Evaluation of the anti-tumor effects of an anti-Human Epidermal growth factor receptor 2 (HER2) monoclonal antibody in combination with CD11b+/Gr-1+ myeloid cells depletion using a recombinant peptibody in 4T1-HER2 tumor model.

Abstract

Clinical efficacy of Human Epidermal growth factor Receptor 2 (HER2) targeted strategies is limited due to impaired anti-tumor responses negatively regulated by immunosuppressive cells. We thus, investigated the inhibitory effects of an anti-HER2 monoclonal antibody (1T0 mAb) in combination with CD11b+/Gr-1+ myeloid cells depletion in 4T1-HER2 tumor model. BALB/c mice were challenged with human HER2-expressing 4T1 murine breast cancer cell line. A week post tumor challenge, each mouse received 50µg of a myeloid cells specific peptibody every other day, or 10mg/kg of 1T0 mAb two times a week, and their combination for two weeks. The treatments effect on tumor growth was measured by calculating tumor size. Also, the frequencies of CD11b+/Gr-1+ cells and T lymphocytes were measured by flow cytometry. Peptibody treated mice indicated tumor regression and 40% of the mice eradicated their primary tumors. The peptibody was capable to deplete notably splenic CD11b+/Gr-1+ cells as well as intratumoral CD11b+/Gr-1+ cells (P<0.0001) and led to an increased number of tumor infiltrating CD8+ T cells (3.3 folds) and also that of resident tumor draining lymph nodes (TDLNs) (3 folds). Combination of peptibody and 1T0 mAb resulted in enhanced expansion of tumor infiltrating CD4+and CD8+ T cells which was associated with tumor eradication in 60% of the mice. Peptibody is able to deplete CD11b+/Gr-1+ cells and increase anti-tumoral effects of the 1T0 mAb in tumor eradication. Thus, this myeloid population have critical roles in development of tumors and their depletion is associated with induction of anti-tumoral responses.