Preclinical development of molecular imaging antibodies targeting the ZnT8 protein for the diagnosis and follow-up of diabetes – SAFE-BETA

Diabetes results from an absolute or relative decline in pancreatic beta cell mass (BCM) leading to insufficient insulin secretion and hyperglycemia. In type 1 diabetes, hyperglycemia occurs when the beta cells are selectively destroyed by an autoimmune process. In type 2 diabetes, metabolic stress results in insulin resistance and increased insulin demand. Measurement of insulin secretory capacity is currently used as a surrogate measure of BCM, an imprecise reflection of BCM. Because the pancreas is a heterogeneous hard-to-biopsy organ, there is no reliable measure of BCM available: it is currently not possible to distinguish reliably between anatomical versus functional defects of insulin secretion. There are major efforts to develop strategies for the in vivo imaging of pancreatic BCM as a clinical and investigational tool. Imaging agents are needed that are specific for the beta cell or its function.
According to the World Health Association (WHO), the current rates of diabetes are at epidemic levels. In 1985, an estimated 30 million people worldwide had diabetes, and that number continues to grow. The number was up to 135 million by 1995, and by 2005 it was estimated at 217 million. By 2030, the WHO predicts that at least 366 million people will be affected. The increasing prevalence of T2DM will fuel most of this growth - the increasing prevalence of T2D parallels that of obesity, defined as a body mass index over 30 kg•m-2 (11,3% en 2003), a condition frequently associated with T2D - but a dramatic increase in the incidence of T1D is also seen.
Diabetes accounts for approximately 10% of the total healthcare budget in many countries, as in the USA and in France. The American Diabetes Association has estimated that the total cost of diabetes in the United States in 2002 was approximately $132 billion. Costs could rise as high as $192 billion by 2020. Therefore, improvements in basic knowledge in diabetes, new biomarkers for clinical classification and therapeutic stratification in its different forms and new therapeutic strategies are urgently needed to improve the lives of diabetic patients and reduce the skyrocketing costs associated with the disease. This requires an increased ability to identify people before they become fully hyperglycemic, new ways to monitor therapy, and a greater understanding of the pathogenesis and natural history of diabetes.

SAFE-BETA builds an innovative approach related to the discovery of the zinc transporter ZnT8, a new diabetes biomarker specifically expressed in the pancreatic islet and mainly in the beta cells. ZnT8 has 2 extracellular loops which showed to be reachable by antibodies, thus enabling to image beta cells while they are secreting insulin. MELLITECH is the expert in ZnT8 modulators identification and ZnT8 potential as a target for BCM evaluation. Gathering this ZnT8 expertise and the knowledge of its partners in the fields of diabetes (INSERM U986 & U859), immunology (CEA/SPI & INSERM U986) and optical/SPECT imaging (UJF/INSERM U823 & U877), the consortium aims at developing an antibody-based imaging technology targeting a protein which is highly islet-specific and mainly expressed in the beta cell: the ingredients are here to overcome the challenge of functional beta cell sorting and to provide new tools for treatment optimization and therapeutic orientation/follow-up in order to better prevent and treat diabetes.