EUREKA PROJECT > 3717 VEGFK
FRANCE
VEGF KINOID: ANTI-CANCER VACCINE: PHARMACEUTICAL, PRECLINICAL AND PHASE I/II CLINICAL DEVELOPMENT
VEGF KINOID ANTI-ANGIOGENESIS NOVEL VACCINE CANDIDATE: THE ACCELERATED DEVELOPMENT AS AN ADD-ON TREATMENT OF COLORECTAL CANCER SHOULD OFFER A MORE COST-EFFECTIVE AND CONVENIENT ADMINISTRATION AND DOSAGE WHEN COMPARED TO COMPETING TREATMENTS.
Status > FINISHED - 28-Aug-2011 Technological Area Market Area Start Date > 01-Feb-2007 Duration > 26 Months Participating countries > FRANCE, BELGIUM | Main contactNEOVACS S.A. Mrs. Geraldine Grouard-Vogel > Director R & D Organisation type > SME |
Project Description
VEGF-kinoid(R) is a novel active immunotherapy approach to cancer treatment aimed at delivering a more convenient administration and dose frequency, and better efficacy, and at considerably reducing treatment costs of current anti-angiogenesis therapies given in combination with chemotherapy. The Vascular Endothelial Growth Factor (VEGF) is abnormally produced by cancer cells and triggers the generation of new capillaries (neoangiogenesis). This process is essential to tumour growth which requires a dense vascular network to supply nutrients. VEGF-Kinoid(R) targets neoangiogenesis in cancer by eliciting highly neutralising polyclonal antibodies against VEGF. This approach has been validated by passive anti-VEGF monoclonal antibody therapies such as Avastin(R) (bevacizumab). NEOVACS was the first company to develop the anti-cytokine Active Immunisation concept. NEOVACS benefits from a dominant IP (Intellectual Property) position regarding this concept which is protected by an initial patent with priority date 1991 and many subsequent patents that extend the protection duration. The potential indications could be solid tumour diseases responding to angiogenesis inhibition, such as: - first indication sought: treatment of patients suffering from metastatic or recurrent colorectal cancer in combination with intravenous 5-FU based chemotherapy; - follow-on indications (not included in the EUREKA programme): use in combination with chemotherapy in the treatment of renal, breast and non-small cell lung cancers as well as in ovarian cancer, melanoma and several types of solid tumour cancers. NEOVACS, in recent months, has achieved animal proof of concept in various cancer animal models such as an HT29 colorectal model versus Avastin in NOD/SCID (NOD/Severe Combined Immunodeficiency) mice, or A673 rhabdomyosarcoma versus Avastin in Nude Swiss mice. Also, initial exploratory toxicity and tolerance studies performed have demonstrated a good safety profile. These encouraging results will be confirmed by a comprehensive programme of pharmacodynamic and toxicological studies in the framework of the EUREKA programme. NEOVACS has produced in an optimised and reproducible way a large number of lab-scale batches of both human and murine VEGF kinoid. These have undergone physico-chemical characterisation and have been controlled for cytokine inactivation (in-vitro) and immunogenicity (in-vivo), and used as a potency test. The laboratory-scale process and test procedures will be transferred to EUROGENTEC BIOLOGICS, NEOVACS' selected EUREKA partner, for the scale-up and GMP (Good Manufacturing Process) manufacture of human VEGF Kinoid. The preparation of toxicological and clinical batches of VEGF kinoid requires GMP grade recombinant human VEGF as a starting material. This protein will be manufactured under GMP and tested by Eurogentec, using a microbial fermentation process and an E. coli transformed production strain. The NEOVACS-EUROGENTEC EUREKA collaboration should enable, within a two-year timeframe (2006 & 2007), preclinical (toxicology, tolerance and pharmacodynamic) studies and a Phase I/II clinical trial in colorectal cancer patients to be carried out. This accelerated proof-of-concept in humans should demonstrate the safety and immunogenicity of VEGF kinoid vaccines used as an anti-angiogenesis immune-therapy agent in combination with chemotherapy. The preclinical and clinical development programme will be ensured by NEOVACS while EUROGENTEC BIOLOGICS will carry-out the process & analytical development and GMP manufacture of both the starting material ’recombinant human VEGF’ and of the VEGF Kinoid. Keywords: cancer, vaccine, VEGF.
Technological Development Envisaged
NEOVACS (Paris, FRANCE): PRECLINICAL AND PHASE I/II CLINICAL DEVELOPMENT OF VEGF KINOID: - Additional pharmacodynamics studies in animal models: colorectal carcinoma, rhabdomyosarcoma, renal cell carcinoma and pancreas/liver cancer; - Toxicology testing: dose-range finding and sub-acute toxicity study (monkey), genotoxicity study (Ames test), acute toxicity study (mice), local tolerance study (rabbit), chronic toxicity study (monkey), safety pharmacology studies; - Phase I/II study: open-label, dose ranging, placebo-controlled study of the therapy in 30-40 patients suffering from metastatic colorectal cancer. The primary objective will be to demonstrate the safety of active r-hu-VEGF Kinoid Ab therapy, in combination with chemotherapy. The secondary objectives will be to determine the immunogenicity and the evidence of anti-tumour activity of this regimen in these patients. EUROGENTEC BIOLOGICS (Liege, BELGIUM): PHARMACEUTICAL DEVELOPMENT OF r-hu-VEGF AND VEGF KINOID: - Development and GMP manufacture of ‘recombinant human VEGF 165’: Technology transfer and cell line construction, cell banking, upstream (fermentation) and downstream (recovery and purification) process development, analytical development and qualification, scale-up, GMP manufacturing and controls, stability studies. This portion of the programme will deliver a robust process and qualified testing procedures as well as approximately 2 grams of r-hu-VEGF-165 to be used as a GMP grade starting material for the preparation of the VEGF Kinoid; - Development and GMP manufacture of r-hu-VEGF Kinoid: Technology transfer of laboratory-scale process and initial testing package, process development and scale-up, analytical development and qualification, GMP manufacture and controls (toxicology/clinical batch), stability studies.
Main contactNEOVACS S.A. Mrs. Geraldine Grouard-Vogel > Director R & D Organisation type > SME |
Contribution to project
PRECLINICAL AND PHASE I/II CLINICAL DEVELOPMENT OF VEGF KINOID: - Additional pharmacodynamics studies in animal models: colorectal carcinoma, rhabdomyosarcoma, renal cell carcinoma and pancreas/liver cancer; - Toxicology testing: dose-range finding and sub-acute toxicity study (monkey), genotoxicity study (Ames test), acute toxicity study (mice), local tolerance study (rabbit), chronic toxicity study (monkey), safety pharmacology studies; - Phase I/II study: open-label, dose ranging, placebo-controlled study of the therapy in 30-40 patients suffering from metastatic colorectal cancer. The primary objective will be to demonstrate the safety of active r-hu-VEGF Kinoid Ab therapy, in combination with chemotherapy. The secondary objectives will be to determine the immunogenicity and the evidence of anti-tumour activity of this regimen in these patients.
Expertise
?The organisation?s focus is on immunology and oncology. NEOVACS develops the next generation of antibody therapy based on patient immunisation using immunogenic cytokine derivatives in order to induce a potent neutralising polyclonal antibody response against overproduced cytokines (VEGF, TNF alpha, IFN, etc.). It offers superior and long-lasting efficacy and lower risk of immunogenicity, i.e. no risk of serious allergic reactions or resistance to treatment (no blocking anti-idiotypic response) versus monoclonal antibodies. Potential indications include solid/liquid tumours, rheumatoid arthritis, IBD (Inflammatory Bowel Disease) and lupus. The company has developed 2 leading edge technology platforms, Toxoid (viral immunogens) & Kinoid (cytokine immunogens), validated by strategic alliances with SANOFI-AVENTIS and DEBIOPHARM as well as clinical trials on over 200 patients. NEOVACS has a strong intellectual property position (16 patents to date, 13 granted) and a broad portfolio that comprises eight products, 2 of which are in clinical development and 2 partnered. The company is pursuing a dual edged strategy, developing a pipeline of proprietary products to market in selected territories and establishing broad strategic alliances to maximise value creation. NEOVACS? anti-cytokine Ab therapy is achieved by patient immunisation procedures using a Kinoid(R) immunogen: inactivated (1) yet immunogenic (2) cytokines chemically coupled to a foreign T-helper carrier protein. Kinoids(R) promote a T-dependent B cell response. (1) loss of the specific biological activity (or set of activities) of the cytokine, (2) capacity to induce in man the production of neutralising anti-cytokine antibodies, inhibiting the undesired biological activity of the native cytokine. As opposed to the passive Ab therapy approach, the induction of neutralising Abs by vaccine procedures requires a source of pre-existing anticytokine B cells to synthesize and release them. Given the evidence for considerable censoring of self-reactive B cells, the common occurrence of effective auto-antibody responses under physiological conditions seems paradoxical. Nevertheless, vaccine procedures might trigger high titers of circulating auto-Abs neutralising pathogenic self cytokines by breaking B cell tolerance under certain conditions such as the presence of T cell help supplied by a foreign carrier protein. NEOVACS' expertise, as it relates to the VEGF kinoid programme relies on multi-facetted capabilities: - biochemistry and pharmaceutical development of kinoid immunogenic protein complexes: preparation of kinoid complexes by conjugation and inactivation biochemistry; characterisation by physico-chemical methods (e.g. SDS-PAGE (Sodium-Dodecyl-Sulphate-PAGE)), immuno-chemical methods(ELISA (Enzyme-Linked Immuno-Sorbent Assay), Western Blot), in-vitro testing (cell-based tests), in-vivo testing (immunisation of mice and immunogenicity testing - antiserum assays for anti-VEGF antibody titers and neutralizing capacity of those); - study of the immune response: fine-tuning of immunisation schedule and study of the nature and kinetics of the antibody response; - conduct of relevant animal models: immunogenicity, cancer models, etc.; - conduct of toxicology studies: e.g. acute toxicology in mice; - Management of drug development: pharmaceutical, preclinical and clinical development managed by internal industry experts in collaboration with contractors and consultants. Of note, NEOVACS benefits from a strong academic network for performing exploratory pharmacodynamic, safety or pharmaceutical studies and relies on GLP/GMP/GCP (Good Laboratory Practice / Good Manufacturing Practice / GCP) contractors for the realisation of all regulatory studies.
Main contactEUROGENTEC BIOLOGICS MR. FLORENCE XHONNEUX > MANAGER BUSINESS DEVELOPMENT http://www.biologics.eurogentec.com Organisation type > SME |
Contribution to project
PHARMACEUTICAL DEVELOPMENT OF r-hu-VEGF AND VEGF KINOID: - Development and GMP manufacture of ‘recombinant human VEGF 165’: technology transfer and cell line construction, cell banking, upstream (fermentation) and downstream (recovery and purification) process development, analytical development and qualification, scale-up, GMP manufacturing and controls, stability studies. This portion of the programme will deliver a robust process and qualified testing procedures as well as approximately 2 grams of r-hu-VEGF-165 to be used as a GMP grade starting material for the preparation of the VEGF Kinoid; - Development and GMP manufacture of r-hu-VEGF Kinoid: technology transfer of laboratory-scale process and initial testing package, process development and scale-up, analytical development and qualification, GMP manufacture and controls (toxicology/clinical batch), stability studies.
Expertise
The organisation (EB) is one of the two ‘business units’ of the Belgian company EUROGENTEC S.A. EB brings to biotech and pharmaceutical companies its capacities and expertise in microbial fermentation-based GMP (Good Manufacturing Practice) manufacture of clinical batches of therapeutic proteins, DNA (Deoxyribose Nucleic Acid) plasmid products, vaccines and other ‘biopharmaceuticals’. EB collaborates with biotech companies in manufacturing and control activities, including gene cloning, the construction of production strains and cell banking, technology transfer, process and analytical development and validation, and GMP manufacturing of clinical batches. EB has approximately 75 employees from among the total EUROGENTEC S.A. staff of 220: circa 20 in Process Transfer and Development (PT&D), 20 in Quality Control, 20 in GMP manufacture, 5 in Quality Assurance, 10 in management. EUROGENTEC, headed by Jean-Pierre Delwart as CEO and Joseph Martial as Chairman of the Board, is privately owned by the Delwart-Solvay family who holds 66% of the 17.7 million euro capital. The turnover amounted to 26.2 million euro in 2004, circa 28% of which was garnered by the EUROGENTEC BIOLOGICS BUSINESS UNIT. The other BU, ‘Tools for Genomics and Proteomics’ is a supplier of reagents, oligonucleotides, RNAi and PCR (Polymerase Chain Reaction) products and services as well as custom peptide and antibody production. EUROGENTEC has invested massively in development and production facilities and equipment: 1,700 square metres of process and analytical development laboratories and GMP suites (clean rooms), GMP space extension in 2000, fermentors up to 350 litres. EB is regularly inspected by the Belgian drug agency and will shortly undergo FDA (Food and Drug Administration) inspection (PAI) for the up-coming commercial production of a therapeutic protein. EB, with more than 15 years expertise in microbial fermentation of biologic drugs, has complementary capabilities and competences to NEOVACS and can ensure the development and GMP production of both recombinant VEGF and the VEGF kinoid end-product. EB has recently successfully achieved the development and robust production of a homodimeric cytokine of the same complexity as VEGF. EB promotes innovation among its autonomous and empowered lead scientists, an illustration being the design and implementation of a factorial analysis approach to process design for yield improvement.