Quantitative biochemical response profiling as a methodology for comparing biosimilar compounds

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A major market area for biotechnology products is monoclonal antibodies, which have applications as diagnostic tools, pharmaceuticals and molecular biology reagents. However, methods for producing monoclonal antibodies do not typically produce a single type of biomolecule, but instead produce an assemblage of closely related biomolecules that can have differences in glycosylation patterns and other secondary features. This may result in subtle differences in biological effects of the monoclonal antibody. Developing methods for identifying potential variations of biological effects of monoclonal antibodies is therefore of considerable practical importance. One area that is potentially impacted by these variations is subsequent-entry pharmaceuticals including biosimilars and interchangeable biologics, which are analogs of established pharmaceuticals. To demonstrate that these compounds are equivalent to originator biologics, manufacturers must satisfy regulatory requirements that involve rigourous tests of statistical equivalence. This can be challenging for complex biomolecules such as monoclonal antibodies, as secondary features including glycosylation are often variable for both the originator and biosimilar compound. Novel approaches are therefore needed to meet statistical requirements of equivalency, especially where potency and immunological function are influenced by glycans. This project will develop quantitative methodology, through the use of high-throughput expression analysis, to assess and compare biochemical effects of biosimilars and originator compounds. The proposed study will investigate the effectiveness of high-throughput gene and protein expression analysis as tools to compare the biological effects of biosimilars with corresponding originator biologics. The specific target used as a model within this project is Trastuzumab (Herceptin), a monoclonal antibody that interferes with the HER2/neu receptor, which is unregulated in certain cancers. Responses to trastuzumab biosimilars will be investigated, which will either show equivalence of effect within appropriate margins, or may reveal unexpected effects that could point to novel biological impacts.