Managing the Impact of Immunogenicity in an Era of Immunotherapy: From Bench to Bedside

Biotherapeutics have revolutionized our ability to treat life-threatening diseases. Despite clinical success, the use of biotherapeutics has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs). The multifactorial nature of immunogenicity has prevented a standardized approach for assessing this and each of the assessment methods developed so far does not exhibit high enough reliability to be used alone, due to limited predictiveness. This prompted the Roche Pharma Research and Early Development (pRED) Immunogenicity Working Group to establish an internal preclinical immunogenicity toolbox of in vitro/in vivo approaches and accompanying guidelines for a harmonized assessment and management of immunogenicity in early development. In this article, the complex factors influencing immunogenicity and their associated clinical ramifications are discussed to highlight the importance of an end-to-end approach conducted from lead optimization to clinical candidate selection. We then examine the impact of the resulting lead candidate categorization on the design and implementation of a multi-tiered ADA/immunogenicity assay strategy prior to phase I (entry into human) through early clinical development. Ultimately, the Immunogenicity Toolbox ensures that Roche pRED teams are equipped to address immunogenicity in a standardized manner, paving the way for lifesaving products with improved safety and efficacy.     

在线继续医学教育对医生知识、态度和行为的效果

有越来越多的医生选择学习在线课程来进行继续医学教育,但却很少有严格的评估方法来确定在线继续医学教育活动的效果.鉴于此,美国阿拉巴马大学医学院继续医学教育部的研究人员进行了相关研究.应用时间序列设计的方法,来比较完成了继续医学教育网站提供的任意30分钟在线继续医学教育课程的医生在教育活动前后其知识、态度和自我报告的在临床实践中诊疗行为的变化.     

Birth Weight and Risk Factors for Cardiovascular Disease and Type 2 Diabetes in US Children and Adolescents: 10 Year Results from NHANES

Previous studies have shown that birth weight and other birth characteristics may be associated with risk for type 2 diabetes and cardiovascular disease (CVD) later in life; however, results using large US national survey data are limited. Our goal was to determine the aforementioned associations using nationally representative data. We studied children and adolescents 6–15 years using data from the National Health and Nutrition Examination Survey cycles 2001–2010. Survey and examination data included demographic and early childhood characteristics, current health status, physical activity information, anthropometric measurements, dietary data (total energy, saturated fat, sodium, and sugar intakes), biomarkers related to selected risk factors of CVD [systolic blood pressure (SBP), plasma C-reactive protein (CRP) and lipid profiles], and type 2 diabetes [fasting glucose, insulin, and homeostasis model assessment (HOMA)]. Birth weight (proxy-reported) was inversely associated with SBP among girls; SBP levels increased 1.4 mmHg for each 1,000 g decrease in birth weight (p = 0.003) after controlling for potential confounders. Birth weight was not associated with levels of CRP or lipid profiles across the three racial groups. In addition, birth weight was inversely related to levels of fasting insulin and HOMA among non-Hispanic Whites; for each 1,000 g decrease in birth weight, fasting insulin levels increased 9.1 % (p = 0.007) and HOMA scores increased 9.8 % (p = 0.007). Birth weight was inversely associated with the levels of SBP, fasting insulin, and HOMA. These results support a role for birth weight, independent of the strong effects of current body weight status, in increasing risk for CVD and type 2 diabetes.     

Effect of underlying disease and age on pneumococcal serotype distribution

The hospital records of 264 patients with 277 episodes of pneumococcal bacteremia occurring at New York Hospital-Cornell Medical Center over the period 1970 to 1980 were examined to determine whether serotype distribution varied with the underlying disease or age of the patient. The patients were placed into three groups according to their underlying disease. Group A consisted of all patients with significant impairment of their immune system. Group B included those patients with underlying conditions that were not associated with immune deficiency. Group C comprised those patients considered to be normal hosts. Overall, 84 percent of blood isolates were serotypes included in the vaccine. In Group A, only 73 percent of these isolates were vaccine types, compared with 85 percent in Group B and 97 percent in Group C (differences significant at p < 0.001). Vaccine serotypes were more common in children than adults (92 versus 81 percent), but in analysis that controlled for underlying disease, the elderly did not differ from younger adults in serotype distribution. The apparent predilection of nonvaccine serotypes to cause bacteremia in immunocompromised patients may be one factor limiting vaccine efficacy in this high-risk population.     

Intestinal pseudo-obstruction as an initial presentation of systemic sclerosis in two children

Two children are reported in whom intestinal pseudo-obstruction was the initial manifestation of systemic sclerosis. Gastrointestinal symptoms and skin changes resolved or improved in both children following treatment with prednisone and penicillamine (case 1) or methotrexate (case 2), although radiological changes of the gastrointestinal tract persisted at 3 and 2 yr of follow-up, respectively.      

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.