Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks.

BACKGROUND: Approved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy. METHODS: In this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of "a little better" on the Patient Global Impression of Change scale (ratings range from "much worse" to "much better") at two or more consecutive time points within 12 hours after the first administration of the trial agent. Key secondary end points, assessed in a time-to-event analysis, were a reduction in attack severity (an improved rating on the Patient Global Impression of Severity [PGI-S] scale, with ratings ranging from "none" to "very severe") at two or more consecutive time points within 12 hours and complete attack resolution (a rating of "none" on the PGI-S scale) within 24 hours. RESULTS: A total of 136 participants were assigned to one of six trial sequences, with 110 treating 264 attacks. The time to the beginning of symptom relief with the 300-mg dose and the 600-mg dose was faster than with placebo (P<0.001 and P = 0.001 for the two comparisons, respectively), with median times of 1.61 hours (interquartile range, 0.78 to 7.04), 1.79 hours (1.02 to 3.79), and 6.72 hours (1.34 to >12), respectively. The time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P = 0.004 and P = 0.003), with median times of 9.27 hours (interquartile range, 1.53 to >12), 7.75 hours (2.19 to >12), and more than 12 hours (6.23 to >12). The time to complete resolution was faster with the 300-mg and 600-mg doses than with placebo (P = 0.002 and P<0.001). The percentage of attacks with complete resolution within 24 hours was 42.5% with the 300-mg dose, 49.5% with the 600-mg dose, and 27.4% with placebo. Sebetralstat and placebo had similar safety profiles; no serious adverse events related to the trial agents were reported. CONCLUSIONS: Oral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo. (Funded by KalVista Pharmaceuticals; KONFIDENT ClinicalTrials.gov number, NCT05259917; EudraCT number, 2021-001226-21.).

Publisher Correction: Martian dust storm impact on atmospheric H2O and D/H observed by ExoMars Trace Gas Orbiter.

The surname of author Cathy Quantin-Nataf was misspelled 'Quantin-Nata' , authors Ehouarn Millour and Roland Young were missing from the ACS Science Team list, and minor changes have been made to the author and affiliation lists; see accompanying Amendment. These errors have been corrected online.

Martian dust storm impact on atmospheric H2O and D/H observed by ExoMars Trace Gas Orbiter.

Global dust storms on Mars are rare1,2 but can affect the Martian atmosphere for several months. They can cause changes in atmospheric dynamics and inflation of the atmosphere3, primarily owing to solar heating of the dust3. In turn, changes in atmospheric dynamics can affect the distribution of atmospheric water vapour, with potential implications for the atmospheric photochemistry and climate on Mars4. Recent observations of the water vapour abundance in the Martian atmosphere during dust storm conditions revealed a high-altitude increase in atmospheric water vapour that was more pronounced at high northern latitudes5,6, as well as a decrease in the water column at low latitudes7,8. Here we present concurrent, high-resolution measurements of dust, water and semiheavy water (HDO) at the onset of a global dust storm, obtained by the NOMAD and ACS instruments onboard the ExoMars Trace Gas Orbiter. We report the vertical distribution of the HDO/H2O ratio (D/H) from the planetary boundary layer up to an altitude of 80 kilometres. Our findings suggest that before the onset of the dust storm, HDO abundances were reduced to levels below detectability at altitudes above 40 kilometres. This decrease in HDO coincided with the presence of water-ice clouds. During the storm, an increase in the abundance of H2O and HDO was observed at altitudes between 40 and 80 kilometres. We propose that these increased abundances may be the result of warmer temperatures during the dust storm causing stronger atmospheric circulation and preventing ice cloud formation, which may confine water vapour to lower altitudes through gravitational fall and subsequent sublimation of ice crystals3. The observed changes in H2O and HDO abundance occurred within a few days during the development of the dust storm, suggesting a fast impact of dust storms on the Martian atmosphere.

An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial.

BACKGROUND: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. METHODS: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 × 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. FINDINGS: Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. INTERPRETATION: Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917). FUNDING: KalVista Pharmaceuticals.

Distinct adaptation processes underlie multidigit force coordination for dexterous manipulation.

The human sensorimotor system can adapt to various changes in the environmental dynamics by updating motor commands to improve performance after repeated exposure to the same task. However, the characteristics and mechanisms of the adaptation process remain unknown for dexterous manipulation, a unique motor task in which the body physically interacts with the environment with multiple effectors, i.e., digits, in parallel. We addressed this gap by using robotic manipulanda to investigate the changes in the digit force coordination following mechanical perturbation of an object held by tripod grasps. As the participants gradually adapted to lifting the object under perturbations, we quantified two components of digit force coordination. One is the direction-specific manipulation moment that directly counteracts the perturbation, whereas the other one is the direction-independent internal moment that supports the stability and stiffness of the grasp. We found that trial-to-trial improvement of task performance was associated with increased manipulation moment and a gradual decrease of the internal moment. These two moments were characterized by different rates of adaptation. We also examined how these two force coordination components respond to changes in perturbation directions. Importantly, we found that the manipulation moment was sensitive to the extent of repetitive exposure to the previous context that has an opposite perturbation direction, whereas the internal moment did not. However, the internal moment was sensitive to whether the postchange perturbation direction was previously experienced. Our results reveal, for the first time, that two distinct processes underlie the adaptation of multidigit force coordination for dexterous manipulation.NEW & NOTEWORTHY Changes in digit force coordination in multidigit object manipulation were quantified with a novel experimental design in which human participants adapted to mechanical perturbations applied to the object. Our results show that the adaptation of digit force coordination can be characterized by two distinct components that operate at different timescales. We further show that these two components respond to changes in perturbation direction differently.

Food insecurity predicts well-being inequality.

The concept of well-being offers researchers an alternative to understanding inequality and poverty primarily through income and consumption, and recent research has emphasized the importance of examining well-being inequality. Food insecurity has been identified as an important driver of average levels of well-being; in this paper, we show it also predicts changes in the distribution of well-being. We use individual-level data from the Gallup World Poll for 135 countries between 2014 and 2017 (N = 446,741) and apply a flexible moments-based approach. We use the estimated conditional variance as a measure of inter-personal inequality in subjective well-being at the individual-level. Findings indicate that higher food insecurity is associated with higher inequality in well-being in middle- and high-income countries, but not in low-income countries. We also find that being severely food insecure correlates with peoples' well-being inequality in every income group. Understanding disparities in peoples' lives offers important, policy-relevant information that cannot be inferred from mean values alone and offers important insights to achieve SDG Goals 2 and 3 for all people.

KVD900, an oral on-demand treatment for hereditary angioedema: Phase 1 study results.

BACKGROUND: Attacks of hereditary angioedema are attributed to excessive plasma kallikrein (PKa) activity, which cleaves high-molecular-weight kininogen to generate the proinflammatory hormone bradykinin. OBJECTIVE: We evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of KVD900, an orally administered inhibitor of PKa in healthy adults. METHODS: KVD900 was administered in 2 clinical studies. In the first study, healthy adult men received single ascending doses (5-600 mg) of KVD900 capsule or placebo, single 100 mg doses of KVD900 tablet and KVD900 capsule (crossover), and single 600 mg doses of KVD900 (6 × 100 mg tablets) under fed and fasting conditions (crossover). In a second study, 3 cohorts of healthy adults were provided 600 mg of KVD900 tablets at 8-, 4-, and 2-hour intervals. RESULTS: Overall, 98 healthy participants received KVD900. All adverse events (AEs) were mild, except for a single moderate AE (headache). Exposure to KVD900 was proportional to dose. The PK parameters for KVD900 600 mg in tablet form under fasted conditions were mean (coefficient of variation) maximum plasma concentration of 6460 (22.0) ng/mL, mean (coefficient of variation) area under the curve (AUC0-24) of 18,600 (22.5) h⋅ng/mL, and median (range) time to maximum plasma concentration of 0.5 (0.33-1.5) hours. Mean PKa inhibition was essentially complete (>98%) between 20 minutes and 3 hours, and >90% inhibition was maintained for at least 8 hours after dosing. High-molecular-weight kininogen cleavage protection at the 600 mg dose was attained within 20 minutes and maintained for 8 to 10 hours. CONCLUSION: These phase 1 studies evaluated the PK/PD profile of KVD900, showing that KVD900 rapidly achieves near-complete PKa inhibition and is generally safe and well tolerated. GOV IDENTIFIER: NCT04349800.

Radiation and Dust Sensor for Mars Environmental Dynamic Analyzer Onboard M2020 Rover.

The Radiation and Dust Sensor is one of six sensors of the Mars Environmental Dynamics Analyzer onboard the Perseverance rover from the Mars 2020 NASA mission. Its primary goal is to characterize the airbone dust in the Mars atmosphere, inferring its concentration, shape and optical properties. Thanks to its geometry, the sensor will be capable of studying dust-lifting processes with a high temporal resolution and high spatial coverage. Thanks to its multiwavelength design, it will characterize the solar spectrum from Mars' surface. The present work describes the sensor design from the scientific and technical requirements, the qualification processes to demonstrate its endurance on Mars' surface, the calibration activities to demonstrate its performance, and its validation campaign in a representative Mars analog. As a result of this process, we obtained a very compact sensor, fully digital, with a mass below 1 kg and exceptional power consumption and data budget features.

Clinical Policy: Critical Issues in the Management of Adult Patients Presenting to the Emergency Department With Community-Acquired Pneumonia.

This clinical policy from the American College of Emergency Physicians is a revision of the 2009 "Clinical Policy: Critical Issues in the Management of Adult Patients Presenting to the Emergency Department With Community-Acquired Pneumonia." A writing subcommittee conducted a systematic review of the literature to derive evidence-based recommendations to answer the following clinical questions: (1) In the adult emergency department patient diagnosed with community-acquired pneumonia, what clinical decision aids can inform the determination of patient disposition? (2) In the adult emergency department patient with community-acquired pneumonia, what biomarkers can be used to direct initial antimicrobial therapy? (3) In the adult emergency department patient diagnosed with community-acquired pneumonia, does a single dose of parenteral antibiotics in the emergency department followed by oral treatment versus oral treatment alone improve outcomes? Evidence was graded and recommendations were made based on the strength of the available data.

Pharmacokinetics and Catabolism of [3H]TAK-164, a Guanylyl Cyclase C Targeted Antibody-Drug Conjugate.

TAK-164 is an antibody-drug conjugate (ADC) comprising human anti-guanylyl cyclase C (GCC) monoclonal antibody conjugated to indolinobenzodiazepine DNA alkylator IGN-P1 through a cleavable alanine-alanine dipeptide linker. TAK-164 is currently being evaluated for the treatment of gastrointestinal cancers expressing GCC. The catabolism of TAK-164 was studied using 3H-labeled ADC using GCC-expressing HEK-293 (GCC-HEK-293) cells, rat tritosomes, cathepsin B, and tumor-bearing mice. Time- and target-dependent uptake of [3H]TAK-164 was observed in GCC-HEK-293 cells with approximately 12% of radioactivity associated with DNA after 24 hours of incubation. Rat liver tritosomes and cathepsin B yielded IGN-P1 aniline, sulfonated IGN-P1 (s-IGN-P1) aniline, and a lysine conjugate of IGN-P1 (IGN-P1-Lys) aniline as catabolites. In tumor-bearing mice, [3H]TAK-164 exhibited a terminal half-life of approximately 41 and 51 hours in plasma and blood, respectively, with low plasma clearance (0.75 ml/h per kilogram). The extractable radioactivity in plasma and tumor samples revealed the presence of s-IGN-P1 aniline and IGN-P1 aniline as payload-related components. The use of a radiolabeled payload in the ADC in tumor uptake investigations provided direct and quantitative evidence for tumor uptake, DNA binding, and proof of mechanism of action of the payload. SIGNIFICANCE STATEMENT: Since payload-related species are potent cytotoxins, a thorough characterization of released products of ADCs, metabolites, and their drug interaction potential is necessary prior to clinical investigations. This study characterized in vitro and in vivo DNA binding mechanisms and released products of TAK-164. The methodologies described here will be highly useful for characterization of payload-related products of ADCs in general.

COVID-19, Food Insecurity, and Migration.

In this policy piece, we investigate the coronavirus disease 2019 (COVID-19)-food-insecurity migration channel and develop a policy agenda. The interaction between COVID-19 and the drop in economic activity will lead to increased food insecurity within and across countries. Higher food insecurity may act as a multiplier for the epidemic due to its negative health effects and increased migration. Research has shown that food insecurity affects within-country and cross-border migration. Besides the mean prevalence rate, the distribution of food insecurity affects the migration decision. The impacts of COVID-19 are particularly strong for people in the lower tail of the food-insecurity distribution. In the current context, the effect of food insecurity therefore could be increased migration, including both rural-urban migration and international migration. Importantly, the crisis might lead to a structural break in migration patterns. People might avoid heavily affected COVID-19 destination countries (e.g., United States, Italy, or Spain) and move to other countries. Due to the persistent nature of migration flows, this could have long-lasting effects.

Food insecurity, acculturation and diagnosis of CHD and related health outcomes among immigrant adults in the USA.

OBJECTIVE: To deepen understanding of the relationship between food insecurity, acculturation, and diagnosis of CHD and related health outcomes among immigrant adults. DESIGN: Using cross-sectional, nationally representative data from the National Health Interview Survey 2011 to 2015, we address two research questions. First, what is the relationship of household food insecurity and acculturation with: CHD, angina pectoris, heart attack, self-rated poor health and obesity? Second, what is the association of food insecurity with these health outcomes over years of living in the USA? We estimate multivariate logistic regressions without (question 1) and with (question 2) an interaction term between food insecurity and acculturation for CHD and related health outcomes. SETTING: USA. PARTICIPANTS: Low-income immigrant adults. RESULTS: Food insecurity and acculturation are both associated with diagnosis of CHD and related health outcomes among immigrant adults. Food insecurity and acculturation are associated with the health of female immigrants more than males. Also, the differences by food security status in the probability of having several poor health outcomes (self-rated heath, obesity, women's angina pectoris) are largest for those in the USA for less than 5 years, decrease for those who have lived in the USA for 5-14 years, and are larger again for those in the USA for 15 or more years. CONCLUSIONS: Recent and long-term food-insecure immigrants are more vulnerable to CHD and related health outcomes than those in the USA for 5-14 years. Further research is needed to understand why.

The protein kinase CK2 substrate Jabba modulates lipid metabolism during Drosophila oogenesis.

Lipid metabolism plays a critical role in female reproduction. During oogenesis, maturing oocytes accumulate high levels of neutral lipids that are essential for both energy production and the synthesis of other lipid molecules. Metabolic pathways within the ovary are partially regulated by protein kinases that link metabolic status to oocyte development. Although the functions of several kinases in this process are well established, the roles that many other kinases play in coordinating metabolic state with female germ cell development are unknown. Here, we demonstrate that the catalytic activity of casein kinase 2 (CK2) is essential for Drosophila oogenesis. Using an unbiased biochemical screen that leveraged an unusual catalytic property of the kinase, we identified a novel CK2 substrate in the Drosophila ovary, the lipid droplet-associated protein Jabba. We show that Jabba is essential for modulating ovarian lipid metabolism and for regulating female fertility in the fly. Our findings shed light on a CK2-dependent signaling pathway governing lipid metabolism in the ovary and provide insight into the long-recognized but poorly understood association between energy metabolism and female reproduction.

Food Insecurity Is More Strongly Associated with Poor Subjective Well-Being in More-Developed Countries than in Less-Developed Countries.

BACKGROUND: Food insecurity is strongly associated with subjective well-being. People compare their well-being to a subjective reference that adjusts over time, which is called hedonic adaptation. OBJECTIVE: We aimed to deepen understanding of the relation between food insecurity and subjective well-being among countries from the perspective of possible hedonic adaptation between food insecurity and subjective well-being. METHODS: Global data from the Gallup World Poll 2014 were collected from 152,206 individuals in 147 countries. Telephone and face-to-face surveys were conducted in 37 and 111 countries, respectively, collecting data on law and order; food and shelter; institutions and infrastructure; job climate; and financial, social, physical, and evaluative well-being, including the Food Insecurity Experience Scale. Data were aggregated to country level and merged with economic and social measures from World Bank and United Nations sources: infant mortality, gross domestic product, economic inequality, agricultural value added, fertility, maternal mortality, female schooling, and female participation in the labor force. Multilevel linear regression was used to examine associations between well-being and food insecurity. RESULTS: Experiencing moderate or severe food insecurity was prevalent among countries, with a mean probability of 0.273 ± 0.220. Countries that were less developed economically and socially had a higher probability of experiencing food insecurity, lower subjective well-being as measured by the daily experience index, and less negative slopes for the relation between daily experience index and food insecurity. Food insecurity was the strongest predictor of daily experience from among the measures of economic and social development. CONCLUSIONS: The prevalence of food insecurity was strongly and negatively associated with subjective well-being across 147 countries. The association between food insecurity and poor subjective well-being within countries was stronger for more-developed countries, providing evidence of hedonic adaptation between food insecurity and subjective well-being. Food insecurity explained substantial variation in subjective well-being both among and within countries.

Feeding Outcomes in Neonates With Trisomy 21 and Duodenal Atresia.

BACKGROUND: Duodenal atresia (DA), a common cause of congenital duodenal obstruction, is associated with trisomy 21. The postoperative feeding issues are not well described in this population. We hypothesize that the combination of DA and trisomy 21 is associated with the need for postoperative enteral feeding access. METHODS: A retrospective cohort of patients between 2010 and 2017 with the diagnosis of DA or duodenal stenosis was identified. Relevant prenatal and postnatal clinical data were abstracted. Univariate analyses were performed. RESULTS: Forty-three patients were identified. Nineteen patients (44%) were diagnosed with trisomy 21. Eight patients (25% with trisomy 21) had gastrostomy placed at the time of DA repair. In the remaining patients (n = 35), 40% ultimately had a gastrostomy button placed. The indications for placement included poor oral skills (n = 8), aspiration (n = 5), and failure to thrive (n = 1). All these patients had trisomy 21, resulting in 82.4% of trisomy 21 patients having a gastrostomy. There was a significant association between trisomy 21 and placement of a gastrostomy button both during index admission (P = 0.003) and lifetime (P < 0.001). All trisomy 21 patients with congenital heart disease (n = 9) had a gastrostomy placed versus only five of eight trisomy 21 patients (62.5%) without structural heart disease (P = 0.006). CONCLUSIONS: Our data suggest that a correlation exists between trisomy 21, structural congenital heart anomalies, DA, and the eventual need for gastrostomy. These data should inform operative planning for this patient population.

A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Intranasal Human Abuse Potential Study of Oxycodone ARIR, a Novel, Immediate-Release, Abuse-Deterrent Formulation.

OBJECTIVE: Prescription opioid abuse continues to be a public health concern. Oxycodone ARIR is an immediate-release (IR) oxycodone tablet composed of multiple overlapping barriers that deter manipulation of the tablet for non-oral abuse. DESIGN: This randomized, double-blind, double-dummy, active- and placebo-controlled, four-way crossover, intranasal human abuse potential study assessed the pharmacodynamics and pharmacokinetics of crushed intranasal oxycodone ARIR compared with crushed intranasal IR oxycodone and intact oral oxycodone ARIR. OUTCOME MEASURES: Pharmacodynamic end points included mean maximum drug liking (Emax), as measured by subjects on a bipolar 100-mm visual analog scale (primary), and desire to take the drug again, overall drug liking, drug high, and good effects (secondary). Pharmacokinetic assessments included peak concentration and time to peak concentration. RESULTS: Twenty-nine subjects completed the treatment phase. Crushed intranasal oxycodone ARIR demonstrated a significant reduction of 46.9% and 23.4% in drug liking Emax compared with crushed intranasal IR oxycodone and intact oral oxycodone ARIR, respectively (P < 0.0001 for both). Significant reductions also were observed in desire to take the drug again, drug high, overall drug liking, and good effects when comparing crushed intranasal oxycodone ARIR with crushed intranasal IR oxycodone and intact oral oxycodone ARIR (P < 0.001 for all). Crushed intranasal oxycodone ARIR exhibited lower peak oxycodone plasma concentrations and slower time to peak concentration compared with crushed intranasal IR oxycodone and intact oral oxycodone ARIR. All treatments were well tolerated; adverse effects were typical of opioids or intranasal administration. CONCLUSIONS: These data indicate that oxycodone ARIR has the potential to reduce abuse via the intranasal route.

Immunocapture-LC/MS-Based Target Engagement Measurement in Tumor Plasma Membrane.

For targeted therapies, immunocapture-liquid chromatography mass spectrometry (IC-LC/MS) technology has become an important tool for determination of both drug exposures, target antigen densities, and engagement in the systemic circulation and/or in total target tissue homogenates. Although the information collected from the circulation and tissue homogenates is useful in establishing the correlations of the exposure and target engagement with the pharmacodynamic response and efficacy of a therapy, the measurement at the cell plasma membrane within the target tissue is preferred, since it is the primary action site for antigen and the target drug. However, to the best of our knowledge, IC-LC/MS-based methodologies to conduct the assays at the plasma membrane from tissue sample has been quite limited. In this paper, we reported an IC-LC/MS-based assay platform for assessing the target engagement in tumor plasma membrane prepared from the tumor tissue samples. In addition, tumor samples with guanylyl cyclase C (GCC) expression after fully human IgG1 monoclonal antibody-based antibody-drug conjugate (ADC) treatment were used as a case study. The methodology can differentiate between the total and target-drug bound fraction of GCC with minimal potential equilibrium shift between in-cell surface protein and organelle protein in tumor samples to calculate in vivo target engagement. This approach to determine in vivo target engagement in tumor plasma membrane will provide better understanding of pharmacokinetic/pharmacodynamic relationship to achieve the desired antitumor efficacy.