Development of a bispecific immune engager using a recombinant malaria protein

Mie A., Nordmaj, Morgan E., Roberts, Emilie S., Sachse, Robert, Dagil, Anne Poder, Andersen, Nanna, Skeltved, Kaare V., Grunddal, Sayit Mahmut, Erdoğan, Swati, Choudhary, Tobias, Gustsavsson, Maj Sofie, Ørum-Madsen, Igor, Moskalev, Weihua, Tian, Zhang, Yang, Thomas M., Clausen, Thor G., Theander, Mads, Daugaard, Morten A., Nielsen, Ali, Salanti

Cell Death and Disease |

As an immune evasion and survival strategy, the Plasmodium falciparum malaria parasite has evolved a protein named VAR2CSA. This protein mediates sequestration of infected red blood cells in the placenta through the interaction with a unique carbohydrate abundantly and exclusively present in the placenta. Cancer cells were found to share the same expression of this distinct carbohydrate, termed oncofetal chondroitin sulfate on their surface. In this study we have used a protein conjugation system to produce a bispecific immune engager, V-aCD3, based on recombinant VAR2CSA as the cancer targeting moiety and an anti-CD3 single-chain variable fragment linked to a single-chain Fc as the immune engager. Conjugation of these two proteins resulted in a single functional moiety that induced immune mediated killing of a broad range of cancer cells in vitro and facilitated tumor arrest in an orthotopic bladder cancer xenograft model.