Comparative Effect of Herceptin and Its Biosimilar: Transcriptomic and Proteomic Insights from HER2-Positive Cancer Cell Lines

Abstract

The first patent for the therapeutic monoclonal antibody Herceptin expired in 2019, opening the door for the development of biosimilars. Biosimilars are copies of the originator product that must demonstrate biosimilarity for regulatory approval. This is a very difficult task. Antibodies are large molecules that undergo extensive post-translational modifications (PTMs), which affect their potency, stability, binding affinity, and immunogenicity. Batches of the originator products often vary in their PTM patterns, making structural similarity very difficult to prove. Despite these challenges, most biosimilar development workflows rely on targeted wet-lab assays to assess structural similarity, purity, and efficacy, often without addressing the full complexity of the task. Herceptin targets the surface receptor HER2 (human epidermal growth factor receptor 2) on breast cancer cells, inducing global cellular changes including cell arrest, programmed cell death, reduced motility, and angiogenesis. The complete mode of action is under investigation, and the development of resistance to Herceptin is common and complex. Due to these gaps in knowledge and complexity of Herceptin’s effect, untargeted omics techniques, such as transcriptomics and proteomics, are ideally suited for functionally comparing biosimilars to their originator product. Therefore, the primary goal of this thesis is to evaluate whether transcriptomics and proteomics experiments are useful for investigating the impact of the biosimilar on target cells compared to the originator product. To this end, Herceptin’s effect on the breast cancer cell lines BT474, SKBR3 and MCF7 will be compared to a biosimilar, called Apotex- Trastuzumab (ApoTras), provided by Apobiologix (Toronto, Canada). This analysis will allow us to investigate the sensitivity of the methods in detecting differences and determining how many of the known effects can be identified. This work will provide valuable insights into the use of untargeted omics approaches for investigating the functional similarity of a biosimilar to its originator product.