Chae Young Kim

Increased in vivo immunological potency of HB-110, a novel therapeutic HBV DNA vaccine, by electroporation

Pulse-induced permeabilization of cellular membranes, generally referred to as electroporation (EP), has been used for years as a tool to increase macromolecule uptake in tissues, including nucleic acids, for gene therapeutic applications, and this technique has been shown to result in improved immunogenicity. In this study, we assessed the utility of EP as a tool to improve the efficacy of HB-110, a novel therapeutic DNA vaccine against chronic hepatitis B, now in phase 1 of clinical study in South Korea. The potency of HB-110 in mice was shown to be improved by EP. The rapid onset of antigen expression and higher magnitude of humoral and cellular responses in electric pulse-treated mice revealed that EP may enable a substantial reduction in the dosage of DNA vaccine required to elicit a response similar in magnitude to that achievable via conventional administration. This study also showed that EP-based vaccination at 4-week-intervals elicited a cellular immune response which was about two-fold higher than the response elicited by conventional vaccination at 2-week intervals. These results may provide a rationale to reduce the clinical dose and increase the interval between the doses in the multidose vaccination schedule. Electric pulsing also elicited a more balanced immune response against four antigens expressed by HB-110: S, preS, Core, and Pol.

In Vivo kinetics and biodistribution of a HIV-1 DNA vaccine after administration in mice

In this study we have investigated the pharmacokinetics and tissue distribution of GX-12, a multiple plasmid DNA vaccine for the treatment of HIV-1 infection. Plasmid DNA was rapidly degraded in blood with a half-life of 1.34 min and was no longer detectable at 90 min after intravenous injection in mice. After intramuscular injection, plasmid DNA concentration in the injection site rapidly declined to less than 1 % of the initial concentration by 90 min post-injection. However, sub-picogram levels (per mg tissue) were occasionally detected for several days after injection. The relative proportions of the individual plasmids of GX-12 remained relatively constant at the injection site until 90 min post-injection. The concentration of plasmid DNA in tissues other than the injection site peaked at 90 min post-injection and decreased to undetectable levels at 8 h post-injection. The rapidin vivo degradation of GX-12 and absence of persistence in non-target tissues suggest that the risk of potential gene-related toxicities by GX-12 administration, such as expression in non-target tissues, insertional mutagenesis and germline transmission, is minimal

Safety and immunogenicity of therapeutic DNA vaccine with antiviral drug in chronic HBV patients and its immunogenicity in mice

Here, we evaluated the safety and immunogenicity of hepatitis B virus (HBV) DNA vaccine, HB‐110, in mice and Korean patients with chronic hepatitis B (CHB) undergoing adefovir dipivoxil (ADV) treatment.

Safety Evaluation of GX-12, a New HIV Therapeutic Vaccine: Investigation of Integration into the Host Genome and Expression in the Reproductive Organs

AIDS is one of the greatest infectious disease threats to human health despite the extensive efforts made since the discovery of HIV in 1983. The use of plasmid DNA vaccination to elicit humoral and cell-mediated immune responses against HIV infection has produced promising results in animal and in human trials. However, there are several safety concerns about the use of a DNA vaccine, which include the possibility of integration into the host genome, adverse immunopathology, and anti-DNA autoantibody induction. In this study, we examined the potential integration and distribution of GX-12, a new therapeutic vaccine for HIV infection, at various times in muscles and reproductive organs of rats. Animals of both sexes were injected with GX-12 at the dose of 400 µg/animal i.m. once a week for 4 weeks, and host genome integration and tissue distribution were examined on day 1, 5, 15, 30 and 45 days after the final injection. A PCR-based assay revealed that GX-12 was not integrated into the host genome, nor expressed in reproductive organs at any time. These findings suggest that the risk of mutation or germline transmission due to GX-12 injection is negligible.

In vivo kinetics and biodistribution of HB-110, a novel HBV DNA vaccine, after administration in Mice

This study investigated the pharmacokinetic profile and biodistribution of HB-110, a novel HBV therapeutic vaccine candidate, in mice. HB-110 was rapidly degraded in the blood after i.v. injection with a half-life of 1.9±0.083 min, and was no longer detected at 60 min except in one individual near the detection limit. In the i.m. injection, plasmid DNA was detectable at the injection site until 11 days after administration, but the amounts were just above the detection limit. The blood concentration of HB-110 showed a maximum of 604 pg/mL at 15 min after i.m. injection, which was followed by degradation to undetectable levels at 90 min. The plasmid DNA in tissues peaked at 90 min after administration. The highest concentration of plasmid DNA was detected in the liver (24.172 pg/mg tissue), and considerable amounts were also observed in the lung (9.467 pg/mg tissue) and spleen (7.688 pg/mg tissue). The amount of plasmid DNA in tissues was 2 to 3 orders of magnitude lower than in the injection site at the same time points. The HB-110 concentration in tissues, including gonads, decreased rapidly and was undetectable 24 h after administration.

Safety evaluation of GX-12. A new DNA vaccine for HIV infection in rodents.

Abstract Toxicity studies for the evaluation of the safety of GX-12, a naked DNA vaccine for the treatment of human immunodeficiency virus (HIV) infection, were performed in rodents. In a single dose intramuscular or intravenous toxicity study, animals were treated with up to 4000 µg/kg of GX-12. During the experimental period, no abnormalities in mortality, clinical finding, or body weight change were observed. For subacute toxicity study, GX-12 was administered intramuscularly once a week for thirteen weeks to rats at dosages of 0, 250, 1000, or 4000 µg/kg. Throughout the experimental period, no dead animals, notable clinical signs, changes in body weight gain, or food and water consumptions were observed. Ophthalmic examination, urinalysis, hematology, and serum chemistry, revealed no abnormalities. In addition, there were no changes in gross findings, organ weight, and histological findings. Based on these results, the NOAEL was estimated to be excess of 4000 µg/kg. To assess the possible effects on the immune system, we investigated the induction of anti-DNA or anti-myosin autoantibodies in mice immunized and boosted with GX-12, and anti-GX-12 antibodies in rat serum obtained from the subacute toxicity study. GX-12 neither stimulated the production of anti-DNA or myosin autoantibodies nor induced the development of myositis or glomerulonephritis. Therefore, we concluded that GX-12 has no toxicity up to 4000 µg/kg in this rat model, which is 60 times higher than the expected human dose. Furthermore, given the limitations of this study, GX-12 neither initiated nor accelerated the development of systemic autoimmune responses.