Soshin AHN - Academia.edu (original) (raw)

Papers by Soshin AHN

Research paper thumbnail of Cell with Surface Coated with ANXA1 and Use Thereof

Research paper thumbnail of A Randomized Pharmacokinetic Study in Healthy Male Subjects Comparing a High-concentration, Citrate-free SB5 Formulation (40 mg/0.4 ml) and Prior SB5 (Adalimumab Biosimilar)

Rheumatology and therapy, Jul 1, 2022

Introduction: SB5 is an approved biosimilar of adalimumab, a monoclonal anti-tumor necrosis facto... more Introduction: SB5 is an approved biosimilar of adalimumab, a monoclonal anti-tumor necrosis factor (anti-TNF) antibody. This study compared pharmacokinetics (PK), safety, tolerability, and immunogenicity between a new highconcentration, low-volume, and citrate-free formulation (40 mg/0.4 ml, SB5-HC) and the current low-concentration formulation with higher volume (40 mg/0.8 ml, SB5-LC) to evaluate the bioequivalence of the two formulations. Methods: This study was a randomized, singleblind, two-arm, parallel-group, single-dose study in healthy male subjects. Subjects were randomized to receive either SB5-HC or SB5-LC via subcutaneous injection using a pre-filled syringe. Primary endpoints were the area under the curve of the concentration-time curve from zero to infinity (AUC inf) and maximum serum concentration (C max). Bioequivalence was achieved if the 90% confidence intervals (CIs) for the ratios of the geometric least squares mean (LSMean) of primary endpoints were within the pre-defined bioequivalence margins of 0.80-1.25. Secondary endpoints included safety, tolerability, and immunogenicity. Results: Subjects (n = 188) were randomized to SB5-HC (n = 94) or SB5-LC (n = 94). Baseline characteristics were comparable between the two treatment groups. The mean values for AUC inf and C max were similar between the SB5-HC and SB5-LC groups. For the primary endpoints, the geometric LSMean ratios (90% CI) for AUC inf and C max were 0.920 (0.8262-1.0239) and 0.984 (0.9126-1.0604), respectively, placing the corresponding 90% CIs well within the pre-defined bioequivalence margin of 0.80-1.25. All treatment-emergent adverse events (TEAEs) were considered mild to moderate and were reported for 44.7% and 51.1% of subjects in the SB5-HC and SB5-LC groups, respectively. Immunogenicity assessed by frequency of occurrence of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) was comparable between groups. Conclusions: This bridging study demonstrated PK equivalence and comparable safety and tolerability of subcutaneous injection of SB5 via SB5-HC or SB5-LC. Clinicaltrials.gov identifier: https://clinicaltrials. gov/ct2/show/NCT04514796.

Research paper thumbnail of AIDS Vaccine Development: the Past, the Present, and the Future

Research paper thumbnail of REVIEW ARTICLE AIDS Vaccine Development: the Past, the Present, and the Future

men with pneumocystis carinii pneumonia and mucosal candidiasis had deficiency in CD4 T lymphocyt... more men with pneumocystis carinii pneumonia and mucosal candidiasis had deficiency in CD4 T lymphocyte, a critical immune defense cell (1). In 1983, Dr. F. Barré-Sinoussi and L. Montagnier isolated a new human T-lymphotropic retrovirus, later named HIV-1(human immunodeficiency virus type 1) which turned out to be one of the causes of AIDS (2). Through their discovery, they received the 2008 Nobel Prize in Physiology or Medicine award. Discovery of the causative agent of AIDS had been the driving force to investigate its genomic structure, function, and replication mechanism. Most importantly, the development of a diagnostic kit contributed to the knowledge of AIDS as an infectious disease especially in the route of transmission. In addition, the development of antiretroviral drugs reduced the mortality of some HIV-infected individuals.

Research paper thumbnail of AIDS vaccine development: the past, the present, and the future

Research paper thumbnail of Mucosal prior to systemic application of recombinant adenovirus boosting is more immunogenic than systemic application twice but confers similar protection against SIV-challenge in DNA vaccine-primed macaques

Virology, 2009

We investigated the immunogenicity and efficacy of a bimodal prime/boost vaccine regimen given by... more We investigated the immunogenicity and efficacy of a bimodal prime/boost vaccine regimen given by various routes in the Simian immunodeficiency virus (SIV) rhesus monkey model for AIDS. Twelve animals were immunized with SIV DNA-vectors followed by the application of a recombinant adenovirus (rAd5) expressing the same genes either intramuscularly (i.m.) or by oropharyngeal spray. The second rAd5-application was given i.m. All vaccinees plus six controls were challenged orally with SIVmac239 12 weeks post-final immunization. Both immunization strategies induced strong SIV Gag-specific IFN-γ and T-cell proliferation responses and mediated a conservation of CD4 + memory T-cells and a reduction of viral load during peak viremia following infection. Interestingly, the mucosal group was superior to the systemic group regarding breadth and strength of SIV-specific T-cell responses and exhibited lower vector specific immune responses. Therefore, our data warrant the inclusion of mucosal vector application in a vaccination regimen which makes it less invasive and easier to apply.

Research paper thumbnail of Immunogenicity of a DNA prime and recombinant adenovirus boost regime significantly varies between rhesus macaques of Chinese and Indian origins

Journal of Medical Primatology, 2007

Background Due to an ever increasing shortage of rhesus macaques of Indian origin (InR) that hav... more Background Due to an ever increasing shortage of rhesus macaques of Indian origin (InR) that have been generally used for preclinical AIDS vaccine trials in non‐human primates, demand is rising for Chinese rhesus macaques (ChR). However, the immunogenicity of an AIDS vaccine candidate has not been compared in parallel in both rhesus macaque subspecies.Methods ChR and InR were immunized with SIV/HIV DNA and adenovirus vaccine and their immune responses to SIV and HIV evaluated.Results SIV Gag‐ and Env‐specific T‐cell responses and SIV‐specific lymphoproliferative responses measured in ChR were significantly weaker than those in InR (P < 0.05). By contrast, antibody responses to SIV Env, Tat, and Nef in ChR were stronger than those in InR (P < 0.05).Conclusions Immunogenicity of an AIDS vaccine can vary significantly depending on the geographic origin implying genetic differences of macaques. This must be considered when describing and interpreting results of such vaccine st...

Research paper thumbnail of Protein grafting of p53TAD onto a leucine zipper scaffold generates a potent HDM dual inhibitor

Nature Communications, 2014

Reactivation of the p53 pathway by a potential therapeutic antagonist, which inhibits HDM2 and HD... more Reactivation of the p53 pathway by a potential therapeutic antagonist, which inhibits HDM2 and HDMX, is an attractive strategy for drug development in oncology. Developing blockers towards conserved hydrophobic pockets of both HDMs has mainly focused on small synthetic compounds; however, this approach has proved challenging. Here we describe an approach to generate a potent HDM dual inhibitor, p53LZ2, by rational protein grafting of the p53 transactivation domain onto a homodimeric leucine zipper. p53LZ2 shows tight binding affinity to both HDMs compared with wild-type p53 in vitro. X-ray crystallographic, comparative modelling and small-angle X-ray scattering studies of p53LZ2-HDM complexes show butterfly-shaped structures. A cell-permeable TAT-p53LZ2 effectively inhibits the cancer cell growth in wild-type but not mutant p53 by arresting cell cycle and inducing apoptosis in vitro. Thus, p53LZ2, designed by rational grafting, shows a potential therapeutic approach against cancer.

Research paper thumbnail of Nonlytic Fc-fused IL-7 synergizes with Mtb32 DNA vaccine to enhance antigen-specific T cell responses in a therapeutic model of tuberculosis

Vaccine, 2013

Improvement to the immunogenicity of DNA vaccines was evaluated in a Mycobacterium tuberculosis (... more Improvement to the immunogenicity of DNA vaccines was evaluated in a Mycobacterium tuberculosis (MTB) infection mouse model examining the combined effects of nonlytic Fc-fused IL-7 DNA (IL-7-nFc) and Flt3-ligand fused Mtb32 (F-Mtb32) DNA. Mice were treated with conventional chemotherapy for 6 weeks from 4 weeks after aerosol infection of MTB. Following the start of chemotherapy, DNA immunizations were administered five times with 2-week intervals. Coadministration of IL-7-nFc and F-Mtb32 DNA given during chemotherapy synergistically enhanced the magnitude of Mtb32-specific T cell responses and sustained for one-year after the last immunization assessed by IFN-␥ ELISPOT assay. After dexamethasone treatment, a significantly reduced MTB reactivation was observed in mice received both IL-7-nFc and F-Mtb32 DNA, compared with F-MTb32 DNA alone or with control mice. In addition, mice treated with IL-7-nFc and F-Mtb32 DNA together showed improved lung pathology and reduced pulmonary inflammation values relative to F-Mtb32 DNA or saline injected mice. Intracellular cytokine staining revealed that the protection levels induced by combination therapy with IL-7-nFc and F-Mtb32 DNA was associated with enhanced Mtb32-specific IFN-␥ secreting CD4 + T cell responses and CD8 + T cell responses stimulated with CTL epitope peptide in the lungs and spleens. These data suggest that IL-7-nFc as a novel TB adjuvant may facilitate therapeutic TB DNA vaccine to the clinics through significant enhancement of codelivered DNA vaccine-induced T cell immunity.

Research paper thumbnail of Intranasal introduction of Fc-fused interleukin-7 provides long-lasting prophylaxis from lethal influenza infection

Journal of virology, Jan 9, 2015

Influenza A virus (IAV) infection frequently causes hospitalization and mortality due to severe i... more Influenza A virus (IAV) infection frequently causes hospitalization and mortality due to severe immunopathology. Annual vaccination and antiviral drugs are the current countermeasures against IAV infection, but have a limited efficacy against new IAV variants. Here, we show that intranasal pretreatment of Fc-fused interleukin-7 (IL-7-mFc) protect mice from lethal IAV infections. Protective activity of IL-7-mFc relies on transcytosis via neonatal Fc receptor (FcRn) in the lung and lasts for several weeks. Introduction of IL-7-mFc alters pulmonary immune environments, leading to recruitment of T cells from circulation and their subsequent residency as the tissue-resident memory-like T (TRM-like) cells. IL-7-mFc-primed pulmonary TRM-like cells contribute to protection upon IAV infection by dual modes. Firstly, TRM-like cells, although not antigen specific but polyclonal, attenuate viral replication at the early phase of IAV infection. Secondly, TRM-like cells augment expansion of IAV-s...

Research paper thumbnail of Cell with Surface Coated with ANXA1 and Use Thereof

Research paper thumbnail of A Randomized Pharmacokinetic Study in Healthy Male Subjects Comparing a High-concentration, Citrate-free SB5 Formulation (40 mg/0.4 ml) and Prior SB5 (Adalimumab Biosimilar)

Rheumatology and therapy, Jul 1, 2022

Introduction: SB5 is an approved biosimilar of adalimumab, a monoclonal anti-tumor necrosis facto... more Introduction: SB5 is an approved biosimilar of adalimumab, a monoclonal anti-tumor necrosis factor (anti-TNF) antibody. This study compared pharmacokinetics (PK), safety, tolerability, and immunogenicity between a new highconcentration, low-volume, and citrate-free formulation (40 mg/0.4 ml, SB5-HC) and the current low-concentration formulation with higher volume (40 mg/0.8 ml, SB5-LC) to evaluate the bioequivalence of the two formulations. Methods: This study was a randomized, singleblind, two-arm, parallel-group, single-dose study in healthy male subjects. Subjects were randomized to receive either SB5-HC or SB5-LC via subcutaneous injection using a pre-filled syringe. Primary endpoints were the area under the curve of the concentration-time curve from zero to infinity (AUC inf) and maximum serum concentration (C max). Bioequivalence was achieved if the 90% confidence intervals (CIs) for the ratios of the geometric least squares mean (LSMean) of primary endpoints were within the pre-defined bioequivalence margins of 0.80-1.25. Secondary endpoints included safety, tolerability, and immunogenicity. Results: Subjects (n = 188) were randomized to SB5-HC (n = 94) or SB5-LC (n = 94). Baseline characteristics were comparable between the two treatment groups. The mean values for AUC inf and C max were similar between the SB5-HC and SB5-LC groups. For the primary endpoints, the geometric LSMean ratios (90% CI) for AUC inf and C max were 0.920 (0.8262-1.0239) and 0.984 (0.9126-1.0604), respectively, placing the corresponding 90% CIs well within the pre-defined bioequivalence margin of 0.80-1.25. All treatment-emergent adverse events (TEAEs) were considered mild to moderate and were reported for 44.7% and 51.1% of subjects in the SB5-HC and SB5-LC groups, respectively. Immunogenicity assessed by frequency of occurrence of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) was comparable between groups. Conclusions: This bridging study demonstrated PK equivalence and comparable safety and tolerability of subcutaneous injection of SB5 via SB5-HC or SB5-LC. Clinicaltrials.gov identifier: https://clinicaltrials. gov/ct2/show/NCT04514796.

Research paper thumbnail of AIDS Vaccine Development: the Past, the Present, and the Future

Research paper thumbnail of REVIEW ARTICLE AIDS Vaccine Development: the Past, the Present, and the Future

men with pneumocystis carinii pneumonia and mucosal candidiasis had deficiency in CD4 T lymphocyt... more men with pneumocystis carinii pneumonia and mucosal candidiasis had deficiency in CD4 T lymphocyte, a critical immune defense cell (1). In 1983, Dr. F. Barré-Sinoussi and L. Montagnier isolated a new human T-lymphotropic retrovirus, later named HIV-1(human immunodeficiency virus type 1) which turned out to be one of the causes of AIDS (2). Through their discovery, they received the 2008 Nobel Prize in Physiology or Medicine award. Discovery of the causative agent of AIDS had been the driving force to investigate its genomic structure, function, and replication mechanism. Most importantly, the development of a diagnostic kit contributed to the knowledge of AIDS as an infectious disease especially in the route of transmission. In addition, the development of antiretroviral drugs reduced the mortality of some HIV-infected individuals.

Research paper thumbnail of AIDS vaccine development: the past, the present, and the future

Research paper thumbnail of Mucosal prior to systemic application of recombinant adenovirus boosting is more immunogenic than systemic application twice but confers similar protection against SIV-challenge in DNA vaccine-primed macaques

Virology, 2009

We investigated the immunogenicity and efficacy of a bimodal prime/boost vaccine regimen given by... more We investigated the immunogenicity and efficacy of a bimodal prime/boost vaccine regimen given by various routes in the Simian immunodeficiency virus (SIV) rhesus monkey model for AIDS. Twelve animals were immunized with SIV DNA-vectors followed by the application of a recombinant adenovirus (rAd5) expressing the same genes either intramuscularly (i.m.) or by oropharyngeal spray. The second rAd5-application was given i.m. All vaccinees plus six controls were challenged orally with SIVmac239 12 weeks post-final immunization. Both immunization strategies induced strong SIV Gag-specific IFN-γ and T-cell proliferation responses and mediated a conservation of CD4 + memory T-cells and a reduction of viral load during peak viremia following infection. Interestingly, the mucosal group was superior to the systemic group regarding breadth and strength of SIV-specific T-cell responses and exhibited lower vector specific immune responses. Therefore, our data warrant the inclusion of mucosal vector application in a vaccination regimen which makes it less invasive and easier to apply.

Research paper thumbnail of Immunogenicity of a DNA prime and recombinant adenovirus boost regime significantly varies between rhesus macaques of Chinese and Indian origins

Journal of Medical Primatology, 2007

Background Due to an ever increasing shortage of rhesus macaques of Indian origin (InR) that hav... more Background Due to an ever increasing shortage of rhesus macaques of Indian origin (InR) that have been generally used for preclinical AIDS vaccine trials in non‐human primates, demand is rising for Chinese rhesus macaques (ChR). However, the immunogenicity of an AIDS vaccine candidate has not been compared in parallel in both rhesus macaque subspecies.Methods ChR and InR were immunized with SIV/HIV DNA and adenovirus vaccine and their immune responses to SIV and HIV evaluated.Results SIV Gag‐ and Env‐specific T‐cell responses and SIV‐specific lymphoproliferative responses measured in ChR were significantly weaker than those in InR (P < 0.05). By contrast, antibody responses to SIV Env, Tat, and Nef in ChR were stronger than those in InR (P < 0.05).Conclusions Immunogenicity of an AIDS vaccine can vary significantly depending on the geographic origin implying genetic differences of macaques. This must be considered when describing and interpreting results of such vaccine st...

Research paper thumbnail of Protein grafting of p53TAD onto a leucine zipper scaffold generates a potent HDM dual inhibitor

Nature Communications, 2014

Reactivation of the p53 pathway by a potential therapeutic antagonist, which inhibits HDM2 and HD... more Reactivation of the p53 pathway by a potential therapeutic antagonist, which inhibits HDM2 and HDMX, is an attractive strategy for drug development in oncology. Developing blockers towards conserved hydrophobic pockets of both HDMs has mainly focused on small synthetic compounds; however, this approach has proved challenging. Here we describe an approach to generate a potent HDM dual inhibitor, p53LZ2, by rational protein grafting of the p53 transactivation domain onto a homodimeric leucine zipper. p53LZ2 shows tight binding affinity to both HDMs compared with wild-type p53 in vitro. X-ray crystallographic, comparative modelling and small-angle X-ray scattering studies of p53LZ2-HDM complexes show butterfly-shaped structures. A cell-permeable TAT-p53LZ2 effectively inhibits the cancer cell growth in wild-type but not mutant p53 by arresting cell cycle and inducing apoptosis in vitro. Thus, p53LZ2, designed by rational grafting, shows a potential therapeutic approach against cancer.

Research paper thumbnail of Nonlytic Fc-fused IL-7 synergizes with Mtb32 DNA vaccine to enhance antigen-specific T cell responses in a therapeutic model of tuberculosis

Vaccine, 2013

Improvement to the immunogenicity of DNA vaccines was evaluated in a Mycobacterium tuberculosis (... more Improvement to the immunogenicity of DNA vaccines was evaluated in a Mycobacterium tuberculosis (MTB) infection mouse model examining the combined effects of nonlytic Fc-fused IL-7 DNA (IL-7-nFc) and Flt3-ligand fused Mtb32 (F-Mtb32) DNA. Mice were treated with conventional chemotherapy for 6 weeks from 4 weeks after aerosol infection of MTB. Following the start of chemotherapy, DNA immunizations were administered five times with 2-week intervals. Coadministration of IL-7-nFc and F-Mtb32 DNA given during chemotherapy synergistically enhanced the magnitude of Mtb32-specific T cell responses and sustained for one-year after the last immunization assessed by IFN-␥ ELISPOT assay. After dexamethasone treatment, a significantly reduced MTB reactivation was observed in mice received both IL-7-nFc and F-Mtb32 DNA, compared with F-MTb32 DNA alone or with control mice. In addition, mice treated with IL-7-nFc and F-Mtb32 DNA together showed improved lung pathology and reduced pulmonary inflammation values relative to F-Mtb32 DNA or saline injected mice. Intracellular cytokine staining revealed that the protection levels induced by combination therapy with IL-7-nFc and F-Mtb32 DNA was associated with enhanced Mtb32-specific IFN-␥ secreting CD4 + T cell responses and CD8 + T cell responses stimulated with CTL epitope peptide in the lungs and spleens. These data suggest that IL-7-nFc as a novel TB adjuvant may facilitate therapeutic TB DNA vaccine to the clinics through significant enhancement of codelivered DNA vaccine-induced T cell immunity.

Research paper thumbnail of Intranasal introduction of Fc-fused interleukin-7 provides long-lasting prophylaxis from lethal influenza infection

Journal of virology, Jan 9, 2015

Influenza A virus (IAV) infection frequently causes hospitalization and mortality due to severe i... more Influenza A virus (IAV) infection frequently causes hospitalization and mortality due to severe immunopathology. Annual vaccination and antiviral drugs are the current countermeasures against IAV infection, but have a limited efficacy against new IAV variants. Here, we show that intranasal pretreatment of Fc-fused interleukin-7 (IL-7-mFc) protect mice from lethal IAV infections. Protective activity of IL-7-mFc relies on transcytosis via neonatal Fc receptor (FcRn) in the lung and lasts for several weeks. Introduction of IL-7-mFc alters pulmonary immune environments, leading to recruitment of T cells from circulation and their subsequent residency as the tissue-resident memory-like T (TRM-like) cells. IL-7-mFc-primed pulmonary TRM-like cells contribute to protection upon IAV infection by dual modes. Firstly, TRM-like cells, although not antigen specific but polyclonal, attenuate viral replication at the early phase of IAV infection. Secondly, TRM-like cells augment expansion of IAV-s...