serine threonine protein kinase Insight into how antibodies
Insight into how serine threonine protein kinase alter the kinetics of clearance of ADAMTS13 perhaps has more profound and immediate implications. ADAMTS13 has a relatively long active plasma half-life of 2–3days (Furlan et al., 1999), suggesting its baseline rate of clearance is normally relatively slow. As over 70% of the TTP patients\' samples that we analysed had no or low inhibitory potential, this could suggest that provision of recombinant ADAMTS13 to acquired TTP patients may not result in rapid inhibition of the enzyme in an appreciable proportion of patients. If the autoantibodies in these patients are non-inhibitory and their enhancement of clearance is not very rapid (which seems unlikely), this may allow recombinant ADAMTS13 a window of therapeutic benefit in these patients, and potentially reduce the number of PEX required to achieve remission.
Role of the Funding Source
Conflict of Interest Disclosures
Acknowledgements The authors thank Dr Richard Syzdlo, Imperial College London, UK, for assistance with statistical analyses; Dr Vickie McDonald, Guys and St Thomas\' NHS Foundation Trust, UK, for clinical and basic laboratory data, and Ms Katy Langley, University College London, UK, for assistance with routine ADAMTS13 assays. We thank Dr Hendrik Feys and Prof Karen Vanhoorelbeke (KU Leuven, Belgium) for provision of mAb 3H9. This work was supported by British Heart Foundation Clinical Fellowship (London, United Kingdom) grant FS/10/13/28073 awarded to MRT, MAS and JTBC. The funding source had no involvement in the study design; data collection, analysis and interpretation; the writing of the manuscript; and the decision to submit the article for publication.
Introduction Trastuzumab (Herceptin®) is widely and successfully used in the treatment of patients with solid tumours overexpressing the human epidermal growth factor receptor-2 (HER2, also known as ErbB2) most notably with mamma carcinoma or metastatic gastric cancer. Notwithstanding its widespread use in oncology, trastuzumab is feared for its association with cardiotoxic side effects, occurring in 1–7% of treated patients, depending on the concomitant and previous chemotherapeutic regimens (Garcia-Alvarez et al., 2010; Seidman et al., 2002). The exact mechanism by which trastuzumab causes cardiac side effects is not completely unravelled. Existing evidence suggests that interaction with the HER2-signalling pathway by trastuzumab in cardiomyocytes, induces apoptosis, and interferes with cell survival mechanisms (Fuller et al., 2008; Gordon et al., 2009; Riccio et al., 2009). Compatible with these in vitro findings, electron microscopy evaluation of endocardial biopsies from patients who developed trastuzumab-associated cardiomyopathy showed ultrastructural changes in the mitochondria (Guarneri et al., 2006). It is, however, unknown how these findings translate into clinical practice. The main reason for this uncertainty is that trastuzumab is often administered in an adjuvant setting, in combination with or after previous use of radiation therapy or cytostatics with untoward cardiac effects, such as anthracyclines. Furthermore, trastuzumab is used in a heterogeneous population regarding gender, age, and co-morbidities. Seemingly, therefore, exploring trastuzumab in a homogenous population of healthy subjects could be of value to further delineate its cardiac effects and its time. We recently performed a bio-equivalence trial in which the currently approved formulation of trastuzumab (Herceptin®) was compared with a trastuzumab drug product under development, code-named FTMB (Wisman et al., 2014). Aside from establishing bio-equivalence, serial assessments of echocardiographic measurements, body weight and laboratory parameters such as the N-terminal pro-peptide of B-type natriuretic peptide (NT-proBNP) were included in the trial design, both to safeguard the participant\'s well-being and to investigate the (cardiotoxic) side effects of trastuzumab. The aim of the analysis presented in this article was to compare the registered form of trastuzumab (Herceptin®) with placebo in healthy volunteers, in terms of the assessments of cardiac function, and thus to cardiotoxicity.