VIB and the biopharmaceutical company Complix today announce the publication of a joint study in the journal Science Advances. In this work the scientific teams could design an Alphabody™ that efficiently penetrates the cell membrane, disrupts an intracellular protein-protein interface, and carries an in vivo serum half-life extension technology. The unique combination of these three features in one protein scaffold is without precedent. The development of an Alphabody that targets the intracellular tumorigenic protein MCL–1 is a showcase of the technology’s potential. 

Therapeutic antibodies for the treatment of diseases
Therapeutic antibodies have become the best-selling drugs worldwide, treating various cancers, infections and (auto)immune diseases. Monoclonal antibodies have many favorable characteristics as therapeutics, such as long serum half-life, high specificity, and immunological effector functions.

Drawbacks are low tissue penetration and inability to directly address intracellular drug targets. On top of that, they impose high production or formulation costs, and bring along complexities in drug administration and patient care. Alternative approaches like engineered antibody fragments and non-antibody protein scaffolds are often hampered by the limited serum half-life of such small-sized proteins, and, like antibodies, their inability to reach intracellular targets.

Alphabodies as targeted therapies
Alphabodies can overcome these limitations in drug discovery and development. Alphabodies are small and exceptionally stable proteins that can be engineered to bind to a variety of antigens. Their biophysical and structural properties tolerate challenging design features well, rendering Alphabodies ideal candidate scaffolds to address intracellular drug targets.

The VIB team of professor Savvas Savvides worked together with Belgian biopharmaceutical company Complix to engineer Alphabodies that can efficiently penetrate the cell membrane and disrupt an intracellular protein-protein interface, while featuring an in vivo serum half-life extension technology.

The combination of all these desirable features into a single protein scaffold is demonstrated by the development of an Alphabody that targets the intracellular tumorigenic protein MCL-1. Many tumors evade programmed cell death by upregulating MCL-1, which makes this an attractive candidate for anti-cancer therapy. Although therapeutic inhibition of MCL–1 has been pursued for more than a decade, the protein has proven to be recalcitrant to targeting.

Prof. Dr. Savvas Savvides says: “By aiming to develop Alphabodies targeting the well-known intracellular drug target MCL–1, a protein upregulated in multiple tumour types and correlated with therapy resistance, our study goes beyond the currently charted protein-based drug-targeting landscape. It is very exciting and rewarding to see how our longstanding collaboration with Complix has matured to provide essential knowledge for tackling such a major challenge in the design of novel therapeutics.”

Dr. Ignace Lasters, CTO of Complix, says:  “We are pleased to see the publication of this important collaborative study, which is a clear validation of our platform and highlights the potential of cell-penetrating Alphabodies 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 cell-penetrating Alphabodies 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.”

This study provides proof-of-concept for the use of Alphabodies against intracellular disease mediators, which to date were only targeted by small molecule 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. 2021. Science Advances. 

Questions from patients
A breakthrough in research is not the same as a breakthrough in medicine. The realizations of VIB researchers can form the basis of new therapies, but the development path still takes years. This can raise a lot of questions. That is why we ask you to please refer questions in your report or article to the email address that VIB makes available for this purpose: patienteninfo@vib.be. Everyone can submit questions concerning this and other medically-oriented research directly to VIB via this address.

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