PRIAT

Profiling Responders In Antibody Therapies

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 Obiettivo del progetto (Objective)

'Therapeutic antibodies are the largest and fastest growing class of pharmaceutical biotechnology products, with annual sales above 30 billion US$. In some cases, antibody products have revolutionized the management of patients, e.g. TNF-blocking antibodies in Arthritis or Rituxan in lymphoma. However, for most antibody therapies, only a subset of patients benefit from treatment. Thus, there is an urgent need to develop more potent therapeutic antibodies and to understand the molecular basis for the differential responses of patients to treatment. This consortium consists of European centres of excellence being pioneers in the field of therapeutic antibody development and (pre-) clinical studies and will tackle both of these challenges: Innovative immunocytokines L19-IL2 and F8-IL10 are developed by Philogen for the treatment of metastatic melanoma and rheumatoid arthritis respectively at multiple clinical centres including Graz and Tübingen. Building on the strong background in proteomics biomarker discovery of ETH Zurich and Philochem, an innovative methodology (“HLA-peptidome analysis”) will be utilized for gaining information on the immune response in animal models and patients which receive antibody treatments. This method is based on the observation that HLA molecules in complex with peptides can be detected in the patient blood and that hundreds of HLA-associated peptides can be sequenced by mass spectrometry. The technology will be used for the profiling of responses following antibody treatment for patients with cancer and rheumatoid arthritis, as well as animal models of transplant rejection. This systems biology approach has the potential to revolutionize patient stratification in very short time. Finally, patient selection strategies will be investigated using the clinical-grade immunocytokine (F8-IL10) as an example, monitoring antibody uptake at the site of disease by immuno-PET imaging methodologies at VUMC Amsterdam in collaboration with Philogen.'

Introduzione (Teaser)

Therapeutic antibodies represent one of the fastest growing areas in pharmaceutical biotechnology. Pioneers in the field joined forces to comprehensively study and further optimise these promising therapeutic agents.

Descrizione progetto (Article)

Therapeutic antibodies provide considerable benefit to some cancer patients as well as those with chronic inflammatory conditions such as rheumatoid arthritis. Ongoing development efforts should expand their applicability in the cardiovascular field to prevent graft rejection.

The EU-funded http://www.priat.eu/ (PRIAT) (Profiling responders in antibody therapies) project set out to develop novel methodologies for the characterisation of therapeutic antibodies in patients. Since T cells recognise peptides presented on HLA molecules, it is essential to profile the HLA peptidome to identify targets for future immunomodulation strategies.

Scientists performed HLA peptidome analysis of melanoma patient-derived specimens and identified hundreds of antigens that could be therapeutically exploited. The identified peptides included previously reported melanoma rejection antigens, thus supporting the robustness of the procedure.

PRIAT also carried out multiplex analysis of specimens to gain functional information about the status of immune activation and/or cytokine levels in these patients. Similar analyses on leukocyte infiltration and cytokine levels were carried out in preclinical experiments to elucidate the mechanism of action of antibody-based therapeutics.

Not all therapeutic antibodies localise efficiently at the site of disease. The consortium employed innovative imaging techniques such as PET and near-infrared fluorescence imaging to address antibody biodistribution. Studies were performed in various animal models of disease through administration of radiolabelled preparations of therapeutic antibody products. This provided important insight into antibody selectivity in vivo in rodent models of cancer, rheumatoid arthritis and graft rejection.

In a worldwide clinical trial in patients with rheumatoid arthritis, scientists utilised PET imaging to assess antibody biodistribution and optimise future development of antibody products. Assessment of the impact of antibody therapy in oncology patients has also demonstrated significant benefit.

Overall, the PRIAT methodologies and tools facilitate the development and mechanistic study of antibody-based drugs, which should lead to improved antibody products. Study findings also support the therapeutic validity of antibodies such as the therapeutic agent that cured established rheumatoid arthritis in preclinical models.