Click and link: a chemistry-driven approach to bispecific antibodies

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The development of new therapeutic agents which specifically target malignant over healthy tissues has become a paradigm of modern cancer therapy. Bispecific antibodies (bsAbs) combine two monospecific antibodies onto a common scaffold, triggering the bridging of a target (e.g. cancerous) cell to an effector (eg. immune) cell which will effectively kill it. Despite their modular nature, a major drawback of bsAbs is that the current development process is slow due to their tedious and linear production process, which relies on genetic approaches. The present project constitutes a chemistry-driven effort to exploit site-specifically click reactions for the ligation of two different proteins, and its application to explore the structural and functional space of bsAbs. The main objective is to develop an integrated approach for combinatorial construction of bsAbs libraries through the design of linkers that site-specifically bridge two different proteins under biocompatible conditions and in a stoichiometric manner. The methodology will be applied for the generation of a small library of bsAbs capable of triggering immunomodulatory responses towards cancerous cells. The immunomodulatory potential of the bsAbs library will be determined using cell-cell interaction profiling through high-content imaging methods, and the best candidates will be further analyzed using classical cancer immune biology and cutting-edge -omics approaches.