Antibodies (also known as immunoglobulins) are used by the immune system to recognize foreign substances (so-called ‘antigens’), triggering an immune response that leads to the destruction of the offending cells. Antigen recognition occurs at the tips of the two “arms” of the antibody, so-called ‘antigen-binding fragments’ or, in short, ‘Fab’s. Turning the immune response towards cancer cells, by using tumor-specific antibodies, allows targeted cancer treatment.
About the project
Our attention has been foremost on two groups of anti-tumor antibodies, those against N-glycolyl sialic acid-containing molecules like NeuGc GM3, and antibodies targeting the epidermal growth factor. Both molecules are commonly over-expressed in human tumors (Krengel & Bousquet, 2014). By selectively recognizing tumor tissues, such antibodies can distinguish between normal and tumor cells and be employed for both passive and active (vaccines) cancer therapies.
Our main expertise is in structural biology. To gain a full understanding of the mechanism of action and to engineer the binding site of the antibodies in order to improve the antibody's binding properties, we frequently collaborate with other labs. One important collaborator has been the Center of Molecular Immunology in Havana, Cuba (see e.g., Rojas et al., 2013). We are also very excited about our collaboration with Anders A. Tveita and Geir Åge Løset in Oslo (see e.g., Bjerregaard-Andersen et al., 2018).
Research Highlights
After a long journey, we recently solved the crystal structure of 14F7 Fab in complex with its ligand, which explains the unique binding characteristics of this antibody (Bjerregaard-Andersen et al., 2021). We found that a key role is played by a structural water molecule (see Figure). However, the interaction of 14F7 with the membrane is more complicated than that, and we are only beginning to understand the full picture, in collaboration with the group of Ünal Coskun in Dresden (Bjerregaard-Andersen et al., 2020).
In some cases, it can be interesting to work with so-called anti-idiotypic antibodies, which have been thought to mimic the antigens, with potential for therapeutic cancer vaccines. But how can an antibody, which is a protein, mimic a carbohydrate? The crystal structure of the antibody P3 and its modeled complexes with N-glycolyl GM3 and its anti-idiotypic antibody 1E10 (Talavera et al., 2009a) shed light on this phenomenon: It appears that the anti-idiotpypic antibody (Ab2) serves as an imprint of the primary antibody (Ab1), P3, providing a cast to generate Ab3 antibodies similar to Ab1, rather than providing strict structural mimicry.
A second, unrelated, research project on anti-tumor antibodies is concerned with Nimotuzumab (also known as h-R3), an antibody targeting the EGF receptor. This antibody has been approved in several countries for the treatment of head and neck tumors and glioma, and is in clinical trials for various other tumor types. Intriguingly, Nimotuzumab shows only minor side effects (Allan, 2005), while still being effective.
Based on the crystal structure that we solved to 2.5 Å resolution and its modeled complex with the extracellular domain of the EGF receptor, we proposed a model for the favorable mechanism of action of this antibody (Talavera et al., 2009b), and probed it in collaboration with the group of Inger Helene Madshus at the Norwegian National Hospital (Berger et al., 2011).