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Novel bispecific antibodies for treating HBV infection!!! Download Presentation
!!! Video Presentation
Prof. Ulrike Protzer, Helmholtz Zentrum München and Technische Universität München; Dr Felix Bohne, Helmholtz Zentrum München; Dr Frank Momburg, German Cancer Research Center; Dr Gerhard Moldenhauer, German Cancer Research Center
Ascenion  Dimerization of two polypeptides, each comprising a bispecific bivalent antibody, by formation of disulfide bonds resulting in formation of a bispecific tetravalent antibody.
Challenge
Chronic infection caused by the Hepatitis B Virus (HBV) remains a major cause of liver diseases worldwide. Although efficient vaccines against HBV are available and based on various vaccination programs the overall global prevalence of HBV infection has decreased, still more than 240 million people suffer from chronic HBV infection. Many of them progress to life threatening liver diseases like cirrhosis, liver failure and hepatocellular carcinoma (HCC) leading to an estimated 0.5 - 1.2 million annual deaths. Current treatment options include interferon (IFN)-based therapy (PEG-IFN) and nucleoside/nucleotide analogues resulting in varying outcomes (response rates between 20 - 90% depending on HBeAg status and HBV DNA) leaving much room for further improvements. It is therefore of highly demanding need to provide more and better therapies not only reducing HBV levels but to eradicate HBV considering deleting intrahepatic cccDNA from infected hepatocytes.
Technology
Bispecific antibody constructs allow the cross-linking of two antigens and mediate the killing of HBV-infected cells by recruitment of cytotoxic T cells or NK cells. The invention from Helmholtz Zentrum München and German Cancer Research Center (DKFZ) relates to bispecific antibodies with a first binding to HBsAg on the surface of HBV-infected cells and a second binding to CD3 or CD28 and CD16 or CD56, respectively, on immune effector cells (T cells, NK cells). Both, T cell and NK cell mediated cytotoxicity could be shown in vitro with either T cell or NK cell ligand specificity or in combination in a synergistic manner. By retargeting T cells it could be demonstrated that both, CD8+ as well as CD4+ T cells, are induced. Treating of HBV-positive tumors in mice in vivo with application of bispecific constructs resulted in a marked reduction of tumor size (about 50%).
Commercial Opportunity
The bispecific antibody constructs, either as scFv, whole IgG, tetravalent bi-, tri- or tetraspecific antibody describe a new class of effective products to treat HBV-infected patients to eradicate infected hepatocytes by reducing/destroying the viral reservoir of transcription, namely the HBV cccDNA which resides episomally in the nucleus of the infected hepatocyte. The technology is available for exclusive or non-exclusive licensing as well as for joint collaboration for further development.
Development Status
Further in vivo evaluations in various animal models of HBV are currently performed awaiting data on reduction of HBV viremia, data on cytotoxicity and liver-specific markers of eradication of HBV positive target cells. Furthermore, in depth analyses of immune cell subpopulations, factors of functionality and homing performance will shed new light on the parameters underlying the therapeutic effect of these bispecific constructs. Finally, experiments utilizing immunodeficient mice with humanized livers which are infectable with HBV are planned to detail the therapeutic efficiency of administered bispecific constructs upon adoptive transfer of human blood lymphocytes. This in vivo model most closely resembles the situation in the chronic HBV infected patient.
Patent Situation
A PCT application has been filed (priority 2013).
Further Reading
Bohne et al. (2008), Gastroenterology 134:239-247
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发表于 2015-6-10 16:25
