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Novel Bi-Specific Immuno-Modulatory Tribodies Potentiate T Cell Activation and Increase Anti-Tumor Efficacy
Authors:Margherita Passariello  Asami Yoshioka  Kota Takahashi  Shu-ichi Hashimoto  Rosa Rapuano Lembo  Lorenzo Manna  Koji Nakamura  Claudia De Lorenzo
Affiliation:1.Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy; (M.P.); (L.M.);2.Ceinge-Biotecnologie Avanzate s.c.a.r.l., Via Gaetano Salvatore 486, 80145 Naples, Italy;3.Chiome Bioscience Inc., 3-12-1 Hommachi Shibuya-Ku, Tokyo 151-0071, Japan; (A.Y.); (K.T.); (S.-i.H.); (K.N.);4.European School of Molecular Medicine, University of Milan, 20122 Milan, Italy
Abstract:Cancer immunotherapy has already shown significant improvements by combining different antibodies specific for distinct immune checkpoints, such as Ipilimumab and Nivolumab. Here, we tested combinatorial treatments of immunomodulatory antibodies, previously generated in our laboratory, for their effects on hPBMC activation, either upon stimulation with SEB or in co-cultures with tumor cells by cytokine secretion assays. We found that some of them showed additive or synergistic effects, and on the basis of these observations, we constructed, for the first time, four novel bispecific tribodies (TR), made up of a Fab derived from one anti-IC mAb and two scFvs derived from another mAb targeting a different IC. All four TRs cotargeting either programmed cell death protein 1 (PD-1) and Lymphocyte Activating 3 (LAG-3) or programmed death-ligand 1 (PD-L1) and LAG-3 retained binding affinity for their targets and the antagonistic effects of their parental mAbs, but some of them also showed an increased ability to induce lymphocyte activation and increased in vitro cytotoxicity against tumor cells compared to parental antibodies used either alone or in combinatorial treatments. Furthermore, none of the tribodies showed significant increased cytotoxicity on human cardiomyocytes. Considering that the tribody format reduces production costs (as only one construct provides the inhibitory effects of two antibodies), has an intermediate molecular size (100 kDa) which is well suited for both tumor penetration and an acceptable half-life, we think that these novel immunomodulatory TRBs have the potential to become precious tools for therapeutic applications, particularly in monotherapy-resistant cancer patients.
Keywords:immunotherapy   cancer   bispecific antibodies   targeted-therapy   intracellular pathways
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