Complix, a biopharmaceutical company developing a pipeline of transformative Alphabody therapeutics announces the publication in Science Advances of the results from a joint, multidisciplinary study with Belgian life sciences research Institute VIB and Ghent University. The proof-of-concept study demonstrates the potential of Cell-Penetrating Alphabodies™ (CPABs) to efficiently penetrate the cancer cell membrane, disrupt an intracellular protein-protein interface, and cause an anti-tumor effect upon in vivo administration in relevant xenograft models.
CPABs are a revolutionary class of small proteins that have been designed to overcome the limitations of conventional antibodies and small molecules through combining the specific potency of biologics with the cell-penetrating capacity and stability of small molecules. Data available show that CPABs have the potential to address a wide range of disease targets, particularly intracellular targets, that are difficult for current therapies to reach.
The study, published in Science Advances, demonstrates that CPABs can be designed to efficiently penetrate the cell membrane, disrupt an intracellular protein-protein interface, and carry an albumin-binding moiety to extend their serum half-life to therapeutically relevant levels. The unique combination of these three features in a single protein scaffold is without precedent. In this publication a CPAB was engineered against MCL-1, an intracellular protein target in cancer.
The findings from this study provide strong proof of concept for the use of CPABs against intracellular disease mediators, which, to date, have remained in the realm of small-molecule therapeutics.
Dr. Ignace Lasters, CTO of Complix, commented: “We are pleased to see the publication of this important study, which is a clear validation of our platform and highlights the potential of CPABs to directly address intracellular drug targets in oncology. Reaching the intracellular space has been a critical limiting factor in broadening the therapeutic potential of current biologicals such as monoclonal antibodies. This proof-of-concept study clearly demonstrates the potential of CPABs as a transformative, “membrane crossing” technology to address a variety of cutting-edge and challenging intracellular disease targets. This holds the promise for the creation of an entirely novel class of therapeutics with applications in oncology and beyond.”
Prof. Savvas Savvides, Group leader at VIB Center for Inflammation Research, and Professor of Structural Biology at Ghent University, said: “Our study clearly extends the currently charted protein-based drug-targeting landscape by targeting the well-known intracellular drug target MCL–1, a protein upregulated in multiple tumor types and correlated with therapy resistance. It is very exciting and rewarding to see how our longstanding collaboration with Complix has matured to provide the essential knowledge needed to tackle such a major and important challenge in the design of novel therapeutics.”
Erwin Pannecoucke, Maaike Van Trimpont, Johan Desmet, Tim Pieters, Lindy Reunes, Lisa Demoen, Marnik Vuylsteke, Stefan Loverix, Karen Vandenbroucke, Philippe Alard, Paula Henderikx, Sabrina Deroo, Franky Baatz, Eric Lorent, Sophie Thiolloy, Klaartje Somers, Yvonne McGrath, Pieter Van Vlierberghe, Ignace Lasters, Savvas N. Savvides. Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting. Science Advances, 26 March 2021: Vol. 7, no. 13.
The article by Pannecoucke et al. can be accessed by clicking here.