Project:
Engineering Monoclonal Human IgG Antibodies for Treatment of Basal-Like Breast cancers

Principal Investigator - Yu Zhou, PhD

ABSTRACT

Monoclonal antibodies (Abs) are being increasingly utilized in the treatment of cancer. "Naked" antibodies; including trastuzumab (HER2), cetuximab (EGFR), bevacizumab (VEGF), alemtuzumab (CD52), and rituximab (CD20) are already approved for use in oncology, and are an important components of clinical treatment strategies for various cancers. Antibodies have activity against cancer for a variety of reasons. Overexpression of the target antigen on cancer cells enables the recognition of cancer cells by monoclonal antibody. Blocking the cancer target-mediated signaling pathway leads to direct inhibition of cancer cell growth. Engagement of immune effector function by monoclonal antibody allows destruction of the cancer by cells of the immune system. However, each Ab-targeted therapy only "works" for a fraction of patients shown to have the "target" antigen. Among the target-positive patients, a proportion of patients will not respond to the therapy for several possible reasons. First, the target density is not high enough for antibody recognition. Second, the signaling pathway stimulated by the cancer target is impaired in the non-responding group of patients. Third, the nonresponding patients may have altered immune effector functions. How to maximize this anti-cancer effect in target-positive patients remains a challenge to the design of therapeutic antibody. To overcome the ineffectiveness of monoclonal antibody caused by low target density, dysfunction of target signaling, inhibition of effector cell activities in the non-responding patients, we propose to design a bispecific antibody that contains two human single chain Fv (scFv) domains specific to different tumor antigen, and a human Fc domain to modulate ADCC effect. The bispecific antibody will target two basal subtype breast cancer antigens, EGFR and EphA2, which play critical roles in cancer progression and invasion. Targeting both EGFR and EphA2 with bispecific antibodies may lead to potent anti-tumor efficacy for basal like breast cancers.