Immunotherapy Using a Bispecific Malaria Protein and antiCD3 Molecule at Københavns Universitet

Master study project at University of Copenhagen, Department of Immunology and Microbiology.

In our research on pregnancy-associated malaria, we discovered a unique glycosaminoglycan named oncofetal chondroitin sulfate (ofCS) exclusively expressed by the placenta and curiously also by 95% of tested cancer cells. This highly interesting tumor target can be targeted by the malaria protein VAR2CSA or in a recombinant version named rVAR2.

Within the field of cancer immunotherapy, the use of bispecific T cell engaging antibodies is showing promising potential. Here, one part of the molecule targets and activates the T cell receptor (CD3), while the other targets a tumor associated antigen (TAA), thereby bringing tumor cells and T cells into close proximity of one another. Our research have focused on the development of an rVAR2-anti-CD3 bispecific molecule. This bispecific molecule facilitates a redirection of T cells into the tumor tissue with subsequent killing of the cancer cells.

It is normally difficult to demonstrate efficacy of bispecific T-cell engagers in mice that can translate into what will happen in humans. This is because efficacy needs to be demonstrated in immunocompetent mice, and in these you cannot xenograft human tumors. In our case, VAR2CSA binds both murine and human tumors, allowing us to work in allograft models, and to mimic the most natural conditions we engineered a bispecific molecule consisting of an anti-murineCD3 molecule combined with rVAR2. Mouse cancer models receiving treatment with the rVAR2-anti-CD3 conjugate has shown promising results in tumor elimination in vivo.

In this project, we will be bridging from a murine specific aCD3 treatment to a human aCD3 specific anti-tumor treatment to pave the way for human clinical trials. The candidate will focus on creating and implementing an optimized mouse model to mimic tumors found in patients and look into the effects of different bispecific antibody treatment modalities.

The candidate will be taught appropriate methods, such as;

Recombinant protein expression to generate bispecific molecules.

Quality control of compounds using immuno and chemical based assays such Westernblot, ELISA, SDS page, HPLC, Attana affinity measurements.

  • In vitro killing assays of cancer cell lines using immune cells.
  • Flow cytometry to evaluate the immunological profile of cells in tumor tissue and blood.
  • Transplantation of cancer cells in

in vivo mouse models, tumor measurements, treatment and in vivo imaging.

Contact Group leader Mie Anemone Nordmaj https://cmp.ku.dk/research/var2csa-team/

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