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Human monoclonal antibody therapy to prevent hepatitis C virus reinfection of liver transplants: advancing lead monoclonal antibodies into clinical trial

Final Report Summary - HEPAMAB (Human monoclonal antibody therapy to prevent hepatitis C virus reinfection of liver transplants: advancing lead monoclonal antibodies into clinical trial)

Executive Summary:
The consortium was formed to advance monoclonal antibody therapies for the treatment of HCV infection. Despite significant changes in the HCV treatment landscape that prevented clinical trials form taking place, the consortium were able to make significant progress, particularly in manufacturing process development, production and generation of tools and reagents for testing vaccine and therapeutic antibody efficacy, as well as establishment of a robust back-up antibody pipeline. The consortium also delivered training to a number of early career and experienced researchers as well as produce new products that are currently being patented.
Project Context and Objectives:
Worldwide, 200 million people are infected with the hepatitis C virus (HCV), and around 3 million individuals are newly infected each year (WHO). An estimated 15 million individuals are living with CV infection within the European Community. The economic, health and societal costs of chronic HCV infection are significant. 0% of HCV infected individuals fail to clear the virus, and persistent infection, which frequently causes very severe liver disease, ensues. HCV is the leading cause of primary liver cancer. By the end of the decade there will be over 50% more cases of cirrhosis and hepatocellular cancer. Hepatitis C is the principal cause of death from liver disease and the leading indication for liver transplantation. Currently, over 17,000 individuals are awaiting orthotopic liver transplantation.
· The only treatment available for end-stage liver disease is a liver transplant, yet the transplanted liver becomes rapidly re-infected and is frequently destroyed within 5 years after transplantation.
· Intense research activity has generated a powerful armoury of antiviral drugs that can be used for the treatment of chronic hepatitis C virus infection. However, there is still an urgent need to develop safer and more effective treatments for those patients who are most ill, particularly those in receipt of a liver transplant, where current treatments are toxic and their use hampered by complex drug-drug interactions.
· There is an increasing incidence of HIV/HCV co-infection. The death rate from HCV is seven times higher among H1V-infected individuals than those with HCV alone.
· Biologics, such as monoclonal antibodies that target virus entry, are as yet an underutilised and potentially highly effective and safe weapon in the armoury against HCV infection.
The main objective of the HepaMAb Consortium is to progress human monoclonal antibodies into phase I/II clinical trial for the prevention of hepatitis C virus reinfection following liver transplantation. It will directly lead to the development of new therapeutic approaches to prevent reinfection of HCV infected individuals receiving a liver transplant. This will significantly improve the outcome of liver transplantation in this, the largest, cohort of liver transplant recipients. This will be achieved by:
1) Standardising manufacturing processes and pre-clinical and clinical assays to measure the safety and efficacy of mAb therapy, by
a) Defining appropriate conditions for cGMP production and obtaining regulatory approval.
b) Performing in vitro and in vivo preclinical efficacy and safety checks on lead MAbs.
c) Establishing assays and developing molecular and immunological tools to monitor the emergence of antibody escape and resistance.
2) Performing phase I/IIa clinical trials
a) To perform a Phase I clinical trial with anti-virus and anti-receptor MAbs to define safety and tolerability in healthy or HCV-infected individuals, and
b) To progress to a Phase IIa safety / efficacy trial in the target group of HCV positive patients at risk of requiring a liver transplant.
3) Establishing a robust antibody pipeline for this target group of patients.
a) By isolating and characterising at least one additional anti-receptor and one additional anti-viral monoclonal antibody

Project Results:
Please refer to the attached report for a full description of project outcomes. However, significant results and achievements include
• Extensive panel of HCVcc and HCVpp produced, validated and shared with the scientific community
• Improved in vivo models
• Target therapeutic doses of anti-HCV and anti-SRBI mAbs identified using in vitro and in vivo modelling
• Novel anti-viral and anti-receptor mAbs isolated
• Data obtained showing that virus cure using therapeutic mAbs is achievable
• Development of a robust process small- to medium-scale manufacture of therapeutic antibodies
• Establishment of Master Cell Banks for anti-viral and anti-receptor mAbs
• Development and validation of a robust pipeline for anti-HCV and anti-receptor mAbs that have potent and broad activity against HCV

Potential Impact:
Please see the attached report for a description of the impacts and dissemination activities.
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