Impact of Natural IgM Concentration on Gene Therapy with Adenovirus Type 5 Vectors

Qiu, Qi Hong; Xu, Zhili; Tian, Jie; Moitra, Rituparna; Gunti, Sreenivasulu; Notkins, Abner Louis; Byrnes, Andrew P.

doi:10.1128/jvi.03217-14

Cited by 27 publications

(35 citation statements)

References 26 publications

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“…However, the impact of individual complement factors as well as of IgM antibodies on the neutralization activity has been reported for viruses such as hepatitis C, vesicular stomatitis and adenovirus type 5. [52][53][54] Therefore, it is conceivable that the decrease of NAB activity following IA is partially dependent on the depletion of non-IgG plasma proteins and further investigations are needed to address this point.…”

Section: Discussionmentioning

confidence: 99%

Immunoadsorption enables successful rAAV5-mediated repeated hepatic gene delivery in nonhuman primates

et al. 2019

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Key Points• IA procedure decrease anti-AAV5 NABs to levels compatible with a successful AAV5 vector readministration.• Patients positive for anti-AAV antibodies could benefit from AAVbased gene therapy after IA treatment.Adeno-associated virus (AAV)-based liver gene therapy has been shown to be clinically successful. However, the presence of circulating neutralizing antibodies (NABs) against AAV vector capsids remains a major challenge as it may prevent successful transduction of the target cells. Therefore, there is a need to develop strategies that would enable AAV-mediated gene delivery to patients with preexisting anti-AAV NABs. In the current study, the feasibility of using an immunoadsorption (IA) procedure for repeated, liver-targeted gene delivery in nonhuman primates was explored. The animals were administered IV with recombinant AAV5 (rAAV5) carrying the reporter gene human secreted embryonic alkaline phosphatase (hSEAP). Seven weeks after the first rAAV treatment, all of the animals were readministered with rAAV5 carrying the therapeutic hemophilia B gene human factor IX (hFIX). Half of the animals administered with rAAV5-hSEAP underwent IA prior to the second rAAV5 exposure.The transduction efficacies of rAAV5-hSEAP and rAAV5-hFIX were assessed by measuring the levels of hSEAP and hFIX proteins. Although no hFIX was detected after rAAV5-hFIX readministration without prior IA, all animals submitted to IA showed therapeutic levels of hFIX expression, and a threshold of anti-AAV5 NAB levels compatible with successful readministration was demonstrated. In summary, our data demonstrate that the use of a clinically applicable IA procedure enables successful readministration of an rAAV5-based gene transfer in a clinically relevant animal model. Finally, the analysis of anti-AAV NAB levels in human subjects submitted to IA confirmed the safety and efficacy of the procedure to reduce anti-AAV NABs. Furthermore, clinical translation was assessed using an immunoglobulin G assay as surrogate.

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Section: Discussionmentioning

confidence: 99%

Immunoadsorption enables successful rAAV5-mediated repeated hepatic gene delivery in nonhuman primates

et al. 2019

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“…Following systemic administration of virus, rAd5 virions are exposed to diverse serum factors. Serum proteins such as factor X (41-43), native antibodies (3,4,44), or preexisting serotype-specific antibody (45) can bind virus and influence mechanisms contributing to virus uptake, transduction, localization, and intracellular signaling. How these interactions impact antiadenovirus responses has not been fully established.…”

Section: Pser396mentioning

confidence: 99%

Diminished Innate Antiviral Response to Adenovirus Vectors in cGAS/STING-Deficient Mice Minimally Impacts Adaptive Immunity

Anghelina

Lam

Falck-Pedersen

2016

J Virol

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“…This combination of multivalency and polyreactivity makes natural IgM an important component of the innate immune system for recognizing microbes and allows IgM to function as the first line of defense against invading pathogens before antigen‐specific IgG come into play . Accordingly, the serum of naïve mice contains polyreactive IgM antibodies that can bind AdV .…”

Section: Antibodies and Their Interactions With Advmentioning

confidence: 99%

“…Instead, natural IgM can enhance the clearance of AdV by liver macrophages known as Kupffer cells (KCs) , which reduces the amount of virions available to transduce hepatocytes. IgM‐deficient mice show increased hepatocyte transduction by AdV‐5 vectors when compared with wild‐type mice . Moreover, the concentration of IgM in different strains of mice inversely correlates with the ability of intravenously administered AdV vectors to transduce hepatocytes.…”

Section: Antibodies and Their Interactions With Advmentioning

confidence: 99%

“…Moreover, the concentration of IgM in different strains of mice inversely correlates with the ability of intravenously administered AdV vectors to transduce hepatocytes. For example, BALB/c mice have high levels of IgM and low hepatocyte transduction, C57BL/6 mice have low levels of IgM and high hepatocyte transduction, and hybrid crosses between these two mouse strains have intermediate levels of IgM and hepatocyte transduction . These effects of natural IgM are mainly mediated by the ability of IgM to enhance clearance of AdV by macrophages .…”

Section: Antibodies and Their Interactions With Advmentioning

confidence: 99%

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Interaction of adenovirus with antibodies, complement, and coagulation factors

Allen

Byrnes

2019

FEBS Letters

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Edited by Urs GreberAdenovirus (AdV) is one of the most widely used vectors for gene therapy and vaccine studies due to its excellent transduction efficiency, capacity for large transgenes, and high levels of gene expression. When administered intravascularly, the fate of AdV vectors is heavily influenced by interactions with host plasma proteins. Some plasma proteins can neutralize AdV, but AdV can also specifically bind plasma proteins that protect against neutralization and preserve activity. This review summarizes the plasma proteins that interact with AdV, including antibodies, complement, and vitamin K-dependent coagulation factors. We will also review the complex interactions of these plasma proteins with each other and with cellular proteins, as well as strategies for developing better AdV vectors that evade or manipulate plasma proteins.

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Impact of Natural IgM Concentration on Gene Therapy with Adenovirus Type 5 Vectors

Cited by 27 publications

References 26 publications

Immunoadsorption enables successful rAAV5-mediated repeated hepatic gene delivery in nonhuman primates

Immunoadsorption enables successful rAAV5-mediated repeated hepatic gene delivery in nonhuman primates

Diminished Innate Antiviral Response to Adenovirus Vectors in cGAS/STING-Deficient Mice Minimally Impacts Adaptive Immunity

Interaction of adenovirus with antibodies, complement, and coagulation factors

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