Mart Ustav JR., Chief Scientific Officer at Icosagen, introduced his company as a contract research and development manufacturing organisation (CDRMO) that has developed unique technologies in antigen production, antibody discovery engineering, and GMP manufacturing. The aim is to foster a seamless transition when working with projects in clinical stages and transferring the know-how into CMC processes.
Icosagen has developed an antibody discovery platform using virus-like particles (VLPs) to express complex membrane proteins, facilitating the development of antibodies against challenging targets like GPCRs and transporters. The platform enhances the discovery and development of antibodies targeting complex multi-transmembrane proteins like GPCRs, ion channels, and transporters. Ustav added that the engineered HIV Gag-based VLP platform improves the display of target membranes, which should aid antibody discovery.
One of the key hallmarks of cancer is the deregulated levels of cellular metabolism of cancer, which Icosagen aims to tackle by improving the specificity of antibodies towards targets. Many small molecule inhibitors that have been developed show preclinical efficacy but lack the desired specificity to have a therapeutic window. Ustav explained that antibodies have a better PK compared to small molecules.
The team decided to target GLUT1: GLUT1 is a transmembrane protein commonly overexpressed in many cancers. Ustav stated: “The design objective that we had was to develop highly specific inhibitors of GLUT1, evaluate the effects as a combination of therapy with some approved or clinically evaluated small molecule drugs in order to switch off multiple potential metabolic pathways and confirm that there is a therapeutic window within these this combination therapy.”
The antibodies developed against GLUT1 inhibit glucose uptake in cancer cells, potentially limiting cancer cell proliferation. Ustav uncovered that combining GLUT1 inhibitors with OXPHOS inhibitors creates a synergistic effect in diminishing cancer cell proliferation.
The study then investigated the efficacy of combination therapy in reducing cancer cell proliferation in animal models. However, several antibodies displayed severe toxicity whereas others like ICO-33 were well tolerated. The usefulness of combined therapy was confirmed in a MIAPACA-2 xenograft animal model. This data showed that where individual drugs had no impact, the combination therapy effectively reduced cancer cell proliferation. Currently, Ustav and his team are looking to distinguish between GLUT1 expressed on cancer cells and the blood-brain barrier to minimise toxicity.
In conclusion, Icosagen's VLP-based antigen display platform has proven effective in antibody discovery campaigns. Finally, with more toxicity studies, the combination therapy targeting cancer cell metabolism could offer a promising way forward for combatting hypoxic tumours.
