryo-electron microscopy. The majority of the bound antibodies do not conform to the icosahedral symmetry of the capsid, thus requiring localized reconstructions. These complex structures provide unprecedented details of the mAbs binding interfaces, with some antibodies inducing structural perturbations of the capsid upon binding. Key surface capsid amino acid residues were identified facilitating the design of capsid variants with an antibody escape phenotype, with the potential to expand the patient cohort treatable with AAV9 vectors to include those that were previously excluded due to their pre-existing neutralizing antibodies, and possibly also to those requiring redosing.

show abstract

Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Enzyme-linked immunosorbent assays (ELISA) were performed as previously described 24 . Briefly, sera were assayed for reactivity to AAV9 or hAEV6 by ELISA.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Structural characterization of antibody-responses from Zolgensma treatment provides the blueprint for the engineering of an AAV capsid suitable for redosing

Mietzsch,

Nelson,

Hsi

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…An in-depth analysis using a matrix approach would be useful to identify immunodominant peptides depending on donor's HLA genotype and to develop engineered capsids to lower or prevent the adaptive immune response without altering AAV tropism such as described for neutralizing antibody response. 27,30 Then, we performed an in-depth analysis of the positive response to AAV8 and AAV9 (which are currently preferred for systemic administration and used in patients (NCT02122952; NCT03199469; NCT03368742). They also appear to be the most prevalent serotypes for a cellular immune response in our healthy donor cohort.…”

Section: Discussionmentioning

confidence: 99%

Prevalence study of cellular capsid-specific immune responses to AAV2, 4, 5, 8, 9 and rh10 in healthy donors

Xicluna,

Avenel,

Vandamme

et al. 2023

Preprint

View full text Add to dashboard Cite

Recombinant adeno-associated virus (rAAV) vectors appear, more than ever, to be efficient viral vectors forin vivogene transfer as illustrated by the approvals of 7 drugs across Europe and the USA. Nevertheless, pre-existing immunity to AAV capsid in humans remains one of the major limits for a successful clinical translation. Whereas pre-existing humoral response to AAV capsid is well documented, the prevalence of pre-existing capsid-specific T cell responses still needs to be studied and characterized. Here, we investigated the prevalence of AAV-specific circulating T cells towards AAV2, 4, 5, 8, 9 and rh10 in a large cohort of healthy donors using the standard IFNγ ELISpot assay. We observed the highest prevalence of pre-existing cellular immunity to AAV9 serotype followed by AAV8, AAV4, AAV2, AAVrh10 and AAV5 independently of the donor’s serological status. An in-depth analysis of T cell responses towards the 2 most prevalent serotypes 8 and 9 shows that IFNγ secretion is mainly mediated by CD8 T cells for both serotypes. A polyfunctional analysis reveals different cytokine profiles between AAV8 and AAV9. Surprisingly, no IL-2 secretion was mediated by anti-AAV9 immune cells suggesting that these cells are rather exhausted than cytotoxic T cells. Altogether, these results suggest that pre-existing immunity to AAV may vary depending on the serotype and support the necessity of using multiparametric monitoring methods to better characterize anti-capsid cellular immunity and foresee its impact in rAAV-mediated clinical trials.

show abstract

Gene therapy clinical trials worldwide to 2023—an update

Ginn,

Mandwie,

Alexander

et al. 2024

The Journal of Gene Medicine

View full text Add to dashboard Cite

To date, 3,900 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical activity from trial databases, official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors. This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our March 2023 update, we have entries on 3,900 trials undertaken in 46 countries. We have analyzed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and which genes have been transferred. Details of the analyses presented, and our searchable database are on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at https://a873679.fmphost.com/fmi/webd/GTCT. We also provide an overview of the progress being made around the world, and discuss key trends since the previous review, namely the unprecedented increase in gene therapy clinical trial activity, including the implementation of genome editing technology with the potential to transform the field moving forward.

show abstract

Structural and functional characterization of capsid binding by anti-AAV9 monoclonal antibodies from infants after SMA gene therapy

Cited by 14 publications

References 50 publications

Structural characterization of antibody-responses from Zolgensma treatment provides the blueprint for the engineering of an AAV capsid suitable for redosing

Structural characterization of antibody-responses from Zolgensma treatment provides the blueprint for the engineering of an AAV capsid suitable for redosing

Prevalence study of cellular capsid-specific immune responses to AAV2, 4, 5, 8, 9 and rh10 in healthy donors

Gene therapy clinical trials worldwide to 2023—an update

Contact Info

Product

Resources

About