BispecificsThatClick · Combinatorial Antibody Synthesis for the Discovery of New Anti-Tumour Immunomodulators

Cancer represents one of the major challenges for modern medicine as we still lack tools to selectively target malignant over healthy tissues. The main issues with state of the art anti-cancer treatments lie on their inefficiency and their associated side-effects. Improving this treatments has focused a lot of attention of the scientific community and has led to the development of new strategies. Harnessing our own immune system to fight malignant cells is one of the strategies with promising potential to improve cancer treatments, although challenges still remain. An emerging therapeutic modality to trigger our immune system against carcinogenic tissues are bispecific antibodies (bsAbs). bsAbs are the combination of two antigen binding specificities on a common scaffold. The potential of these constructs to bind to two antigens can be used to simultaneously target cancer cells and the immune cell which will effectively kill it. The problem of bsAbs is their slow and tedious production process, which is responsible for their linear development. Herein we propose a methodology to speed up and improve the efficiency of their production. Our approach will consist in using novel site-specific bioorthogonal ligation reactions to tag monoclonal antibodies (mAbs) with linkers that will serve as substrates for an inverse electron demand Diels Alder condensation. By condensation of different combinations of tagged mAbs a library of bsAbs will be assembled. The immunondulatory properties of the bsAbs will be tested in high throughput using a high content imaging platform. We will be able to select potential bsAbs for anticancer treatment from our extense library which will study in more depth using classic immunology methods to determine their mode of action and their anti tumour efficacy. The acceleration of both the synthesis and identification of relevant bsAbs for anticancer treatments would significantly increase the presence and value of this technology.