RESEARCH & DEVELOPMENT
VAR2 Pharmaceutical’s core technology is a proprietary recombinant version of the malarial VAR2CSA protein (rVAR2), which binds specifically and with a high affinity to oncofetal chondroitin sulfate A (ofCS) – a distinct carbohydrate found on a wide range of proteoglycans redundantly expressed in of the vast majority of solid tumors.
VAR2 Pharmaceuticals aims to use the rVAR2 technology in development of novel targeted cancer therapies by conjugating or fusing the rVAR2 protein to an active cancer-killing moiety or immune enganger.
Patents covering the use of rVAR2 for treatment of cancer have been issued in all major markets.
Current R&D programs
The main R&D program for VAR2 Pharmaceuticals is development of a rVAR2 Drug Conjugate (VDC), comprised of a potent toxin conjugated to the rVAR2 protein via a cleavable linker molecule (similar concept as antibody drug conjugates). Once the lead molecule has been selected, the development will be continued through partnership or out-licensing.
In parallel with the VDC program, other opportunities are being explored with academic or commercial partners, including combinations of rVAR2 proteins with immune effector moieties and radioisotopes (therapy and/or imaging), as well as combinations with chimeric antigen receptor (CAR) T cell applications.
The current research portfolio is illustrated below.
The core technology: Using a malaria protein to target cancer
VAR2 Pharmaceuticals’ technology is founded on an innovative amalgamation of malaria parasitology and cancer research discoveries. A key feature of malaria pathogenesis is the ability of parasites to invade and multiply in red blood cells. As parasite-infected red blood cells (IRBCs) are susceptible to filtration and destruction in the spleen, the parasites express proteins on the cell surface of IRBCs that mediates sequestration in different tissues of the human host. One such protein, VAR2CSA tethers IRBCs specifically to the placenta via a high-affinity interaction to a distinct type of chondroitin sulfate A, named oncofetal CSA (ofCS). By catching growth factors and promoting cell motility, ofCS ensures that the placenta can grow fast, establish blood supply, and invade the uterine tissue. Fast growth and invasiveness are features shared between solid tumors and the placenta.
Recent research has confirmed that expression of ofCS indeed is a common molecular modification to proteoglycans found exclusively in placenta and most human solid tumors. It has been demonstrated that VAR2 Pharmaceuticals recombinant VAR2CSA protein (rVAR2) binds to tumor cells of epithelial and mesenchymal origin, including epithelial tumor cells that have undergone epithelial- to mesenchymal transition. The ofCS modification has not been detected on any normal cell type investigated to date, which creates an attractive opportunity for rVAR2-based cancer therapy.
The VAR2CSA malaria protein efficiently retrieves circulating tumor cells in an Ep-CAM-independent manner. Agerbæk M. Ø., Bang-Christensen S. R., Ming-Hsin Yang, Clausen T. M., Pereira M. A., Sharma S., Ditlev S. B., Nielsen M. A., Choudhary S., Gustavsson T., Sorensen P. H., Meyer T., Propper D., Shamash J., Theander T. G., Aicher A., Daugaard M., Heeschen C., and Salanti A. Nature Communications, 9, Article number: 3279, 2018 (DOI: 10.1038/s41467-018-05793-2).
Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein. Salanti A, Clausen TM, Agerbæk MØ, Al Nakouzi N, Dahlbäck M, Oo HZ, Lee S, Gustavsson T, Rich JR, Hedberg BJ, Mao Y, Barington L, Pereira MA, LoBello J, Endo M, Fazli L, Soden J, Wang CK, Sander AF, Dagil R, Thrane S, Holst PJ, Meng L, Favero F, Weiss GJ, Nielsen MA, Freeth J, Nielsen TO, Zaia J, Tran NL, Trent J, Babcook JS, Theander TG, Sorensen PH, Daugaard M. Cancer Cell. 2015 Oct 12;28(4):500-14.
Oncofetal Chondroitin Sulfate Glycosaminoglycans are Key Players in Integrin Signaling and Tumor Cell Motility. Clausen TM, Pereira MA, Al Nakouzi N, Oo HZ, Agerbæk MO, Lee S, Orum-Madsen MS, Kristensen AR, El-Naggar A, Grandgenett PM, Grem JL, Hollingsworth MA, Holst PJ, Theander TG, Sorensen PH, Daugaard M, Salanti A. Mol Cancer Res. 2016 Sep 21.
Real-time and label free determination of ligand binding-kinetics to primary cancer tissue specimens; a novel tool for the assessment of biomarker targeting. Clausen TM, Pereira MA, Oo HZ, Resende M, Gustavson T, Mao Y, Sugiura N, Liew J, Fazli L, Theander TG, Daugaard M, Salanti A. Sens Biosensing Res. 2016 Jul;9:23-30.
Molecular dissection of placental malaria protein VAR2CSA interaction with a chemo-enzymatically synthesized chondroitin sulfate library. Sugiura N, Clausen TM, Shioiri T, Gustavsson T, Watanabe H, Salanti A. Glycoconj J. 2016 Jun 10.
Placental Sequestration of Plasmodium falciparum Malaria Parasites Is Mediated by the Interaction Between VAR2CSA and Chondroitin Sulfate A on Syndecan-1. Ayres Pereira M, Mandel Clausen T, Pehrson C, Mao Y, Resende M, Daugaard M, Riis Kristensen A, Spliid C, Mathiesen L, E Knudsen L, Damm P, G Theander T, R Hansson S, A Nielsen M, Salanti A. PLoS Pathog. 2016 Aug 24;12(8):
Burkitt lymphoma express oncofetal Chondroitin Sulfate without being a reservoir for placental malaria sequestration. Mette Ø. Agerbæk, Marina A. Pereira, Thomas M. Clausen, Caroline Pehrson, Htoo Zarni Oo, Charlotte Spliid, Jamie Rich, Vincent Fung, Francis Nkrumah, Janet Neequaye, Robert J. Bigger, Steven J. Reynolds, Giovanna Tosato, Sheeja T. Pullarkat, Leona W. Ayers, Thor G. Theander, Mads Daugaard, Kishor Bhatia, Morten A. Nielsen, Sam M. Mbulaiteye, and Ali Salanti. International Journal of Cancer. 2017 Apr 1;140(7)
VAR2 Pharmaceuticals ApS
Ole Maaløes Vej 3
DK-2200 Copenhagen N
T: +45 78 70 19 00