Background: Sarilumab is the first fully human monoclonal antibody (mAb) directed against the interleukin-6 receptor alpha (IL-6Rα). Sarilumab was developed using VelocImmune ® mice immunized with the human IL-6 (hIL-6) receptor. VelocImmune mice are genetically-engineered to express human antibody variable domain genes in the same robust fashion that the replaced mouse genes are typically expressed. Sarilumab is currently being explored as a new therapeutic modality for the treatment of rheumatoid arthritis. Objectives: To evaluate the kinetic binding parameters and in vitro functional activity of two monoclonal antibodies directed against IL-6Rα: the fully human mAb sarilumab and the humanized mAb tocilizumab. Methods: Kinetic binding parameters were measured using Surface Plasmon Resonance (SPR) technology. The ability to block hIL-6 induced activation of the human IL-6Rα was investigated using several bioassays; a human hepatocellular carcinoma cell line HepG2, transfected with a STAT3-luciferase reporter plasmid, as well as a proliferation assay using the human B-lymphoma cell line, DS-1. Results: Sarilumab bound with high affinity to recombinant monomeric human and monkey IL-6 receptor with a K D value of 61.9 pM and 71.9 pM, respectively. The binding affinity of sarilumab to the dimeric human IL-6 receptor Fc-fusion was 12.8 pM. Cross-reactivity to mouse IL-6 receptor was not observed using SPR, indicating that sarilumab is specific to human and monkey IL-6 receptor. In contrast, tocilizumab bound to monomeric and dimeric forms of the human IL-6 receptor with a 15-22 fold weaker affinity than that of sarilumab as determined by SPR. In the HepG2 cell luciferase reporter assay, sarilumab effectively blocked luciferase activity induced by 50 pM hIL-6 with an IC 50 of 146 pM and was ~4 fold more potent than tocilizumab. Similarly, in the DS-1 cell proliferation assay, sarilumab effectively blocked growth induced by 1.0 pM hIL-6 with an IC 50 of 226 pM and was several fold more potent than tocilizumab. Conclusions: Based on these in vitro assay data, sarilumab has both a higher relative binding affinity for IL-6Rα, blocks IL-6Rα activation, and inhibits IL-6-induced cellular responses such as cell proliferation at lower concentrations than tocilizumab. Acknowledgements: VelocImmune ® is a registered trademark of Regeneron Pharmaceuticals, Inc.

Our meta-analysis suggests that the UCP2 -866G/A polymorphism is unlikely to be associated with increased type 2 diabetes risk in the populations investigated. In contrast, our results indicate that the UCP2 Ala55Val and UCP3 -55C/T polymorphisms may indeed be risk factors for susceptibility to type 2 diabetes in individuals of Asian descent, but not in individuals of European descent. This conclusion warrants confirmation by further studies.

Aims/hypothesis We aimed to evaluate the effect of the mutant Wld S (slow Wallerian degeneration; also known as Wld) gene in experimental diabetes on early experimental peripheral diabetic neuropathy and diabetic retinopathy.Methods The experiments were performed in four groups of mice: wild-type (WT), streptozotocin (STZ)-induced diabetic WT, C57BL/Wld S and STZ-induced diabetic C57BL/Wld S . In each group, intraperitoneal glucose and insulin tolerance tests were performed; blood glucose, glycated haemoglobin and serum insulin were monitored. These mice were also subjected to the following behavioural tests: grasping test, hot-plate test and von Frey aesthesiometer test. For some animals, sciatic-tibial motor nerve conduction velocity, tail sensory nerve conduction velocity and eye pattern electroretinogram were measured. At the end of the experiments, islets were isolated to detect glucose-stimulated insulin secretion, ATP content and extent of apoptosis. The NAD/NADH ratio in islets and retinas was evaluated. Surviving retinal ganglion cells were estimated by immunohistochemistry. Results We found that the Wld S gene is expressed in islets and protects beta cells against multiple low doses of STZ by increasing the NAD/NADH ratio, maintaining the ATP concentration, and reducing apoptosis. Consistently, significantly higher insulin concentrations, lower blood glucose concentrations, and better glucose tolerance were observed in Wld S mice compared with WT mice after STZ treatment. Furthermore, Wld S alleviated abnormal sensory responses, nerve conduction, retina dysfunction and reduction of surviving retinal ganglion cells in STZinduced diabetic models. Conclusions/interpretation We provide the first evidence that expression of the Wld S gene decreases beta cell destruction and preserves islet function in STZ-induced diabetes, thus revealing a novel protective strategy for diabetic models.