Passive immunization with a recombinant adenovirus expressing an HA (H5)-specific single-domain antibody protects mice from lethal influenza infection

Тутыхина, И. Л.; Седова, Е. С.; Gribova, Irina Y.; Иванова, Т. И.; Васильев, Л А; Rutovskaya, M. V.; Лысенко, А. А.; Шмаров, М. М.; Logunov, Denis Y.; Naroditsky, Boris S.; Тиллиб, С. В.; Gintsburg, A. L.

doi:10.1016/j.antiviral.2012.12.021

Cited by 33 publications

(28 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A wide variety of genetic delivery vehicles have already been developed including direct administration of DNA and RNA, recombinant adenoviruses (Ad) [9]–[13], and adeno-associated virus (AAV) [14]–[17]. Furthermore, gene delivery vehicles can effectively promote in vivo expression of a range of antibody species for passive immunotherapy [9]–[11], [18].…”

Section: Introductionmentioning

confidence: 99%

Prolonged Prophylactic Protection from Botulism with a Single Adenovirus Treatment Promoting Serum Expression of a VHH-Based Antitoxin Protein

et al. 2014

View full text Add to dashboard Cite

Current therapies for most acute toxin exposures are limited to administration of polyclonal antitoxin serum. We have shown that VHH-based neutralizing agents (VNAs) consisting of two or more linked, toxin-neutralizing heavy-chain-only VH domains (VHHs), each binding distinct epitopes, can potently protect animals from lethality in several intoxication models including Botulinum neurotoxin serotype A1 (BoNT/A1). Appending a 14 amino acid albumin binding peptide (ABP) to an anti-BoNT/A1 heterodimeric VNA (H7/B5) substantially improved serum stability and resulted in an effective VNA serum half-life of 1 to 2 days. A recombinant, replication-incompetent, adenoviral vector (Ad/VNA-BoNTA) was engineered that induces secretion of biologically active VNA, H7/B5/ABP (VNA-BoNTA), from transduced cells. Mice administered a single dose of Ad/VNA-BoNTA, or a different Ad/VNA, via different administration routes led to a wide range of VNA serum levels measured four days later; generally intravenous > intraperitoneal > intramuscular > subcutaneous. Ad/VNA-BoNTA treated mice were 100% protected from 10 LD50 of BoNT/A1 for more than six weeks and protection positively correlated with serum levels of VNA-BoNTA exceeding about 5 ng/ml. Some mice developed antibodies that inhibited VNA binding to target but these mice displayed no evidence of kidney damage due to deposition of immune complexes. Mice were also successfully protected from 10 LD50 BoNT/A1 when Ad/VNA-BoNTA was administered up to 1.5 hours post-intoxication, demonstrating rapid appearance of the protective VNA in serum following treatment. Genetic delivery of VNAs promises to be an effective method of providing prophylactic protection and/or acute treatments for many toxin-mediated diseases.

show abstract

Section: Introductionmentioning

confidence: 99%

Prolonged Prophylactic Protection from Botulism with a Single Adenovirus Treatment Promoting Serum Expression of a VHH-Based Antitoxin Protein

et al. 2014

View full text Add to dashboard Cite

show abstract

“…A wide variety of genetic delivery vehicles have already been developed, including direct administration of DNA and RNA, recombinant adenovirus (Ad) (28)(29)(30), and adeno-associated virus (AAV) (31,32). Furthermore, gene delivery vehicles can effec-tively promote in vivo expression of a range of antibody species for passive immunotherapy (28,29,33,34). We have shown that gene therapy with an Ad expressing a VNA that neutralizes botulinum neurotoxin serotype A (VNA-BoNT/A) resulted in sustained high levels of VNA-BoNTA in serum that protected mice from BoNT/A challenge for several months (27).…”

Section: Nfection With Shiga Toxin (Stx)-producing Escherichia Colimentioning

confidence: 99%

Adenovirus Vector Expressing Stx1/Stx2-Neutralizing Agent Protects Piglets Infected with Escherichia coli O157:H7 against Fatal Systemic Intoxication

et al. 2015

View full text Add to dashboard Cite

b Hemolytic-uremic syndrome (HUS), caused by Shiga toxin (Stx)-producing Escherichia coli (STEC), remains untreatable. Production of human monoclonal antibodies against Stx, which are highly effective in preventing Stx sequelae in animal models, is languishing due to cost and logistics. We reported previously that the production and evaluation of a camelid heavy-chain-only V H domain (VHH)-based neutralizing agent (VNA) targeting Stx1 and Stx2 (VNA-Stx) protected mice from Stx1 and Stx2 intoxication. Here we report that a single intramuscular (i.m.) injection of a nonreplicating adenovirus (Ad) vector carrying a secretory transgene of VNA-Stx (Ad/VNA-Stx) protected mice challenged with Stx2 and protected gnotobiotic piglets infected with STEC from fatal systemic intoxication. One i.m. dose of Ad/VNA-Stx prevented fatal central nervous system (CNS) symptoms in 9 of 10 animals when it was given to piglets 24 h after bacterial challenge and in 5 of 9 animals when it was given 48 h after bacterial challenge, just prior to the onset of CNS symptoms. All 6 placebo animals died or were euthanized with severe CNS symptoms. Ad/VNA-Stx treatment had no impact on diarrhea. In conclusion, Ad/VNA-Stx treatment is effective in protecting piglets from fatal Stx2-mediated CNS complications following STEC challenge. With a low production cost and further development, this could presumably be an effective treatment for patients with HUS and/or individuals at high risk of developing HUS due to exposure to STEC. I nfection with Shiga toxin (Stx)-producing Escherichia coli (STEC)is the most significant cause of hemolytic-uremic syndrome (HUS), the leading cause of acute renal failure in children (1-4) and in some adults. Of the two antigenically distinct toxins, Stx1 and Stx2, Stx2 is more firmly linked with the development of HUS, since STEC strains producing this toxin are more frequently associated with HUS than strains that produce both Stx1 and Stx2, while Stx1 alone has rarely been associated with HUS (5-7). Stx1 and Stx2 are similar in basic structure (8), binding specificity (8), and mode of action (9, 10). Both toxins consist of an A-subunit monomer and a B-subunit pentamer (8,11,12). The pentameric B subunit binds to its cell surface receptor, CD77, also called globotriaosyl ceramide (Gb3; Gal␣1-4 Gal␤1-4 glucosyl ceramide) (13,14). This binding triggers endocytosis of the holotoxin, mainly through clathrin-coated pits (15). Internalization of the catalytically active A subunit, delivered to the cytosol via retrograde transport, causes the shutdown of protein synthesis and leads to cell death (9, 10). In addition to blocking protein synthesis, a longterm effect of the toxin in several types of cells is the induction of apoptosis (16).We previously reported the production of human monoclonal antibodies (HuMAbs) against Stx1 and Stx2 and their evaluation in animal models for efficacy against systemic toxin challenge (17-19) or oral STEC infection (17,(19)(20)(21). Clinical evaluation of these monoclonal antibodies has been s...

show abstract

“…The muscle and liver (via intravenous delivery) have been most often reported. Others include the brain [34, 37, 75–78], eye [81], intranasal route [38, 55, 72, 79, 80], trachea [56], tumors (either directly injected or via intravenous delivery [30, 36, 39, 99–101, 103, 104, 106–109]), pleura [57, 82, 83], peritoneum [45, 60, 84], skin (intradermal [44] and subcutaneous [45]), and spinal canal [40] …”

Section: The Case For Antibody Gene Transfermentioning

confidence: 99%

“…and intramuscular AdV injection (reviewed in [46]). A series of studies has focused on a more local mAb production in mice, either via intranasal [38, 55], intratracheal [56] or intrapleural administration [56, 57] of the encoding AdV (Fig. 1b).…”

Section: Viral Vector-mediated Antibody Gene Transfermentioning

confidence: 99%

State of play and clinical prospects of antibody gene transfer

Hollevoet

Declerck

2017

J Transl Med

View full text Add to dashboard Cite

Recombinant monoclonal antibodies (mAbs) are one of today’s most successful therapeutic classes in inflammatory diseases and oncology. A wider accessibility and implementation, however, is hampered by the high product cost and prolonged need for frequent administration. The surge in more effective mAb combination therapies further adds to the costs and risk of toxicity. To address these issues, antibody gene transfer seeks to administer to patients the mAb-encoding nucleotide sequence, rather than the mAb protein. This allows the body to produce its own medicine in a cost- and labor-effective manner, for a prolonged period of time. Expressed mAbs can be secreted systemically or locally, depending on the production site. The current review outlines the state of play and clinical prospects of antibody gene transfer, thereby highlighting recent innovations, opportunities and remaining hurdles. Different expression platforms and a multitude of administration sites have been pursued. Viral vector-mediated mAb expression thereby made the most significant strides. Therapeutic proof of concept has been demonstrated in mice and non-human primates, and intramuscular vectored mAb therapy is under clinical evaluation. However, viral vectors face limitations, particularly in terms of immunogenicity. In recent years, naked DNA has gained ground as an alternative. Attained serum mAb titers in mice, however, remain far below those obtained with viral vectors, and robust pharmacokinetic data in larger animals is limited. The broad translatability of DNA-based antibody therapy remains uncertain, despite ongoing evaluation in patients. RNA presents another emerging platform for antibody gene transfer. Early reports in mice show that mRNA may be able to rival with viral vectors in terms of generated serum mAb titers, although expression appears more short-lived. Overall, substantial progress has been made in the clinical translation of antibody gene transfer. While challenges persist, clinical prospects are amplified by ongoing innovations and the versatility of antibody gene transfer. Clinical introduction can be expedited by selecting the platform approach currently best suited for the mAb or disease of interest. Innovations in expression platform, administration and antibody technology are expected to further improve overall safety and efficacy, and unlock the vast clinical potential of antibody gene transfer.

show abstract

Passive immunization with a recombinant adenovirus expressing an HA (H5)-specific single-domain antibody protects mice from lethal influenza infection

Cited by 33 publications

References 71 publications

Prolonged Prophylactic Protection from Botulism with a Single Adenovirus Treatment Promoting Serum Expression of a VHH-Based Antitoxin Protein

Prolonged Prophylactic Protection from Botulism with a Single Adenovirus Treatment Promoting Serum Expression of a VHH-Based Antitoxin Protein

Adenovirus Vector Expressing Stx1/Stx2-Neutralizing Agent Protects Piglets Infected with Escherichia coli O157:H7 against Fatal Systemic Intoxication

State of play and clinical prospects of antibody gene transfer

Contact Info

Product

Resources

About