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.     

Rifampicin reverses nicardipine effect inducing uncontrolled essential hypertension

Dihydropyridine calcium‐channel blockers are a known substrate for the cytochrome P450 isoform 3A4. Rifampicin, an antitubercular agent, is one of the most potent inducers of hepatic and intestinal CYP3A4 thus increasing dihydropyridine metabolism. We report a case of a 67‐year‐old hypertensive female treated with a four‐drug antihypertensive regimen including a dihydropyridine (nicardipine 50 mg bid), who was admitted for septic arthritis of the knee requiring antibiotic treatment with teicoplanin 400 mg od and rifampicin 600 mg bid. Six days after rifampicin initiation, she presented with Posterior Reversible Encephalopathy Syndrome due to uncontrolled hypertension. We hypothesized that disequilibrium of previously controlled hypertension was partially due to nicardipine ineffectiveness. Plasma nicardipine concentration was assessed through high‐performance liquid chromatography 5 hours after coadministration of the two drugs and proved undetectable.     

Predictors of Total Calories Purchased at Fast-food Restaurants: Restaurant Characteristics,Calorie Awareness,and Use of Calorie Information

ObjectiveTo examine purchase patterns at fast-food restaurants and their relation to restaurant characteristics, customer characteristics, and use of calorie information.DesignCross-sectional survey.SettingFast-food restaurants in New York State.ParticipantsAdult fast-food restaurant customers (n = 1,094).Variables MeasuredRestaurant characteristics (fast-food chain type, presence of calorie labels, and poverty of location), participant characteristics (demographics, calorie knowledge, awareness, and use), and customer purchasing patterns (ordering low-calorie or no beverage, small or no fries, or < 3 items) were used as predictors of total calories purchased.AnalysisMultiple regression.ResultsIn a regression model including restaurant and customer characteristics, fast-food chain customer age, sex, calorie use, and calorie awareness were independently associated with total calories purchased (all P < .05; model R² = .19). When 3 purchasing patterns were added to the model, calorie use (P = .005), but not calorie awareness, remained associated with total calories purchased. The 3 purchase patterns collectively accounted for the majority of variance in calorie totals (Δ model R² = .40).Conclusions and ImplicationsPromoting use of calorie information, purchase strategies, and calorie awareness represents complementary ways to support lower-calorie choices at fast-food chains.     

New Definition Criteria of Myocardial Dysfunction in Patients with Liver Cirrhosis: A Speckle Tracking and Tissue Doppler Imaging Study

There are no clear recommendations regarding cirrhotic cardiomyopathy (CC) evaluation in patients with pre-transplant liver cirrhosis. The roles of new methods, tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE) in the diagnosis and prognosis of cirrhotic cardiomyopathy remain controversial. We investigated the utility of TDI/STE parameters in cirrhotic cardiomyopathy diagnosis and also in predicting mortality in patients with liver cirrhosis. Left/right ventricular function was studied using conventional TDI (velocities) and STE (strain/strain rate). We assessed left ventricular diastolic dysfunction, graded into four new classes (I/Ia/II/III). Serum NTproBNP (N-terminal prohormone of brain natriuretic peptide), troponin I, β-crosslaps, QTc interval, arterial compliance and endothelial function were measured. Liver-specific scores (Child–Pugh, MELD, MELDNa) were computed. There was a 1-y follow-up visit to determine mortality. We observed resting biventricular diastolic myocardial dysfunction, not presently included in the definition of cirrhotic cardiomyopathy. We provided an improved characterization of cardiac dysfunction in patients with liver cirrhosis. This might change the current definition. However, the utility of STE/TDI parameters in predicting long-term mortality in patients with liver cirrhosis remains controversial.     

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.