Liver-Directed but Not Muscle-Directed AAV-Antibody Gene Transfer Limits Humoral Immune Responses in Rhesus Monkeys

Fuchs, Sebastian; Martinez-Navío, José M.; Rakasz, Eva G.; Gao, Guangping; Desrosiers, Ronald C.

doi:10.1016/j.omtm.2019.11.010

Cited by 23 publications

(21 citation statements)

References 49 publications

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“…What may be responsible for the absence of ADAs in 84-05 and the continued high level of production of the transgene product over this prolonged period? Factors that have been shown to influence whether, or not, ADAs are observed following AAV-mediated expression of a transgene product include the following: the particular sequence of the transgene product (69); whether the recipient is already making a similar or identical protein (39); the serotype of AAV used (38); and targeted delivery or targeted expression at particular sites or in particular tissues or cells (54,(70)(71)(72)(73)(74)(75)(76). AAV-delivered 5L7 antibody certainly has the potential to be immunogenic in rhesus monkeys since 50% of monkeys receiving it have had robust ADA responses (1).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

et al. 2020

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Long-term delivery of anti-HIV monoclonal antibodies using adeno-associated virus (AAV) holds promise for the prevention and treatment of HIV infection. We previously reported that after receiving a single administration of AAV vector coding for anti-SIV antibody 5L7, monkey 84-05 achieved high levels of AAV-delivered 5L7 IgG1 in vivo which conferred sterile protection against six successive, escalating dose, intravenous challenges with highly infectious, highly pathogenic SIVmac239, including a final challenge with 10 animal infectious doses (1). Here we report that monkey 84-05 has successfully maintained 240-350 µg/ml of anti-SIV antibody 5L7 for over 6 years. Approximately 2% of the circulating IgG in this monkey is this one monoclonal antibody. This monkey generated little or no anti-drug antibodies (ADA) to the AAV-delivered antibody for the duration of the study. Due to the nature of the high-dose challenge used and in order to rule out a potential low-level infection not detected by regular viral loads, we have used ultrasensitive techniques to detect cell-associated viral DNA and RNA in PBMCs from this animal. In addition, we have tested serum from 84-05 by ELISA against overlapping peptides spanning the whole envelope sequence for SIVmac239 (PepScan) and against recombinant p27 and gp41 proteins. No reactivity has been detected in the ELISAs indicating the absence of naturally arising anti-SIV antibodies; moreover, the ultrasensitive cell-associated viral tests yielded no positive reaction. We conclude that macaque 84-05 was effectively protected and remained uninfected. Our data show that durable, continuous antibody expression can be achieved after one single administration of AAV and support the potential for lifelong protection against HIV from a single vector administration.

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Section: Discussionmentioning

confidence: 99%

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

et al. 2020

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“…The liver has been a long-suited target for gene transfer, as research efforts have been directed to targeting the liver for the correction of a variety of genetic and metabolic diseases [167][168][169][170][171] and for other applications in which, for example, hepatocytes are turned into biofactories to supply protein therapeutics directly into the bloodstream. 5,81,[172][173][174] Several important features make the liver an ideal organ for gene therapy, including (1) the fact that hepatocytes are central to several metabolic functions and secrete a variety of proteins into the circulation; (2) its high degree of vascularization, which allows for easy transduction with any gene therapy vector delivered thorough the bloodstream; and (3) its unique immune protolerogenic environment (vide supra).…”

Section: Liver Gene Transfermentioning

confidence: 99%

AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer

2020

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Gene therapy with adeno-associated virus (AAV) vectors has demonstrated safety and long-term efficacy in a number of trials across target organs, including eye, liver, skeletal muscle, and the central nervous system. Since the initial evidence that AAV vectors can elicit capsid T cell responses in humans, which can affect the duration of transgene expression, much progress has been made in understanding and modulating AAV vector immunogenicity. It is now well established that exposure to wild-type AAV results in priming of the immune system against the virus, with development of both humoral and T cell immunity. Aside from the neutralizing effect of antibodies, the impact of pre-existing immunity to AAV on gene transfer is still poorly understood. Herein, we review data emerging from clinical trials across a broad range of gene therapy applications. Common features of immune responses to AAV can be found, suggesting, for example, that vector immunogenicity is dose-dependent, and that innate immunity plays an important role in the outcome of gene transfer. A range of host-specific factors are also likely to be important, and a comprehensive understanding of the mechanisms driving AAV vector immunogenicity in humans will be key to unlocking the full potential of in vivo gene therapy. Pre-existing Immunity to WT AAV in Humans Pre-existing Humoral ImmunitySeveral studies have investigated the seroprevalence of neutralizing antibodies directed against WT AAV in humans. [20][21][22][23][24][25] Seroprevalence varies geographically, with anti-AAV2 neutralizing antibodies displaying the highest prevalence, ranging from 30% to 60% of the population. Due to the broad cross-reactivity between AAV serotypes, 26 neutralizing antibodies recognizing virtually all serotypes can be found in almost all subjects. 27 This cross-reactivity reflects the amino acid sequence and structural homology across capsids of different AAV serotypes. 28 The prevalence of total anti-AAV antibodies is close to 70% of the population for AAV1 and AAV2, 45% for AAV6 and AAV9, and 38% for AAV8. 20 Importantly, titers of anti-AAV immunoglobulin G (IgG) antibodies correlate significantly with titers of

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“…One way to promote tolerance has been to target the liver with rAAV vectors to produce more Tregs. In a recent study, intravenous administration of rAAV8 vectors encoding 4L6 followed by an intramuscular rAAV1 vector inoculation 14 weeks later, resulted in robust 4L6 concentrations in three of three rhesus macaques (Fuchs et al, 2019). Thus, the liver expression of rAAV transgenes may provide a means of tolerance.…”

Section: Current Limitations When Using Raav Vectorsmentioning

confidence: 98%

Promise and Progress of an HIV-1 Cure by Adeno-Associated Virus Vector Delivery of Anti-HIV-1 Biologics

Gardner

2020

Front. Cell. Infect. Microbiol.

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Despite the success of antiretroviral therapy (ART) at suppressing HIV-1 infection, a cure that eradicates all HIV-1-infected cells has been elusive. The latent viral reservoir remains intact in tissue compartments that are not readily targeted by the host immune response that could accelerate the rate of reservoir decline during ART. However, over the past decade, numerous broadly neutralizing antibodies (bNAbs) have been discovered and characterized. These bNAbs have also given rise to engineered antibody-like inhibitors that are just as or more potent than bNAbs themselves. The question remains whether bNAbs and HIV-1 inhibitors will be the effective "kill" to a shock-and-kill approach to eliminate the viral reservoir. Additional research over the past few years has sought to develop recombinant adeno-associated virus (rAAV) vectors to circumvent the need for continual administration of bNAbs and maintain persistent expression in a host. This review discusses the advancements made in using rAAV vectors for the delivery of HIV-1 bNAbs and inhibitors and the future of this technology in HIV-1 cure research. Numerous groups have demonstrated with great efficacy that rAAV vectors can successfully express protective concentrations of bNAbs and HIV-1 inhibitors. Yet, therapeutic concentrations, especially in non-human primate (NHP) models, are not routinely achieved. As new studies have been reported, more challenges have been identified for utilizing rAAV vectors, specifically how the host immune response limits the attainable concentrations of bNAbs and inhibitors. The next few years should provide improvements to rAAV vector delivery that will ultimately show whether they can be used for expressing bNAbs and HIV-1 inhibitors to eliminate the HIV-1 viral reservoir.

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Liver-Directed but Not Muscle-Directed AAV-Antibody Gene Transfer Limits Humoral Immune Responses in Rhesus Monkeys

Cited by 23 publications

References 49 publications

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer

Promise and Progress of an HIV-1 Cure by Adeno-Associated Virus Vector Delivery of Anti-HIV-1 Biologics

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