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Prevalence and pharmacological modulation of humoral immunity to AAV vectors in gene transfer to synovial tissue.

Mingozzi F, Chen Y, Edmonson SC, Zhou S, Thurlings RM, Tak PP, High KA, Vervoordeldonk MJ - Gene Ther. (2012)

Bottom Line: This difference was more evident for AAV2, against which higher titers were measured.A drop of NAb titer was observed in a subset of those subjects carrying NAb titers ≤1:1000; however, only in a minority of subjects titers dropped below 1:5.This work provides insights into strategies to overcome the limitation of pre-existing humoral immunity to AAV vectors.

View Article: PubMed Central - PubMed

Affiliation: Center of Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. mingozzi@email.chop.edu

ABSTRACT
Antibodies against adeno-associated viral (AAV) vectors are highly prevalent in humans. Both preclinical and clinical studies showed that antibodies against AAV block transduction even at low titers, particularly when the vector is introduced into the bloodstream. Here we measured the neutralizing antibody (NAb) titer against AAV serotypes 2, 5, 6 and 8 in the serum and matched synovial fluid (SF) from rheumatoid arthritis patients. The titer in the SF was lower than that in the matched plasma samples, indicating a difference in distribution of NAb to AAV depending on the body fluid compartment. This difference was more evident for AAV2, against which higher titers were measured. Of all serotypes, anti-AAV5 antibodies were the least prevalent in both the serum and SF. We next evaluated the impact of B-cell depletion on anti-AAV antibodies in rheumatoid arthritis patients who received one or two courses of the anti-CD20 antibody rituximab as part of their disease management. A drop of NAb titer was observed in a subset of those subjects carrying NAb titers ≤1:1000; however, only in a minority of subjects titers dropped below 1:5. This work provides insights into strategies to overcome the limitation of pre-existing humoral immunity to AAV vectors.

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Related in: MedlinePlus

Anti-AAV2 total IgG titer in the serum and synovial fluid from subjects affected by rheumatoid arthritis. Total anti-AAV2 IgG were measured with a capture assay; results are expressed in ng ml−1. For each sample, the average of a duplicate reading is reported.
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fig1: Anti-AAV2 total IgG titer in the serum and synovial fluid from subjects affected by rheumatoid arthritis. Total anti-AAV2 IgG were measured with a capture assay; results are expressed in ng ml−1. For each sample, the average of a duplicate reading is reported.

Mentions: Previous reports18, 19 show that anti-AAV antibodies are present in SF. To test the relationship between the prevalence of antibodies in the serum and SF, matched samples were collected from 11 individuals affected by RA. Initial screening with a capture assay for the detection of AAV2-specific total IgG showed a statistically significant (P=0.0284, paired t-test) difference between systemic levels of IgG in the serum vs local anti-AAV IgG levels in the SF, with serum samples generally carrying a modestly higher titer (Figure 1).


Prevalence and pharmacological modulation of humoral immunity to AAV vectors in gene transfer to synovial tissue.

Mingozzi F, Chen Y, Edmonson SC, Zhou S, Thurlings RM, Tak PP, High KA, Vervoordeldonk MJ - Gene Ther. (2012)

Anti-AAV2 total IgG titer in the serum and synovial fluid from subjects affected by rheumatoid arthritis. Total anti-AAV2 IgG were measured with a capture assay; results are expressed in ng ml−1. For each sample, the average of a duplicate reading is reported.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3473155&req=5

fig1: Anti-AAV2 total IgG titer in the serum and synovial fluid from subjects affected by rheumatoid arthritis. Total anti-AAV2 IgG were measured with a capture assay; results are expressed in ng ml−1. For each sample, the average of a duplicate reading is reported.
Mentions: Previous reports18, 19 show that anti-AAV antibodies are present in SF. To test the relationship between the prevalence of antibodies in the serum and SF, matched samples were collected from 11 individuals affected by RA. Initial screening with a capture assay for the detection of AAV2-specific total IgG showed a statistically significant (P=0.0284, paired t-test) difference between systemic levels of IgG in the serum vs local anti-AAV IgG levels in the SF, with serum samples generally carrying a modestly higher titer (Figure 1).

Bottom Line: This difference was more evident for AAV2, against which higher titers were measured.A drop of NAb titer was observed in a subset of those subjects carrying NAb titers ≤1:1000; however, only in a minority of subjects titers dropped below 1:5.This work provides insights into strategies to overcome the limitation of pre-existing humoral immunity to AAV vectors.

View Article: PubMed Central - PubMed

Affiliation: Center of Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. mingozzi@email.chop.edu

ABSTRACT
Antibodies against adeno-associated viral (AAV) vectors are highly prevalent in humans. Both preclinical and clinical studies showed that antibodies against AAV block transduction even at low titers, particularly when the vector is introduced into the bloodstream. Here we measured the neutralizing antibody (NAb) titer against AAV serotypes 2, 5, 6 and 8 in the serum and matched synovial fluid (SF) from rheumatoid arthritis patients. The titer in the SF was lower than that in the matched plasma samples, indicating a difference in distribution of NAb to AAV depending on the body fluid compartment. This difference was more evident for AAV2, against which higher titers were measured. Of all serotypes, anti-AAV5 antibodies were the least prevalent in both the serum and SF. We next evaluated the impact of B-cell depletion on anti-AAV antibodies in rheumatoid arthritis patients who received one or two courses of the anti-CD20 antibody rituximab as part of their disease management. A drop of NAb titer was observed in a subset of those subjects carrying NAb titers ≤1:1000; however, only in a minority of subjects titers dropped below 1:5. This work provides insights into strategies to overcome the limitation of pre-existing humoral immunity to AAV vectors.

Show MeSH
Related in: MedlinePlus