Alphabodies: game changing platform for drug development
Complix is a biopharmaceutical company developing Alphabodies, a unique class of transformative protein therapeutics that can potentially access a broad universe of well-known, but currently undruggable disease targets. At present, 80% of all known human disease targets cannot be addressed by the main drug formats, such as antibodies or small chemical drugs. A large proportion of these undruggable targets belong to the interesting class of intracellular protein-to-protein interactions (PPIs). Intracellular PPIs have been shown to regulate a wide variety of essential cellular processes, many of which are known to be involved in important disease processes, such as those causing cancer, central nervous system and metabolic diseases. The potential to modulate such protein interactions across multiple disease categories, therefore, represents a significant medical and commercial opportunity. To address this exciting opportunity, the founding scientists of Complix have designed the Alphabody platform.
An Alphabody is a small single-chain protein, 70-100 amino acids long, with a molecular weight in the range of 8-12,000 dalton, and comprises three alpha-helices organised in a stable and compact ‘coiled coil’ structure. The target-binding moiety of an Alphabody is created by engineering patches of varying amino acid residues on its surface. Although alpha-helix coils or bundles do exist in nature, the typical three alpha-helix coiled coil of an Alphabody is entirely developed in silico, via computer design, by the protein engineering scientists at Complix. Despite being artificial, Alphabodies have been shown in animal studies to be non-toxic and non-immunogenic.
Given its unique characteristics, an Alphabody is suitable to act as a drug scaffold against a broad range of disease targets including cytokines, cell receptors, viral entry regulators and, most importantly, intracellular PPIs. Alphabodies combine the beneficial features of antibodies, like high-target specificity, with those of small chemicals, like stability and the capacity to penetrate into cells. The Alphabody discovery process involves a combination of in silico design with library screening, allowing us to obtain leads in less than three months. The rigid alpha-helical coil structure of Alphabodies allows them to be created with precision and a high probability of success in silico. Moreover, the in silico design procedure does not require isolation and purification of the target molecule, which is an advantage in case targets are unstable in a test tube, as is the case with many membrane receptors and intracellular
proteins. To transform an Alphabody into a cell penetrating Alphabody, specific sequence patterns are introduced at defined positions in the structure. Cellular uptake studies, conducted with cell penetrating Alphabodies on a variety of cancer cell types, have revealed that uptake can be rapid and concentration dependent, allowing them to reach therapeutically relevant intracellular concentrations within a few hours of incubation. Alphabodies mostly enter directly into the cytosolic space of the cells, and do not end up in the endosomal pathway, an important prerequisite for achieving effective target interaction.
For our initial therapeutic programme with cell penetrating Alphabodies, we have selected the intracellular target protein MCL-1. MCL-1 belongs to the family of BCL-2 proteins, which regulate cellular apoptosis, determining whether a cell dies or survives. In cancer cells, MCL-1 is often overexpressed and prevents these cells from entering the apoptosis phase. We have now designed and produced Alphabodies that antagonise MCL-1, and consequently induce cell death in cancer cells. MCL-1 is a potential drug target and is suspected to be implicated in several types of haematological cancers. More recently, we have generated a panel of anti-MCL-1 Alphabodies that display various cross-reactivities against different other members of the BCL-2 family. Further investigations, including in vivo evaluation in oncology models, will help us to define the optimal profile for a lead candidate that will be taken forward into clinical development.
Complix is building a pipeline of therapeutic Alphabodies against intracellular, as well as extracellular disease targets, with a focus on cancer and autoimmune disease. Complix’ most advanced program CMPX-1023 is an Alphabody targeting the cytokine IL-23. This product is currently in advanced preclinical development and has demonstrated impressive potency in preclinical models of autoimmune disease. Next to its anti-MCL-1 program, which is in lead optimization stage for oncology applications, Complix has several discovery programs against other intracellular targets that play a key role in cancer and autoimmune disease.
Additionally, we have established a strong intellectual property position protecting the AlphabodyTM platform and its emerging product portfolio through filing multiple broad patent applications. Alphabody-based therapeutics have a unique freedom-to-operate position and are completely free from antibody-based patent claims.