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 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.

Enhancing durability of CIS43 monoclonal antibody by Fc mutation or AAV delivery for malaria prevention

“…For clinical translation, a possible limitation for the VIP approach is whether ADA that would limit durability of the antibody are induced. The data presented here show no indication of NHP ADA, and a recent report demonstrated AAV induction of long-lived SIV antibodies in an NHP over 6 years with limited ADA responses ( 42 ).…”

Safety and Tolerability of the Adeno-Associated Virus Vector, AAV6.2FF, Expressing a Monoclonal Antibody in Murine and Ovine Animal Models

“…Previous non-human primate (NHP) studies have shown that AAV expression of monoclonal antibodies against simian immunodeficiency virus (SIV) is an effective method for prolonged antibody-based immunity to challenge [ 25 , 26 ]. Stable vectorized expression of the anti-SIV monoclonal antibody 5L7 has been maintained in NHPs at 240-350 μg/ mL for over 6 years [ 25 ]. While our study was terminated after 4 weeks to evaluate pathology, long term expression studies in the sheep model are currently ongoing.…”

Bringing Gene Therapies for HIV Disease to Resource-Limited Parts of the World

“…These approaches are designed to either inhibit infection of CD4 + target cells (e.g., by transplantation of bone marrow stem cells from a CCR5D32 donor, knockout of the endogenous CCR5 locus, and/or expression of antagonists that prevent viral entry into potential target cells) 6,48,49 or to reverse latency and increase transcription of HIV (e.g., by provision of latency reversal agents such as histone deacetylase inhibitors, Toll-like receptor agonists, or disulfiram), 50 thereby effecting virus-or immunemediated cytolysis of infected cells (''kick-and-kill''). Conversely, it might be possible to ''block-and-lock'' the viral genome, for example, by inhibition of Tat with didehydro-cortistatin A or with the use of interfering RNAs to silence the viral promoter or cause degradation of complementary viral mRNA.…”