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AIMS: This study describes the pharmacokinetic (PK)/target engagement (TE) relationship of tozorakimab, an anti-interleukin (IL)-33 antibody, by building a mechanistic population PK/TE model using phase 1 biomarker data. METHODS: The analysis included tozorakimab PK and TE in serum assessed in 60 tozorakimab-treated participants, including healthy adults and patients with mild chronic obstructive pulmonary disease. Scenarios evaluated three dose frequencies (once every 2, 4 or 6 weeks) administered subcutaneously at seven doses of tozorakimab (30, 60, 90, 120, 150, 300 or 600 mg). For each dose, simulations were performed with 5000 virtual individuals to predict systemic TE. Inhibition of IL-33/soluble ST2 (sST2) complex levels at trough PK at steady state was assessed in each dosing scenario. The PK/TE modelling analyses were performed using a nonlinear mixed-effect modelling approach. RESULTS: The final two-compartment PK model with tozorakimab binding IL-33 in the central compartment adequately described the systemic PK and TE of tozorakimab at population and individual levels. The mean PK parameter estimates of absorption rate, central volume of distribution and clearance were 0.48 (90% confidence interval [CI]: 0.40-0.59, 1/day), 12.64 (90% CI: 8.60-18.62, L) and 0.87 (90% CI: 0.65-1.16, L/day), respectively. Consistent with the observed value, tozorakimab bioavailability was 45%. For all three dose frequencies, predicted inhibition of systemic IL-33/sST2 levels was more than 95% at doses greater than 90 mg. CONCLUSIONS: The PK/TE model reliably quantified the relationship between PK and systemic TE of tozorakimab, with potential utility for predicting clinical dose-response relationships and supporting clinical dose selection.

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Tozorakimab is a human monoclonal antibody that neutralizes interleukin (IL)-33. IL-33 is a broad-acting epithelial "alarmin" cytokine upregulated in lung tissue of patients with chronic obstructive pulmonary disease (COPD). This first-in-human, phase I, randomized, double-blind, placebo-controlled study (NCT03096795) evaluated the safety, tolerability, pharmacokinetics (PKs), immunogenicity, target engagement, and pharmacodynamics (PDs) of tozorakimab. This was a 3-part study. In part 1, 56 healthy participants with a history of mild atopy received single escalating doses of either intravenous or subcutaneous tozorakimab or placebo. In part 2, 24 patients with mild COPD received multiple ascending doses of subcutaneous tozorakimab or placebo. In part 3, 8 healthy Japanese participants received a single intravenous dose of tozorakimab or placebo. The safety data collected included treatment-emergent adverse events (TEAEs), vital signs, and clinical laboratory parameters. Biological samples for PKs, immunogenicity, target engagement, and PD biomarker analyses were collected. No meaningful differences in the frequencies of TEAEs were observed between the tozorakimab and placebo arms. Three tozorakimab-treated participants with COPD experienced treatment-emergent serious adverse events. Subcutaneous or intravenous tozorakimab demonstrated linear, time-independent PKs with a mean half-life of 11.7-17.3 days. Treatment-emergent anti-drug antibody frequency was low. Engagement of tozorakimab with endogenous IL-33 in serum and nasal airways was demonstrated. Tozorakimab significantly reduced serum IL-5 and IL-13 levels in patients with COPD compared with placebo. Overall, tozorakimab was well tolerated, with a linear, time-independent serum PK profile. Additionally, biomarker studies demonstrated proof of mechanism. Overall, these data support the further clinical development of tozorakimab in COPD and other inflammatory diseases.

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PURPOSE: Proliferation of T-follicular helper (TFH) CD4+ T cells is a postulated pathogenic mechanism for T-cell non-Hodgkin lymphomas (T-NHL). The inducible T-cell costimulator (ICOS) is highly expressed by TFH, representing a potential target. MEDI-570 is a monoclonal antibody against ICOS, which eliminates ICOS+ cells in preclinical models. PATIENTS AND METHODS: We report the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of MEDI-570 in T-NHL. NCI-9930 is a phase I, first-in-human study of MEDI-570 in relapsed/refractory malignant T-NHL known to express ICOS. MEDI-570 was administered intravenously every 3 weeks for up to 12 cycles. Primary endpoints were safety, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D). Secondary and exploratory endpoints included efficacy parameters and various correlative studies. This study is supported by the National Cancer Institute (NCT02520791). RESULTS: Twenty-three patients were enrolled and received MEDI-570 at five dose levels (0.01-3 mg/kg). Sixteen (70%) had angioimmunoblastic T-cell lymphoma (AITL); median age was 67 years (29-86) and the median prior lines of therapies was 3 (1-16). Most common grade 3 or 4 adverse events were decreased CD4+ T cells (57%), lymphopenia (22%), anemia (13%), and infusion-related reactions (9%). No DLTs were observed. The RP2D was determined at 3 mg/kg. Analysis of T-cell subsets showed reductions in CD4+ICOS+ T cells reflecting its effects on TFH cells. The response rate in AITL was 44%. CONCLUSIONS: MEDI-570 was well tolerated and showed promising clinical activity in refractory AITL. MEDI-570 resulted in sustained reduction of ICOS+ T lymphocytes.

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Development of biotherapeutics require pharmacokinetic/pharmacodynamic (PK/PD) and immunogenicity assays that are frequently in a ligand-binding assay (LBA) format. Conjugated critical reagents for LBAs are generated conjugation of the biotherapeutic drug or anti-drug molecule with a label. Since conjugated critical reagent quality impacts LBA performance, control of the generation process is essential. Our perspective is that process development methodologies should be integrated into critical reagent production to understand the impact of conjugation reactions, purification techniques and formulation conditions on the quality of the reagent. In this article, case studies highlight our approach to developing process conditions for different molecular classes of critical reagents including antibodies and a peptide. This development approach can be applied to the generation of future conjugated critical reagents.

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Intimate partner violence (IPV) is a worldwide epidemic that has been prevalent in society since biblical times. IPV affects women long after the abuse stops, with victims of IPV having generalized worsening of health, including depression and increased thoughts of suicide and suicide attempts. It is not uncommon for victims of IPV to be killed by their partner. Through regular screening and education clinicians can detect the violence before it is too late. Health care professionals have a unique opportunity to stop the cycle of abuse by intervening, promoting safety, and preventing the death of IPV victims.

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Biotherapeutic proteins induce undesired immune responses that can affect drug efficacy and safety. For this reason, immunogenicity assessment is an integral part of drug development and is mandated by the regulatory authorities. Immunogenicity is typically evaluated by a tiered approach consisting of a screening assay followed by a competitive inhibition with unlabeled drug serving as confirmatory assay and additional characterization of the immune response. The confirmatory assay is intended to reduce the number of false positive responses generated in the screening tier and ensure that all samples are correctly classified as positive or negative. The positive-negative sample decisions are based on screening and confirmatory assay cut points that are statistically derived through evaluation of drug-naive samples. In this paper, we describe the analysis of cut point data for the presence of statistical correlation between the screening and confirmatory results. Data were obtained from validations of solution-phase bridging assays for detection of anti-drug antibodies against monoclonal antibody therapeutics. All data sets showed moderate to strong positive correlation, indicating that the screening and confirmatory assays were not independent and were likely to generate similar information. We present theoretical evidence that correlated results may be a general feature of the tiered approach when the same test platform is used for both screening and confirmatory assays. The competitive inhibition test, therefore, may be of limited value beyond reduction of the overall false positive rate. Our results indicate that similar sample results could be obtained by using just the screening assay with the false positive rate set to 1%.

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This study investigated the role of executive function in relation to aggression in a sample of children (N = 93) aged 9 to 15 years. Based on parent ratings of aggression, the sample was divided into low- (n = 66) and high- (n = 27) aggression groups. Although the groups did not differ significantly on laboratory measures of executive function, significant differences emerged on behavioral regulation and metacognition ratings by parents. Notably, a high level of behavioral dysregulation was predictive of placement in the high-aggression group; both good metacognitive skills and behavior regulation served as significant predictors of prosocial and adaptive skills.

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BACKGROUND: Although intimate partner violence (IPV) is the leading cause of serious injury and the second leading cause of death among reproductive age women in America, effective screening is difficult. Our institution currently screens for IPV during the floor intake assessment by having a registered nurse (RN) ask three unscripted questions about physical, verbal, and sexual abuse during a battery of 81 questions. The patients are frequently in pain, medicated, distraught, or intoxicated, and the RN is juggling multiple responsibilities. We also use a protocol-driven alcohol abuse screen on every trauma admission known as "Screening, Brief Intervention, and Referral for Treatment" (SBIRT). It is conducted by trained counselors when any effects of alcohol are gone in a distraction-free setting after patients have had time to ruminate on their admission. We hypothesized that linking the validated partner violence screening (PVS) to SBIRT would result in higher rates of positive IPV screens than after RN screens. METHODS: This prospective trial was conducted at an urban Level I center. English- and Spanish-speaking female trauma patients underwent the three-question, nonvalidated RN-screen on floor arrival per the local standard of care. Before discharge, they then underwent SBIRT screening per trauma service protocol, after which SBIRT administered the PVS as our investigative intervention. All screens were native language. SBIRT screeners were blinded to the results of the earlier RN screen. If an SBIRT or RN screen was not performed for any reason, it was categorized as a negative screen. Admissions to the surgical intensive care unit had both screens delayed until floor transfer. McNemar's exact test was used for paired categorical data and Fisher's exact test otherwise. Significance was set at an alpha of 0.05. RESULTS: One hundred twenty-five consecutive female inpatients (mean age, 40.9 years±17.7 years; Injury Severity Score, 9.8±7.5) were enrolled, with 14 (11.2%) screening positive for one or both methods. The SBIRT-linked screen was significantly better at detecting IPV than the RN screen (p=0.01). No association was found between the likelihood of giving a discordant response to the two IPV screens and acute alcohol intoxication or polysubstance abuse at the time of admission, being a Spanish-only speaker, or if the initial admission was directly to the surgical intensive care unit. Despite being mandatory on intake, 23 of 125 patients (18.4%) had no RN screen performed, with 2 of these patients screening positive for IPV by SBIRT personnel. CONCLUSION: Linking an IPV screen to an established alcohol abuse screen results in higher rates of detection of IPV than screening by RNs at intake assessment. At our institution, adoption of this practice should result in detecting and referring ∼85 additional female trauma inpatients per year for IPV services.

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This study applied a social identity perspective to the study of adolescent self-concept and social development. British adolescents aged 14-15 years (N=114) completed a questionnaire which asked them to: (i) rate their degree of identification with a school-based friendship group; (ii) complete a measure of multi-dimensional self-concept; and (iii) report their experiences of a variety of personal, relational and socio-institutional (e.g., achieving economic independence) developmental tasks. Compared to low identifiers, participants who were highly identified with a friendship group reported highest levels of self-esteem; and these differences were most marked in non-academic domains of self. High identifiers also displayed higher levels of general self-esteem and reported more positive experiences of personal and relational developmental tasks. The discussion focuses on the potential benefits to understanding of social developmental processes that can be derived from a consideration of adolescents' subjective appraisals of their peer relations.

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There has been much interest in the genetics of attention deficit hyperactivity disorder and molecular genetic studies are now underway. The success of genetic studies will depend on how well the phenotype is defined. Twin studies using parent and teacher rated questionnaires or interviews all appear to yield highly heritable measures. Nevertheless, there is evidence to suggest that parent measures are subject to rater bias. Consequently there has been much interest in obtaining more objective measures of related traits such as attention span and impulsiveness using, computerised neuropsychological tasks. However there have been few twin studies examining the genetic contribution to these neuropsychological measures. The present study aims to investigate whether performance on the Matching Familiar Figures Test (MFFT) and Continuous Performance Task (CPT) is genetically influenced in childhood. 20 monozygotic (MZ) and 20 dizygotic (DZ) twin pairs were randomly selected from the Greater Manchester Twin Register. Preliminary data suggest that MZ twins perform more similarly than DZ twins on the MFFT, but not the CPT. Future work needs to examine whether other neuropsychological measures commonly used in research on ADHD are genetically influenced using larger twin samples.

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