Next generation therapeutic antibodies
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 PRIAT (Profiling responders in antibody therapies) project therefore 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 conducted an HLA peptidome analysis of melanoma patient-derived specimens and identified hundreds of antigens that could be therapeutically exploited. The peptides identified 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 action mechanism 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.
Keywords
Therapeutic antibodies, rheumatoid arthritis, HLA, peptidome, melanoma
