ABSTRACT

High-affinity monoclonal antibodies and antibody drug conjugates (ADCs) have evolved as highly successful class of therapeutics and have led to the development of antibody derivatives as well as other protein-based scaffolds that couple selective targeting with the stimulation of an (adaptive) immune response.1 Peptides themselves can also be potent drugs and bind with high affinity to cancer cells and are intermediate in size between antibodies and small molecules.2 Furthermore, chemical peptide synthesis and chemoselective ligations can be used to generate a variety of molecules with different numbers and combinations of binding moieties in a modular and homogeneous fashion. In several recent studies, we have designed and synthesized a suite of synthetic ‘immune system engagers’ (ISErs) that bind specifically to cell surface receptors on cancer cells and stimulate an immune response.3 To explore avidity and valency effects, we constructed ISErs bearing different numbers and combinations ‘binder’ peptides that target integrin α3 and ephrin A2 receptors linked via monodisperse PEG-based polymers to effector moieties that mimic bacterial danger signals.4 ISErs are able to activate human neutrophils after targeted binding to cancer cells and to elicit a cytokine response. The application of ISErs results in immune cell infiltration and can prevent tumor formation in guinea pig and mouse models. Such an anti-tumor activity and the direct synthetic accessibility of ISErs demonstrate that these compounds could be applied to a wide variety of cancer cell targets as well as towards other diseases with specific cellular markers. Conjugation of small molecule drugs, similar to established antibody-drug-conjugates (ADCs), is easily possible.5
References 1. Sliwkowski, M. X., Mellman, I. (2013) Science 341, 1192-1198 & Paul, S., Konig, M.F., Pardoll, D.M. et al. Nat Rev Cancer 24, 399-426 (2024).
2. Conibear, A. C., Schmid, A., Kamalov, et al. (2020) 27, 1174-1205 & Muttenthaler, M., King, G.F., Adams, D.J. et al. Nat Rev Drug Discov 20, 309-325 (2021)
3. Brehs, M., Potgens, A. J. G., Steitz, J., et al. (2017) Sci. Rep. 7, 17592 & Pötgens, A., Conibear, A.C., Altdorf, C., et al. (2019) Biochemistry, 58, 2642-2652.
4. Conibear, A. C., Potgens, A. J. G., Thewes, K., et al. (2018) ChemBioChem 19, 459-469 & Conibear, A.C., Thewes, K., Groysbeck, N., Becker, C.F. (2019) Front. Chem., 7, 113.
5. Conibear, A.C., Hager, S., Mayr, J., (2017) Bioconj. Chem. 28, 2429-2439.

BIO

Christian F.W. Becker studied chemistry at the University of Dortmund (Germany) and obtained his diploma in 1998. After receiving his PhD in 2001 from the same University he became a postdoctoral fellow with Gryphon Therapeutics in So. San Francisco (USA) from 2002 to 2003. He started his independent career as a group leader at the Max-Planck Institute in Dortmund, Germany in 2004 and was appointed as Professor for Protein Chemistry at the Technische Universität München in 2007. In 2011 he was a co-founder of Syntab Therapeutics and he became Professor and Head of the Institute of Biological Chemistry at the University of Vienna. Since 2024 he serves as Dean of the Faculty of Chemistry. His group develops and uses chemical as well as biochemical means to generate peptides and proteins with otherwise unattainable (posttranslational) modifications to address fundamental biochemical as well as biomedical and biotechnological challenges.