A Novel EGFRvIII T-Cell Bispecific Antibody for the Treatment of Glioblastoma
Raffaella Iurlaro, Inja Waldhauer, Ester Planas‐Rigol, Ester Bonfill‐Teixidor, Alexandra Arias, Valeria Nicolini, Anne Freimoser–Grundschober, Isabel Cuartas, Alba Martínez-Moreno, Francisco Martínez‐Ricarte, Esteban Cordero, Marta Cicuéndez, Simona Casalino, Xavier Guardia-Reyes, Linda Fahrni, Thomas Pöschinger, Virginie Steinhart, Marine Richard, Stefanie Briner, Joerg Mueller, Franz Osl, Johannes Sam, Sara Colombetti, Marina Bacac, Christian Klein, Estela Pineda, Luís Reyes, Alberto Di Somma, José Juan González Sánchez, Paolo Nucíforo, Joan Carles, María Vieito, Josep Tabernero, Pablo Umaña, Joan Seoane
Abstract
T-cell bispecific antibodies (TCB) are engineered molecules that bind both the T-cell receptor and tumor-specific antigens. Epidermal growth factor receptor variant III (EGFRvIII) mutation is a common event in glioblastoma (GBM) and is characterized by the deletion of exons 2-7, resulting in a constitutively active receptor that promotes cell proliferation, angiogenesis, and invasion. EGFRvIII is expressed on the surface of tumor cells and is not expressed in normal tissues, making EGFRvIII an ideal neoantigen target for TCBs. We designed and developed a novel 2+1 EGFRvIII-TCB with optimal pharmacologic characteristics and potent antitumor activity. EGFRvIII-TCB showed specificity for EGFRvIII and promoted tumor cell killing as well as T-cell activation and cytokine secretion only in patient-derived models expressing EGFRvIII. Moreover, EGFRvIII-TCB promoted T-cell recruitment into intracranial tumors. EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft models. Our results warrant the clinical testing of EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.