![]() Trastuzumab and pertuzumab were first developed as mouse MAbs which recognise human HER2, but later made into human antibodies (‘humanised’) for administration to patients. Trastuzumab and pertuzumab are clinically approved humanised monoclonal antibodies used in the treatment of HER2-positive (or HER2-overexpressing) breast cancer. In most cases, the antibodies which bind human/primate antigens do not bind to the equivalent antigen in rodent species, therefore rodents are usually used to assess target-independent safety and non-human primates are used for target-dependent safety signals. Additionally, for some therapeutics it is equally important to use a species in which the antibody does not bind to the drug target (non-binding species) this allows researchers to see if there are any potential toxicities which are not caused by the binding of the antibody (target-independent events). ![]() In safety assessment of monoclonal antibody therapy, it is important to use a species which is similar enough to humans (known as a binding species) so that the antibody can bind to the drug target and demonstrate if there is efficient binding of the antibody and if there are any associated adverse events (ie, toxicities). During therapeutics development, understanding the mechanism of action of a drug and any associated toxicity is vital. Safety studies are routinely conducted during drug development to assess the safety/toxicity of preclinical and clinical drug candidates. Fortunately, there are several approaches which have shown great efficacy in targeting HER2 therapeutically, including humanised monoclonal antibodies (MAbs), antibody–drug conjugates (ADCs), and small molecule kinase inhibitors. Such cancers are often associated with increased tumour growth rates and a poorer prognosis in patients with such malignancies, thus presenting a significant health burden. However, in a proportion of breast cancers and other solid tumours, HER2 is highly overexpressed. ErbB2 is also expressed in epithelial tissues at low levels in healthy adults. ErbB2 is especially important in cardiac tissue, as it is essential in cardiac foetal development. Human epidermal growth factor receptor 2 (HER2 or ErbB2) is a cell surface protein in a complex signalling network which stimulates cell growth. In their studies, Dr Gail Lewis Phillips and colleagues from Genentech Oncology demonstrate how future safety studies for trastuzumab-based therapeutics should be conducted to generate better understanding of toxicities, and to potentially reduce animal experimentation. It is acknowledged that trastuzumab does not bind to the rodent equivalent of HER2 (called ‘neu’), but researchers still use rodent species to study toxicities of trastuzumab-based therapeutics. Safety studies are important in the development of antibody therapeutics and should use animal species which bind the target antigen (HER2) to understand target-mediated effects, in addition to a non-binding species to observe non-targeted effects. Trastuzumab is a clinically approved monoclonal antibody therapy which targets HER2 (or ErbB2) for treatment of HER2-overexpressing breast and gastric cancers.
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