Monoclonal antibody therapy represents a promising therapeutic strategy for many cancer types. The tumor-binding antibodies interact with Fc receptors (FcRs) on the surface of immune cells, such as macrophages. The FcR-activation stimulates the macrophage to kill the target tumor cell by several modes of action, including antibody-dependent phagocytosis, resulting in the engulfment and killing of the target cell. Despite the major evolution of antibody-based cancer therapy, many patients have limited response to the therapy and there is a great need to improve the clinical efficacy. To achieve this, we are exploring a novel precision medicine approach which aims to maximize the interaction between the antibodies on the surface of the target cells with the specific FcRs present on the individual´s macrophages. Overall, the main goal of this project is to improve the efficacy of antibody cancer therapy taking into account the individual diversity.
When monoclonal antibodies bind to a specific molecule on the target cancer cells they serve as a flag to attract disease-fighting molecules such as C1q. This event will start the complement cascade - a system composed of a number of proteins that acts in a sequential cascade. The complement activation will compromise the cell membrane and ultimately lyse the target cell. Complement-dependent cytotoxicity is known to play a role in the killing of malignant cells in vivo, however the true extent of its contribution still remains unknown. Thus, our main aim in this research project is to develop a method based on the use of therapeutic antibodies that best match complement activation. This will provide us with a better understanding of these interactions and to better control the complement response to enhance the lysis of target cells.
3-dimensional cell culture models
One of the main limitations of conventional 2-dimenisonal (2D) cell culture methods is that they are not able to mimic the in vivo spatial tumor organization and it may not reflect the effect of antibody-based therapies as they occur in vivo. To overcome these drawbacks and to better match antibody-based therapy, we are working in the development of a novel 3D cell culture approach. Here the cancer cells are allowed to aggregate into spheroids, mimicking a solid tumor. The use of 3D spheroids in the antibody therapy experiments will help us bridging the gap between in vitro and in vivo methods, as 3D models are much closer to in vivo physiological conditions than those in 2D culture, providing a better tumor target model.