LAUSR

T cell bispecific antibodies (TCBs) are engineered molecules that include, within a single entity, binding sites to the T cell receptor and to a tumor-specific or a tumor-associated antigen. The receptor tyrosine kinase HER2 is a tumor-associated antigen in ~25% of breast cancers. Clinical evidence shows that TCBs targeting HER2 may result in severe toxicities, likely due to the physiologic levels of HER2 in normal epithelia. Approximately 40% of HER2-positive tumors express detectable levels of p95HER2, a carboxy-terminal fragment of HER2. We previously developed different antibodies that specifically recognize p95HER2 but not full-length HER2 and hypothesized that a TCB antibody recognizing p95HER2 would be exquisitely specific for tumor cells. Here, we describe the development of such p95HER2-TCB and show that it has a potent anti-tumor effect on p95HER2-expressing breast cancers. Since p95HER2 is not expressed in normal tissues, in contrast with HER2-TCB, it has no effect on non-transformed cells expressing physiological levels of HER2. These data paves the way for the safe targeting of a subtype of HER2-positive tumors with a novel tumor-specific TCB. Citation Format: Rocio Vicario, Irene Rius Ruiz, Beatriz Morancho, Cristina Bernado Morales, Sylvia Herter, Anne Freimoser-Grundscholber, Jitka Somandin, Johannes Sam, Oliver Ast, Agueda Martinez Barriocanal, Antonio Luque, Marta Escorihuela, Ismael Varela, Paolo Nuciforo, Roberta Fasani, Vicente Peg, Isabel Rubio, Javier Cortes, Violeta Serra, Santiago Escriva, Jeff Sperinde, Ahmed Chenna, Weidong Huang, John Winslow, Maurizio Scaltriti, Josep Baselga, Josep Tabernero, Pablo Umana, Marina Bacac, Cristina Saura, Christian Klein, Joaquin Arribas. p95HER2-T cell bispecific antibody for breast cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-292.