Design of optimal bispecific antibody-based combined therapies against pancreatic tumors: a systems biology approach – DUALPancHER

Members of the HER family (EGFR/EGFR, HER2, HER3, HER4) of receptor tyrosine kinases are key targets for cancer therapy. They are expressed in pancreatic cancers which remain an unmet medical need. Due to cross-talk in HER signaling, we and others proposed to combine monoclonal antibodies (MAb) directed against either different members of the family or different epitopes of the same receptor. For instance, such a strategy was used in the trastuzumab-pertuzumab combination, which is now clinically approved against breast cancer. MAb combinations are thus promising though many questions remain to be solved and little is known about bispecific antibodies (BsAb), which constitute innovative and promising molecules combining the targets of two MAbs. Antibodies have the ability to disrupt HER signaling, affect HER degradation, and recruit immune system effectors to eradicate tumor cells with increased efficacy, e.g. through antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC). Furthermore, as compared with MAbs, BsAbs can feature increased avidity for two different receptors and a natural tendency to favor emergence of receptor lattices thus increasing recognition by NK cells.

In this project, we aim at breaking the intrinsic and acquired resistance of pancreatic tumors by designing optimal antibody pairs. We will combine the strength of unbiased, data-driven investigations relying on mathematical models of HER-signaling pathways with our long standing experience in therapeutic antibody research, including MAbs combinations and BsAbs. The contribution of (i) antibody-induced receptor degradation and (ii) antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), mechanisms amplifying the elimination of the tumor will be combined with systems biology models of signaling interference and receptor dynamics for the first time, thus providing a complete picture of the dual action of MAbs and BsAbs. We will consider six therapeutic antibodies targeting EGFR, HER2 and HER3 (two for each receptor), featuring different binding patterns, i.e. competing with the ligand or not, as monotherapy or in combination versus the 30 corresponding bispecific antibodies (BsAbs). These BsAbs will be produced by our industrial partner Biomunex, which owns a unique IgG-based tetravalent bispecific antibody platform, termed BiXAb®. This technology, which possesses 2 binding sites (Fab domains) for each of the 2 different antigens and a functional Fc domain, originates from a discovery of Dr. M. Cerutti (team 3) and was further developed by the company.

The expected results of our proposal include:
• Innovative knowledge on HER family systems biology including receptor degradation and ADCC/CDC data;
• Novel insights into the new biology generated by BsAbs;
• Discovery of a highly-potent and robust BsAbs against pancreas adenocarcinomas. Robustness of efficacy will be tested against multiple cell lines recapitulating known pancreas cancer subtypes and patient-derived cellular models;
• To dissect the differences and similarities of BsAb versus paired MAbs biological activity, detailed systems biology quantitative models will be derived covering four cell lines and numerous BsAbs. These local pathway models will be complemented by genome-wide transcriptomic, proteomic and phospho-proteomic profiles for the most promising BsAbs.
• To foster the development of a French startup biotech company developing an innovative BsAb platform and portfolio.