GVSVnoitcenκA)%(fIB0051NTCP-targetingHigh affinity AbInhibition of HBV infectionHB426 Ab15012510010075505025migGepithelialcellsmIgGSARS-CoV-2anti-TMPRSS2mAbTMPRSS2mAbNo bindingto protein AKnobs-into-HolesSARS-CoV-2Spike proteinTMPRSS2ACE2enhanced therapeutic efficacy at lower antibody doses.The Drug Discovery Antibody Platform Unit (Ab Platform) is one of nine Recent Major PublicationsTakemori T, Sugimoto-Ishige A, Nishitsuji H, Futamura Y, Harada M, Kimura-Someya T, Matsumoto T, Honma T, Tanaka M, Yaguchi M, Isono K, Koseki H, Osada H, Miki D, Saito T, Tanaka T, Fukami T, Goto T, Shirouzu M, Shi-motohno K, Chayama K. Establishment of a monoclonal antibody against human NTCP that blocks HBV infection. J Virol 96, e0168621 (2022)Kumagai A, Nara T, Uematsu M, Kakinuma Y, Saito T, Ma-suda K. Development and characterization of a unique anti-IgE monoclonal antibody cross-reactive between human and canine IgE. Immun Inflamm Dis 9, 1740-1748 (2021)Tanaka M, Ishige A, Yaguchi M, Matsumoto T, Shirouzu M, Yokoyama S, Ishikawa F, Kitabayashi I, Takemori T, Ha-rada M. Development of a simple new flow cytometric antibody-dependent cellular cytotoxicity (ADCC) assay with excellent sensitivity. J Immunol Methods 464, 74-86 (2019)Drug Discovery Basic Units in the Drug Discovery and Medical Tech-nology Platform (DMP). The Ab Platform creates new monoclonal antibodies (mAb) for therapeutic purposes of preventing/modulating various diseases.We have recently established mAbs against human Transmembrane protease serine 2 (TMPRSS2) to inhibit infection with SARS-CoV2. TMPRSS2 is critical for viral entry, and small molecule inhibitors of TMPRSS2 have been shown to inhibit SARS-CoV2 infection. However, these compounds have side effects and are unstable. Therefore, mAbs against TMPRSS2 might have a more specific inhibitory function. Indeed, several mAbs demonstrated potent inhibition of infection by various SARS-CoV-2 variants including Omicron in human iPS-Lung organoid cultures. The binding affinities of the mAbs to TMPRSS2 were in the nM range and the binding epitopes were further identified using peptide mapping and cryo-EM. These mAbs also potently inhibited SARS-CoV-2 infec-tion in vivo, dramatically reducing lung viral load in both human TMPRSS2/ACE2 knock-in mice and non-human primate models, suggesting their poten-tial therapeutic use.We have also developed a mAb against the sodium-taurocholate co-trans-porting polypeptide (NTCP), which is the human hepatitis B virus (HBV) receptor. Since the preS1-domain of HBV binds to NTCP, it is expected to be a key target for the development of HBV-blocking agents. Indeed, the established mAb inhibits the entry of HBV into human liver cells in vitro and inhibits in vivo infection in human-liver chimeric mice. Since the mAb has the advantage of not blocking bile acid import by NTCP, it becomes an ideal specific inhibitor of HBV infection. Currently, a trial to improve the binding affinity is ongoing for eventual clinical applications. We developed bispecific Abs combining a high-affinity NTCP Ab with an HBV entry-blocking Ab. Preliminary results suggest that the designed bispecific Ab enhances avidity for NTCP, reducing the required dose for clinical use.Figure A: TMPRSS2 mAbs inhibit infection by multiple variants of SARS-CoV-2(Left) Infection of epithelial cells by SARS-CoV2 through binding of the Spike protein to the ACE2 receptor. TMPRSS2-mediated cleavage of Spike is required for ACE2 binding. TMPRSS2 mAbs block the binding and internalization of multiple SARS-CoV-2 Variants of Con-cern (VOC).(Right) Inhibition of infection in epithelial cells (Calu-3) by various SARS-CoV-2 VOC using the representative TM-PRSS2 mAb. Controls for these experiments are mouse IgG (mIgG) and vesicular stomatitis virus G (VSVG), an unrelated virus. Figure B: Design of bispecific Abs with high-affinity NTCP binding for strong inhibition of viral infectionBispecific Abs are designed to simultaneously bind to two different target sites on NTCP. One exhibits high affinity binding to NTCP even at low doses, while the other directly targets the infection-inhibition site. By combining these two specificities, we aim to achieve ααββγγδδοο2228_15(1μg/ml)Drug Discovery Antibody Platform UnitUnit Leader: Kazuhiko Yamamoto
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