The preclinical pharmacology of the high affinity anti-IL-6R Nanobody (R) ALX-0061 supports its clinical development in rheumatoid arthritis

Introduction: The pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of different diseases, including rheumatoid arthritis (RA). ALX-0061 is a bispecific Nanobody (R) with a high affinity and potency for IL-6 receptor (IL-6R), combined with an extended half-life by targeting human serum albumin. We describe here the relevant aspects of its in vitro and in vivo pharmacology. Methods: ALX-0061 is composed of an affinity-matured IL-6R-targeting domain fused to an albumin-binding domain representing a minimized two-domain structure. A panel of different in vitro assays was used to characterize the biological activities of ALX-0061. The pharmacological properties of ALX-0061 were examined in cynomolgus monkeys, using plasma levels of total soluble (s)IL-6R as pharmacodynamic marker. Therapeutic effect was evaluated in a human IL-6-induced acute phase response model in the same species, and in a collagen-induced arthritis (CIA) model in rhesus monkeys, using tocilizumab as positive control. Results: ALX-0061 was designed to confer the desired pharmacological properties. A 200-fold increase of target affinity was obtained through affinity maturation of the parental domain. The high affinity for sIL-6R (0.19 pM) translated to a concentration-dependent and complete neutralization of sIL-6R in vitro. In cynomolgus monkeys, ALX-0061 showed a dose-dependent and complete inhibition of hIL-6-induced inflammatory parameters, including plasma levels of C-reactive protein (CRP), fibrinogen and platelets. An apparent plasma half-life of 6.6 days was observed after a single intravenous administration of 10 mg/kg ALX-0061 in cynomolgus monkeys, similar to the estimated expected half-life of serum albumin. ALX-0061 and tocilizumab demonstrated a marked decrease in serum CRP levels in a non-human primate CIA model. Clinical effect was confirmed in animals with active drug exposure throughout the study duration. Conclusions: ALX-0061 represents a minimized bispecific biotherapeutic of 26 kDa, nearly six times smaller than monoclonal antibodies. High in vitro affinity and potency was demonstrated. Albumin binding as a half-life extension technology resulted in describable and expected pharmacokinetics. Strong IL-6R engagement was shown to translate to in vivo effect in non-human primates, demonstrated via biomarker deregulation as well as clinical effect. Presented results on preclinical pharmacological properties of ALX-0061 are supportive of clinical development in RA

Hybrid life cycle inventory methods – A review

A variety of methods can be used to compile a life cycle inventory (LCI) as part of a life cycle assessment (LCA) study. Hybrid LCI methods attempt to address the limitations inherent in more traditional process and input-output (IO) LCI methods. This paper provides an overview of the different hybrid LCI methods currently in use in an attempt to provide greater clarity around how each method is applied and their specific strengths and weaknesses. A search of publications quoting the use of hybrid LCI was undertaken for the period from 2010 to 2015, identifying 97 peer-reviewed publications referencing the use of a hybrid LCI. In over one third of the literature analysed, authors only refer to their analysis as a hybrid LCI, without naming the actual method used, making it difficult to fully understand which method was used and any potential limitations. Based on the way in which the various hybrid methods are applied and their existing use, the authors propose a set of clear definitions for existing hybrid LCI methods. This assists in creating a better understanding of, and confidence in, applying hybrid LCI methods amongst LCA practitioners, potentially leading to a greater uptake of hybrid LCI

Robust Optimization of a Permanent Magnet Synchronous Machine Considering Uncertain Driving Cycles

This work focuses on the robust optimization of a permanent magnet (PM) synchronous machine while considering a driving cycle. The robustification is obtained by considering uncertainties of different origins. Firstly, there are geometrical uncertainties caused by manufacturing inaccuracies. Secondly, there are uncertainties linked to different driving styles. The final set of uncertainties is linked to ambient parameters such as traffic and weather conditions. The optimization goal is to minimize the PM's volume while maintaining a desired machine performance measured by the energy efficiency over the driving cycle and the machine's maximal torque. The magnetic behavior of the machine is described by a partial differential equation (PDE) and is simulated by the finite-element method employing an affine decomposition to avoid reassembling of the system of equations due to the changing PM geometry. The Sequential Quadratic Programming algorithm is used for the optimization. Stochastic collocation is applied to compute moments of stochastic quantities. The robustness of the optimized configurations is validated by a Monte Carlo sampling. It is found that the uncertainties in driving style and road conditions have significant influence on the optimal PM configuration.Comment: 5 pages, 4 figures, 2 tables, Compumag 2019 conferenc