Abstract
Monoclonal antibodies (mAbs) play an increasingly important role in cancer therapy. To address the wide heterogeneity of the disease, the identification of novel antigen targets and the development of mAbs against them are needed. Our lab previously generated a panel of mAbs against human embryonic stem cells (hESC) using a whole cell immunization approach in mice. These mAbs can potentially target oncofetal antigens and be repurposed for antibody or antibody drug conjugate (ADC) therapy. From this panel, the novel IgG1 2448 was found to bind surface antigens on hESC and multiple cancer cell lines. Here, we show 2448 targets a unique glycan epitope on annexin A2 (ANXA2) and can potentially monitor the Epithelial-Mesenchymal Transition (EMT) in ovarian and breast cancer. To evaluate 2448 as a potential drug, 2448 was engineered and expressed as a chimeric IgG1. Chimeric 2448 (ch2448) demonstrated efficient and specific killing when conjugated to cytotoxic payloads as an ADC. In addition, ch2448 elicited potent antibody-dependent cell-mediated cytotoxicity (ADCC) activity in vitro and in vivo. Further engineering of ch2448 to remove fucose in the Fc domain enhanced ADCC. Overall, these findings indicate that embryonic ANXA2 is an attractive target and suggest that ch2448 is a promising candidate for further therapeutic development.
Highlights
Monoclonal antibodies have emerged as an important class of biologics for targeted cancer therapy
As saporin-based conjugates are not ideal toxins for antibody drug conjugate (ADC) therapy, we focused on ch2448 as a naked antibody with antibody-dependent cellmediated cytotoxicity (ADCC) properties
We described the characterization and development of 2448, a novel Monoclonal antibodies (mAbs) that was generated by whole cell immunization of human embryonic stem cells (hESC), but was shown to recognize ovarian and breast cancer cells
Summary
Monoclonal antibodies (mAbs) have emerged as an important class of biologics for targeted cancer therapy. MAbs can bind to antigens that are expressed on the surface of cancer cells. They can exhibit diverse modes of action: direct tumor cell-killing, modulation of a host immune system and delivery of toxic agents as an antibody-drug conjugate (ADC). Over twenty-five antibody-based therapies have been approved for cancer. These antibodies target a limited number of tumor antigens, such as CD20, ERBB2 and EGFR. To address the molecular heterogeneity of cancer, the discovery and exploitation of new antigen targets is needed
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