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Establishment of Anti-Human ATRX Monoclonal Antibody AMab-6.

ABSTRACT: Gliomas are the most frequently occurring brain tumors with a heterogeneous molecular background. The molecular subgrouping of gliomas more prognostically stratifies patients into distinct groups compared with conventional histological classification. The most important molecules for the subtype diagnosis of diffuse gliomas are mutations of isocitrate dehydrogenase (IDH), TERT promoter, and α-thalassemia/mental-retardation-syndrome-X-linked (ATRX) and the codeletion of 1p/19q. Among them, IDH and ATRX mutations can be diagnosed using specific monoclonal antibodies (mAbs). We have developed many mAbs against IDH mutants, including HMab-1/HMab-2 against IDH1-R132H and multispecific mAbs MsMab-1/MsMab-2 against IDH1/2 mutations. In contrast, highly sensitive mAbs against ATRX remain to be established. In this study, we immunized mice with recombinant human ATRX and developed a novel mAb, AMab-6. The dissociation constant of AMab-6 was determined to be 9.7 × 10^-10 M, indicating that the binding affinity of AMab-6 is very high. Furthermore, AMab-6 sensitively detects ATRX in Western blot and immunohistochemical analyses, indicating that AMab-6 could become the standard marker to determine the ATRX mutation status of gliomas in immunohistochemical analyses.

SUBMITTER: Ogasawara S

PROVIDER: S-EPMC5160166 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Establishment of Anti-Human ATRX Monoclonal Antibody AMab-6.

Ogasawara Satoshi S Fujii Yuki Y Kaneko Mika K MK Oki Hiroharu H Sabit Hemragul H Nakada Mitsutoshi M Suzuki Hiroyoshi H Ichimura Koichi K Komori Takashi T Kato Yukinari Y

Monoclonal antibodies in immunodiagnosis and immunotherapy 20161001 5

Gliomas are the most frequently occurring brain tumors with a heterogeneous molecular background. The molecular subgrouping of gliomas more prognostically stratifies patients into distinct groups compared with conventional histological classification. The most important molecules for the subtype diagnosis of diffuse gliomas are mutations of isocitrate dehydrogenase (IDH), TERT promoter, and α-thalassemia/mental-retardation-syndrome-X-linked (ATRX) and the codeletion of 1p/19q. Among them, IDH an ...[more]

PMID: 27788029

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Project description:Hepatitis B virus (HBV) infects 240 million people worldwide. Current therapy profoundly suppresses HBV replication but requires long-term maintenance therapy. Therefore, there is still a medical need for an efficient HBV cure. HBV enters host cells by binding via the preS1 domain of the viral L protein to the Na+/taurocholate cotransporting polypeptide (NTCP). Thus, NTCP should be a key target for the development of anti-HBV therapeutics. Indeed, myrcludex B, a synthetic form of the myristoylated preS1 peptide, effectively reduces HBV/hepatitis D virus (HDV) infection and has been approved as Hepcludex in Europe for the treatment of patients with chronic HDV infection. We established a monoclonal antibody (MAb), N6HB426-20, that recognizes the extracellular domain of human NTCP and blocks HBV entry in vitro into human liver cells but has much less of an inhibitory effect on bile acid uptake. In vivo, administration of the N6HB426-20 MAb prevented HBV viremia for an extended period of time after HBV inoculation in a mouse model system without strongly inhibiting bile acid absorption. Among the extracellular loops (ECLs) of NTCP, regions of amino acids (aa) 84 to 87 in ECL1 and aa 157 to 165 near ECL2 of transmembrane domain 5 are critically important for HBV/HDV infection. Epitope mapping and the three-dimensional (3D) model of the NTCP structure suggested that the N6HB426-20 MAb may recognize aa 276/277 at the tip of ECL4 and interfere with binding of HBV to the region from aa 84 to 87. In summary, we identified an in vivo neutralizing NTCP-targeting antibody capable of preventing HBV infection. Further improvements in efficacy of this drug will pave the way for its clinical applications. IMPORTANCE A number of entry inhibitors are being developed to enhance the treatment of HBV patients with oral nucleoside/nucleotide analogues (NA). To amplify the effectiveness of NA therapy, several efforts have been made to develop therapeutic MAbs with neutralizing activity against HBs antigens. However, the neutralizing effect of these MAbs may be muted by a large excess of HBsAg-positive noninfectious particles in the blood of infected patients. The advantage of NTCP-targeted HBV entry inhibitors is that they remain effective regardless of viral genotype, viral mutations, and the presence of subviral particles. Although N6HB426-20 requires a higher dose than myrcludex to obtain equivalent suppression of HBV in a model mouse system, it maintained the inhibitory effect for a long time postadministration in proportion to the half-life of an IgG MAb. We believe that further improvements will make this antibody a promising treatment option for patients with chronic hepatitis B.

Dataset Information

Establishment of Anti-Human ATRX Monoclonal Antibody AMab-6.

Publications

Establishment of Anti-Human ATRX Monoclonal Antibody AMab-6.

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