Seminar

Identification of novel tumor-associated antigens and improved antibody formats: the basis for new immunotherapy strategies?

Luis Álvarez-Vallina, PhD

Activating the immune system for therapeutic benefit in cancer has long been a goal in immunology and oncology. Future improvements in this cancer immunotherapy will depend on the identification on accessible targets (tumor-associated antigens) and the availability of appropriate targeting molecules. Phage display is often used as a source of recombinant antibodies against purified antigens or cell suspensions in modern biology. In our laboratory, this technology has been modified in order to obtain antibodies against native antigens in vivo. By using an ex vivo enrichment process against disaggregated tumors to purge the repertoire, and increasing the circulation time in the rounds of in vivo panning we have identified an antibody capable of mediating selective localization of phage to human prostate tumor xenografts. Affinity chromatography followed by mass spectrometric allowed the identification of the target antigen. This strategy should be applicable for the identification and validation of new targets in cancer and other human diseases. Monoclonal antibodies (mAbs) are one of the fastest growing classes of therapeutic agents. However, conventional unmodified mAbs have limitations, such as unfavorable pharmacokinetics and limited tissue penetration as they possess a defined specificity for a single antigen epitope. This is a particularly important aspect because many diseases are multifactorial, involving multiple ligands, receptors, and signaling cascades. Consequently, blockade of different pathological factors and pathways may result in improved therapeutic efficacy. Our laboratory has made great efforts for the development of the next wave of antibody-based reagents for therapy: multivalent and multispecific molecules blocking two or more relevant targets, with a format optimized for the desired pharmacokinetics and adapted to the pathological context.