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  • Periodic Report Summary 1 - HEPAMAB (Human monoclonal antibody therapy to prevent hepatitis C virus reinfection of liver transplants: advancing lead monoclonal antibodies into clinical trial)
FP7

HepaMAb Report Summary

Project ID: 305600
Funded under: FP7-HEALTH
Country: United Kingdom

Periodic Report Summary 1 - HEPAMAB (Human monoclonal antibody therapy to prevent hepatitis C virus reinfection of liver transplants: advancing lead monoclonal antibodies into clinical trial)

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 HCV infection within the European Community. The economic, health and societal costs of chronic HCV infection are significant.
• 80% 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 HIV-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:
a. Standardising manufacturing processes and pre-clinical and clinical assays to measure the safety and efficacy of mAb therapy, by
i. Defining appropriate conditions for cGMP production and obtaining regulatory approval.
ii. Performing in vitro and in vivo preclinical efficacy and safety checks on lead MAbs.
iii. Establishing assays and developing molecular and immunological tools to monitor the emergence of antibody escape and resistance.
b. Performing phase I/IIa clinical trials
i. To perform a Phase I clinical trial with anti-virus and anti-receptor MAbs to define safety and tolerability in healthy individuals, and
ii. To progress to a Phase IIa safety / efficacy trial in the target group of HCV positive patients receiving a liver transplant.
c. Establishing a robust antibody pipeline for this target group of patients.
i. By isolating and characterising at least one additional anti-receptor and one additional anti-viral monoclonal antibody

Project Results:
Research activities have focussed on pre-clinical development of the lead anti-receptor and anti-viral antibodies. The concentrations required to prevent HCV infection in vitro and in vivo have been determined. These experiments highlighted that the anti-receptor antibody might be mediating its antiviral activity via a novel mechanism which is currently under investigation. We have also been looking at ways of improving the potency of these lead antibodies, to increase their antiviral activity and to bring benefit in terms of GMP manufacture and reduced therapeutic dose. One of the outcomes of this work was demonstration of significant synergy between the anti-viral and anti-receptor antibodies. A major aspect of the first period of research was establishment of stable cell lines expressing antibody levels suitable for GMP scale-up and a number of approaches are being explored. Cell lines have been successful created and we are working on ways of increasing total yields, as well as methods of increasing GMP capacity. Significant progress has been made with the development of back-up antibodies and anti-viral and anti-receptor monoclonals have been isolated and characterised. These are showing excellent anti-viral activity and very good safety profiles. Finally, we have generated platforms to enable high throughput neutralisation tests, which are being used to validate hits and pre-clinical and clinical lots of monoclonal antibodies.
Potential Impact:
HepaMAb will progress into clinical trial, human monoclonal antibodies for the prevention of reinfection by HCV post- liver transplantation. An estimated 15 million individuals are living with HCV infection within the European Community. HCV is the leading cause of primary liver cancer and there are likely to be 50% more cases of cirrhosis and hepatocellular cancer by the end of the decade. Hepatitis C is the principal cause of death from liver disease and it is the leading cause of end-stage liver disease requiring liver transplantation. There are more than 17,000 individuals awaiting a liver transplant. In HCV-infected liver transplant recipients, the transplanted liver becomes rapidly re-infected and is frequently destroyed within 5 years after transplantation. There is 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 either toxic or their use hampered by complex drug-drug interactions.

Preventing reinfection by HCV will have a direct and positive impact on liver transplant survival- particularly in those individuals who go onto develop rapid cirrhosis, leading to loss of graft. The need to replace transplants that have become diseased due to HCV reinfection is becoming an increasing problem, which has significant societal, economic and health costs associated with it. The problem with existing anti-HCV treatments is their lack of efficacy in those infected individuals with the most advanced stages of liver disease and their lack of safety and efficacy in those in receipt of a liver transplant. The explicit aim of HepaMAb is to improve outcome of liver transplantation due to HCV infection by advancing into clinical use, safe and effective monoclonal antibodies that prevent HCV reinfection, thereby improving disease-free survival of the graft post-transplantation.

The network will positively impact on the European Research Area and European Competitiveness by promoting biotechnological innovation. The project will enable the partners, which include EU SMEs, to harness and exploit the commercial and economic potential of their proprietary technology and know-how. The design of the project addresses important gender issues, e.g. by recruiting women and men to clinical trial and by identifying gender specific differences that need to be taken into account in future and by using biological specimens from males and females. The project will impact positively on recruited researchers. The skills and knowledge that the researchers involved in the project will give them an internationally competitive edge and equip them for future career openings in industry, health care and academia. The training will overcome European skills shortages and will transcend historical sector, discipline and national divides. There will be a direct impact on the partners and future collaboration. The project will foster a much-needed bio-cluster that will facilitate long-term collaboration by strengthening existing and establishing new collaborations between academia and industry. It will co-ordinate efforts, develop excellence and multi-disciplinary research at the EU level; all of this to the benefit of the partners and ERA as a whole. This will enable significant knowledge, know-how and technology transfer. It will generate new opportunities for wealth creation through biotechnological and clinical advancements and by providing routes to market.

List of Websites:
http://www.hepamab.eu

Related information

Reported by

THE UNIVERSITY OF NOTTINGHAM
United Kingdom
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