Anti-drug Antibody Responses Impair Prophylaxis Mediated by AAV-Delivered HIV-1 Broadly Neutralizing Antibodies

Gardner, Matthew R.; Fetzer, Ina; Kattenhorn, Lisa; Davis-Gardner, Meredith E.; Zhou, Amber S.; Alfant, Barnett; Weber, Jesse A.; Kondur, Hema R.; Martinez-Navío, José M.; Fuchs, Sebastian; Desrosiers, Ronald C.; Gao, Guangping; Lifson, Jeffrey D.; Farzan, Michael

doi:10.1016/j.ymthe.2019.01.004

Cited by 48 publications

(44 citation statements)

References 56 publications

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“…This high level of mutation likely enhances the immunogenicity of these antibodies when delivered to a host other than the one in which those particular sequences originated. Interestingly, when characterizing the humoral responses to the AAV-delivered antibodies we and others have found that the variable regions were predominantly or exclusively targeted (1,11,28,30). We have also reported a highly significant correlation of the magnitude of the host anti-antibody response with the distance from germline of the AAV-delivered antibody: the more mutated, the more immunogenic (28).…”

Section: Introductionmentioning

confidence: 52%

“…For more examples on long-term delivery with AAV of hemophilia factors, please see the following references (61)(62)(63)(64)(65)(66)(67)(68). The long-term delivery described in our report here is significant as the first such report for very long-term delivery of an antibody, particularly given the serious difficulties that have been encountered when AAV has been used to deliver antibodies that are significantly diverged from germ line or contain unusual features (1,14,28,30,31). The findings give hope that long-term delivery of therapeutic antibodies via AAV can be consistently achieved if the ADA problem can be overcome.…”

Section: Discussionmentioning

confidence: 83%

“…One main problem has been encountered in the applicability of this approach. Host antibodies generated against the delivered antibody (generally known as anti-drug antibodies or ADAs) can reduce its functionality and concentration thus drastically reducing its effectiveness (1,11,24,(27)(28)(29)(30)(31)(32). The large repertoire of endogenously generated antibodies present in any individual has gone through a complex checks and balances system to be allowed into circulation (33).…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…The levels of hIgG1 dmAb in the sera declined after d14 to undetectable levels by d35, which is expected in this context in which a xenogeneic human IgG was being expressed in an immune-competent NHP host (29)(30)(31). Accordingly, the decrease in dmAb levels after d14 corresponded with the development of NHP anti-human IgG-dmAb antibodies in the sera (Supplemental Figure 5B and Supplemental Figure 6B).…”

Section: Resultsmentioning

confidence: 56%

In vivo delivery of synthetic DNA–encoded antibodies induces broad HIV-1–neutralizing activity

Wise¹,

Xu²,

Tello‐Ruiz³

et al. 2020

Journal of Clinical Investigation

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Pharmaceuticals and, as such, receive salary and benefits, including ownership of stock and stock options. KM receives grants and consulting fees from Inovio Pharmaceuticals related to DNA vaccine development. DBW has received grant funding, participates in industry collaborations, has received speaking honoraria, and has received fees for consulting, including serving on scientific review committees and board series. Remuneration received by DBW includes direct payments, stock, or stock options, and, in the interest of disclosure, he notes potential conflicts associated with his work with Inovio Pharmaceuticals and possibly others. MCW and DBW have a pending US patent, 62750213.

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“…We have recently published a study that confirms the limitations caused by ADA responses (Gardner et al, 2019b). In our study, we took a different approach, giving four groups of three macaques a combination of rAAV1 vectors encoding either 10-1074 and 3BNC117 or NIH45-46 and PGT121.…”

Section: Adeno-associated Virus Vectors For Delivery Of Hiv-1 Inhibitorsmentioning

confidence: 99%

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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Anti-drug Antibody Responses Impair Prophylaxis Mediated by AAV-Delivered HIV-1 Broadly Neutralizing Antibodies

Cited by 48 publications

References 56 publications

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

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

In vivo delivery of synthetic DNA–encoded antibodies induces broad HIV-1–neutralizing activity

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

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