AUTHOR=Bergado-Báez Gretchen , Gonzalez Suarez Narjara , García Lisset Chao , Pérez-Martínez Dayana , Hernández-Fernández Diana Rosa , Fundora-Barrios Talia , Rodríguez-Álvarez Antonio , Díaz-Ordaz Geidy Diana , Lindzen Moshit , Yarden Yosef , Sánchez-Ramírez Belinda 

TITLE=Polyclonal antibody-induced downregulation of HER1/EGFR and HER2 surpasses the effect of combinations of specific registered antibodies

JOURNAL=Frontiers in Oncology

VOLUME=Volume 12 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.951267

DOI=10.3389/fonc.2022.951267

ISSN=2234-943X

ABSTRACT=Background: Antitumor therapies targeting HER1/EGFR and HER2, such as monoclonal antibodies (MAbs) and tyrosine-kinase inhibitors (TKI) have demonstrated a significant clinical benefit, but emergence of resistance limits long-term efficacy. While secondary HER1 mutations confer tolerance to TKI, compensatory up-regulation of HER2 drives resistance to anti-HER1 MAbs, which identifies MAbs combinations targeting both receptors as an attractive therapeutic strategy. Nevertheless, toxicity hampers clinical validation of this approach. Alternatively, cancer vaccines may induce antibodies directed against several antigens with less concern about induced toxicity.
Methods: Polyclonal antibodies (PAbs) targeting HER1 and HER2 were induced in mice or rabbits through immunization. Recognition of different epitopes on the targets by the PAbs was validated by phage-display technology. Receptor downregulation was evaluated by flow cytometry, immunofluorescence and Western blot. MTT assays assessed cytotoxicity, while antitumor effect of the PAbs was assayed in nude mice.
Results: PAbs promoted degradation of HER1 and HER2 regarding clinical MAbs or their combinations. As a result, inhibition of cytotoxicity on tumor cell lines was improved, even in the presence of oncogenic mutations in HER1, as well as in cetuximab-insensitive cells. Accordingly, the antitumor effect of vaccination-induced PAbs was observed in lung tumor lines representative of sensitivity or resistance to HER1 targeting therapies.
Conclusions: Immunization against HER1 and HER2 receptors offers an alternative to passive administration of combinations of MAbs, since vaccination-induced PAbs promote the downregulation of both receptors and they have a higher impact on the survival of tumor cells.