| Project Detail |
The principal goal of this proof-of-concept study is to explore the feasibility of a cofactor-induced oligomerisation of IgG to potentiate the therapeutic efficacy of anti-cancer antibodies targeting the tumour site. Our idea is based on two phenomena: Firstly, in our previous studies on the interaction of heme with therapeutic antibodies we found that the interaction of Trastuzumab with heme results in the formation of well-organized oligomers through Fab-Fab interactions of two IgG molecules. These species were considerably more potent in activating the complement system and inducing killing of cancer cells. Importantly, we were able to transfer the potential for oligomeriszation mediated by heme on two unrelated monoclonal antibodies used in clinical practice, thus providing strong evidence of the feasibility of the engineering effort and the utility of its application for broad range of IgG molecules. Secondly, there is strong evidence in the literature about the ability of tumours (especially malignant) to provoke haemorrhages. Based on these two phenomena, we formulated our working hypothesis that the locally released heme and hemoproteins at tumour sites can be harnessed as trigger of oligomerization of engineered IgG molecules, thus increasing their pro-inflammatory and cytotoxic activities due to aggregation of the Fc portion in close proximity. This will result in higher antibody avidity, more efficient cross-linking of Fc-gamma receptors, better recruitment of complement proteins (C1q) and, hence, a stronger activation of the immune effector cells and the classical pathway of complement system on the surface of cancer cells. Successful accomplishment of this project will have considerable societal impact due to clinical and social significance of cancer. |
