Ernesto Bermúdez Abreut ¹ Gretchen Bergado Báez ¹ Melissa Martínez ¹ Giuseppe Attanasio ² Carlos Yordan Gonzales Castillo ¹ Diana R. Hernández ¹ Rydell Alvarez Arzola ¹ Andrea Alimonti ² Belinda Sánchez-Ramírez ^1*

• ¹ Center of Molecular Immunology (Cuba), Havana, Cuba
• ² Institute of Oncology Research (IOR), Bellinzona, Switzerland

Despite the cumulative evidence supporting HER3 as a target for antitumor therapies, no agents targeting HER3 have been approved for cancer treatment. Most of the agents evaluated in preclinical or clinical trials have been specific monoclonal antibodies (MAbs), with few examples of active immunotherapy against this receptor. However, some cancer vaccine formats might generate polyclonal antibodies (PAbs) that reproduce a diversity of MAbs' effector mechanisms, such as ligand-neutralization and receptor degradation. In this study, we generate a protein subunit-based monovalent vaccine candidate targeting the extracellular domain (ECD) of HER3. When mice were immunized with a formulation targeting murine ErbB3-ECD, it was able to overcome tolerance to this self-antigen, inducing high titers of ErbB3-specific PAbs. The antitumor potential of this formulation and the induced PAbs was demonstrated in vivo and in vitro in an ErbB3-overexpressing 3LL-D122 derived tumor model. The immunogenicity of the HER3-ECD based vaccine candidate was corroborated by the induction of high titers of HER3-specific PAbs. Consistent with the initial results, HER3-ECD targeting PAbs were cytotoxic in several human epithelial tumor cell lines and exerted antitumor effects in vivo. These results support the value of HER3 as a tumor antigen and the effector mechanisms of HER3-specific therapeutic MAbs, while suggesting the potential of the proposed vaccine candidate for the treatment of HER3-expressing carcinomas