Abstract
Monoclonal antibodies (mAbs) are used as targeted therapies against cancers. These mAbs kill cancer cells via various mechanisms of actions. In this study, human embryonic stem cells (hESCs) was used as the immunogen to generate a panel of antibodies. From this panel of mAbs, A19 was found to bind both hESC and various cancer cell lines. The antigen target of A19 was identified as Erbb-2 and glycan analysis showed that A19 binds to a N-glycan epitope on the antigen. A19 was elucidated to internalize into cancer cells following binding to Erbb-2 and hence developed as an antibody-drug conjugate (ADC). Using ADC as the mechanism of action, A19 was able to kill cancer cells in vitro and delayed the onset of tumour formation in mice xenograft model. When compared to Herceptin, A19 binds to different isoforms of Erbb-2 and does not compete with Herceptin for the same epitope. Hence, A19 has the potential to be developed as an alternative targeted therapeutic agent for cancers expressing Erbb-2.
Highlights
Cancer which is characterized by abnormal cell growth is a major cause of death, killing over 8 million people globally[1]
The Fc-region of antibodies plays a critical role in immune cell activation and killing of tumour cells via antibody-dependent cell mediated-cytotoxicity (ADCC); and in mediating tumour cell killing through complement-mediated cytotoxicity (CDC)[3,11,12,18,19]
The upper band was identified as Isoform 4 of Receptor tyrosine-protein kinase Erbb-2 (Accession #P04626-4) and the lower band was identified as Receptor tyrosine-protein kinase Erbb-2 (Accession #F5H1T4)
Summary
Cancer which is characterized by abnormal cell growth is a major cause of death, killing over 8 million people globally[1]. A19 internalizes into cancer cells that have high expression levels of Erbb-2 and is useful as an antibody drug conjugate (ADC) to kill these cells in vitro. To determine if A19 binds to N-glycans on Erbb-2, the membrane fraction of SKOV3 was digested with PNGase F to remove N-glycans on glyco-proteins and Western blot carried out[53,54,55].
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