Background Neuroblastoma is a childhood malignancy characterized by high expression of the disialoganglioside GD2, which is ranked in the top 15 of prioritized cancer antigens. Its prominent tumor specific expression has let to the development of anti-GD2 immunotherapy, resulting in improved patient survival. Some patients, however, still progress highlighting the need for improvement of the existing therapy. Innate immune checkpoints, like CD47, are a relatively new group of potential targets to stimulate the anti-tumor immune response.CD47 is a ubiquitously expressed protein overexpressed on tumor cells and the ligand for the SIRPα receptor expressed on myeloid cells, key effector cells in anti-GD2 based immunotherapy. Binding of CD47 to SIRPα prevents tumor cell phagocytosis and therefore serves as a don’t eat me signal, providing the tumor with a mechanism to evade destruction and processing by antigen presenting myeloid cells (APCs). Targeting of CD47, however, has proven challenging as its ubiquitous expression on healthy cells forms an antigen sink.
Approach To improve anti-GD2 immunotherapy, we developed bifunctional antibodies able to target neuroblastoma and locally interfere with the CD47/SIRPα axis. These bifunctional antibodies recognize GD2 and contain the extracellular SIRPα domain that is able to block CD47.
Results and Conclusion In-vitrowe found that the bifunctional antibody constructs bind tumor cells and block CD47 in a tumor antigen dependent manner. We are now evaluating these noval constructs for their ability to induce phagocytosis in different APCs. In addition we are looking into the effects these antibodies have on cytokine expression and expression of other immune regulatory markers. In-vivo we are using SPECT/CT and biodistribution analysis to determine their tumor targeting ability. Ultimately, we would like to show whether tumor targeted inhibition of the CD47-SIRPa axis using the bifunctional antibodies results in improved anti-tumor immunity
Disclosure Information F. Schuurmans: None. A. Wittner: None. R.J.E. van den Bijgaart: None. S. Tahk: None. S. Heskamp: None. K. Hopfner: None. G.J. Adema: None.
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