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

ABSTRACT: 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 ?g/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.

SUBMITTER: Martinez-Navio JM

PROVIDER: S-EPMC7089924 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Martinez-Navio José M JM Fuchs Sebastian P SP Mendes Desiree E DE Rakasz Eva G EG Gao Guangping G Lifson Jeffrey D JD Desrosiers Ronald C RC

Frontiers in immunology 20200317

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 <i>in vivo</i> which conferred sterile protection against six successive, escalating dose, intravenous challenges with highly infectious, highly pathogenic SIVmac239, incl ...[more]

PMID: 32256496

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Project description:Monoclonal antibodies targeting cytokines are administered parenterally for the systemic treatment of severe psoriasis. However, systemic exposure to the biologic increases the risk of side-effects including immunosuppression, whereas only a small fraction of the active molecules actually reaches the target organ, the skin. This preclinical study examines the feasibility of delivering a humanized anti-CD29 monoclonal antibody (OS2966) topically to skin using minimally-invasive fractional laser ablation. This approach would enable the targeted use of a biologic for the treatment of recalcitrant psoriatic plaques in patients with less widespread disease while minimizing the risk of systemic exposure. First, the effect of a wide range of laser poration conditions on skin permeation and deposition of OS2966 was tested in vitro to determine optimal microporation parameters. Subsequently, confocal laser scanning microscopy was employed to visualize the distribution of fluorescently-labelled OS2966 in skin. The results demonstrated that delivery of OS2966 into and across skin was feasible. Above fluences of 35.1?J/cm2, skin deposition and permeation were statistically superior to passive delivery reaching values up to 3.7?±?1.2?µg/cm2 at the most aggressive condition. Selective targeting of the skin was also possible since ?70% of the OS2966 was delivered locally to the skin. Although nanogramme quantities were able to permeate across skin, these amounts were orders of magnitude lower than levels seen following subcutaneous or intravenous injection and would result in minimal systemic exposure in vivo. The diffusion of fluorescently-labelled OS2966 into the skin surrounding the pores was clearly higher than in intact skin and demonstrated the feasibility of delivering the antibody at least as deep as the dermo-epithelial junction, a critical border region where inflammatory cells cross to promote disease progression. These preliminary results confirm that fractional laser ablation can be used for the cutaneous delivery of OS2966 and now preclinical/clinical studies are required to demonstrate therapeutic efficacy.

Dataset Information

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

Publications

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

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