Target-Mediated Drug Disposition Affects the Pharmacokinetics of Interleukin-10 Fragment Crystallizable Fusion Proteins at Pharmacologically Active Doses.

Fragment crystallizable (Fc) fusion is commonly used for extending the half-life of biotherapeutics such as cytokines. In this work, we studied the pharmacokinetics of Fc-fused interleukin-10 (IL-10) proteins that exhibited potent antitumor activity in mouse syngeneic tumor models. At pharmacologically active doses of ≥0.1 mg/kg, both mouse Fc-mouse IL-10 and human Fc-human IL-10, constructed as the C terminus of the Fc domain fused with IL-10 via a glycine-serine polypeptide linker, exhibited nonlinear pharmacokinetics after intravenous administration to mice at the doses of 0.05, 0.5, and 5 mg/kg. With a nominal dose ratio of 1:10:100; the ratio of the area under the curve for mouse Fc-mouse IL-10 and human Fc-human IL-10 was 1:181:1830 and 1:75:633, respectively. In contrast, recombinant mouse or human IL-10 proteins exhibited linear pharmacokinetics in mice. Compartmental analysis, using the Michaelis-Menten equation with the in vitro IL-10 receptor alpha binding affinity inputted as the Km, unified the pharmacokinetic data across the dose range. Additionally, nontarget-mediated clearance estimated for fusion proteins was ∼200-fold slower than that for cytokines, causing the manifestation of target-mediated drug disposition (TMDD) in the fusion protein pharmacokinetics. The experimental data generated with a mouse IL-10 receptor alpha-blocking antibody and a human Fc-human IL-10 mutant with a reduced receptor binding affinity showed significant improvements in pharmacokinetics, supporting TMDD as the cause of nonlinearity. Target expression and its effect on pharmacokinetics must be determined when considering using Fc as a half-life extension strategy, and pharmacokinetic evaluations need to be performed at a range of doses covering pharmacological activity. SIGNIFICANCE STATEMENT: Target-mediated drug disposition can manifest to affect the pharmacokinetics of a fragment crystallizable (Fc)-fused cytokine when the nontarget-mediated clearance of the cytokine is decreased due to neonatal Fc receptor-mediated recycling and molecular weight increases that reduce the renal clearance. The phenomenon was demonstrated with interleukin-10 Fc-fusion proteins in mice at pharmacologically active doses. Future drug designs using Fc as a half-life extension approach for cytokines need to consider target expression and its effect on pharmacokinetics at relevant doses.

Criminal legal involvement among recently separated veterans: Findings from the LIMBIC study.

OBJECTIVE: This study investigated individual-level and neighborhood-level predictors of criminal legal involvement of veterans during the critical transition period from military to civilian life. HYPOTHESES: We hypothesized that substance use, mental health, and personality disorders will increase the incidence of criminal legal involvement, which will be highest among veterans living in socioeconomically disadvantaged neighborhoods after military discharge. METHOD: We analyzed data from a longitudinal cohort study of 418,624 veterans who entered Department of Veterans Affairs (VA) health care after leaving the military. Department of Defense (DoD) data on clinical diagnoses, demographics, and military history were linked to VA data on neighborhood of residence and criminal legal involvement. RESULTS: Criminal legal involvement in the 2 years following military discharge was most strongly predicted by younger age, substance use disorder, and being male. Other predictors included the military branch in which veterans served, deployment history, traumatic brain injury, serious mental illness, personality disorder, having fewer physical health conditions, and living in socioeconomically disadvantaged neighborhoods. These factors combined in multivariable analysis yielded a very large effect size for predicting criminal legal involvement after military separation (area under the curve = .82). The incidence of criminal legal involvement was 10 times higher among veterans with co-occurring substance use disorder, serious mental illness, and personality disorder than among veterans with none of these diagnoses, and these rates were highest among veterans residing in more socioeconomically disadvantaged neighborhoods. CONCLUSIONS: To our knowledge, this is the largest longitudinal study of risk factors for criminal legal involvement in veterans following military discharge. The findings supported the hypothesis that veterans with co-occurring mental disorders living in socioeconomically disadvantaged neighborhoods were at higher risk of criminal legal involvement, underscoring the complex interplay of individual-level and neighborhood-level risk factors for criminal legal involvement after veterans leave the military. These results can inform policy and programs, such as the DoD Transition Assistance Program (TAP) and the VA Military to Civilian Readiness Pathway program (M2C Ready), to enhance community reintegration and prevent criminal legal involvement among veterans transitioning from military to civilian life. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Characterization of Mauritian Cynomolgus Macaque FcγR Alleles Using Long-Read Sequencing.

The FcγRs are immune cell surface proteins that bind IgG and facilitate cytokine production, phagocytosis, and Ab-dependent, cell-mediated cytotoxicity. FcγRs play a critical role in immunity; variation in these genes is implicated in autoimmunity and other diseases. Cynomolgus macaques are an excellent animal model for many human diseases, and Mauritian cynomolgus macaques (MCMs) are particularly useful because of their restricted genetic diversity. Previous studies of MCM immune gene diversity have focused on the MHC and killer cell Ig-like receptor. In this study, we characterize FcγR diversity in 48 MCMs using PacBio long-read sequencing to identify novel alleles of each of the four expressed MCM FcγR genes. We also developed a high-throughput FcγR genotyping assay, which we used to determine allele frequencies and identify FcγR haplotypes in more than 500 additional MCMs. We found three alleles for FcγR1A, seven each for FcγR2A and FcγR2B, and four for FcγR3A; these segregate into eight haplotypes. We also assessed whether different FcγR alleles confer different Ab-binding affinities by surface plasmon resonance and found minimal difference in binding affinities across alleles for a panel of wild type and Fc-engineered human IgG. This work suggests that although MCMs may not fully represent the diversity of FcγR responses in humans, they may offer highly reproducible results for mAb therapy and toxicity studies.

Role of FcγRs in Antibody-Based Cancer Therapy.

Monoclonal antibodies can mediate antitumor activity by multiple mechanisms. They can bind directly to tumor receptors resulting in tumor cell death, or can bind to soluble growth factors, angiogenic factors, or their cognate receptors blocking signals required for tumor cell growth or survival. Monoclonal antibodies, upon binding to tumor cell, can also engage the host's immune system to mediate immune-mediated destruction of the tumor. The Fc portion of the antibody is essential in engaging the host immune system by fixing complement resulting in complement-mediated cytotoxicity (CDC) of the tumor, or by engaging Fc receptors for IgG (FcγR) expressed by leukocytes leading to antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) of tumor cells. Antibodies whose Fc portion preferentially engage activating FcγRs have shown greater inhibition of tumor growth and metastasis. Monoclonal antibodies can also stimulate the immune system by binding to targets expressed on immune cells. These antibodies may stimulate antitumor immunity by antagonizing a negative regulatory signal, agonizing a costimulatory signal, or depleting immune cells that are inhibitory. The importance of Fc:FcγR interactions in antitumor therapy for each of these mechanisms have been demonstrated in both mouse models and clinical trials and will be the focus of this chapter.

Examination of PTSD symptom networks over the course of cognitive processing therapy.

OBJECTIVES: Cognitive processing therapy (CPT) is an evidence-based psychotherapy for posttraumatic stress disorder (PTSD); however, little is known about how interrelationships between PTSD symptoms change over the course of treatment. The current study examined baseline, midtreatment, and posttreatment PTSD symptom networks during CPT for PTSD. METHOD: Adults with PTSD (n = 107) received 12 sessions of CPT as part of a randomized trial. Self-reported PTSD symptoms were assessed at pretreatment, midtreatment, and posttreatment, and network analysis was used to examine the interrelationships between symptoms at these three timepoints. Linear regression was conducted to examine whether any baseline symptoms or midpoint symptoms predicted overall treatment change. RESULTS: In the baseline PTSD network, feelings of detachment and feeling upset at reminders of the trauma were central to the symptom network. These symptoms were no longer central at midtreatment, possibly suggesting that CPT quickly reduces the importance of these symptoms. These findings were consistent with regression results that, after accounting for multiple comparisons, high baseline scores of feeling upset at trauma reminders predicted later treatment change. At the conclusion of treatment, strong negative emotions were the most central symptom and may be most important in maintaining or lowering other PTSD symptoms at the conclusion of treatment. CONCLUSIONS: Though replication is necessary, these findings offer insights into identifying which symptoms may be most predictive of treatment outcomes and the course by which CPT reduces PTSD symptoms. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Posttraumatic stress symptoms, posttraumatic growth, and personality factors: A network analysis.

BACKGROUND: After experiencing a traumatic event, two possible outcomes are experiencing positive changes, such as posttraumatic growth (PTG), and/or experiencing distress in the form of posttraumatic stress symptoms (PTSS). These constructs are not mutually exclusive; those who experience PTSS may concurrently or at a later date likewise undergo PTG. Pretrauma factors, such as personality as measured by the Big Five Inventory (BFI), can interact with both PTSS and PTG. METHODS: The present study utilized Network theory to examine the interactions between PTSS, PTG, and personality in 1310 participants. Three networks were computed (PTSS, PTSS/BFI, PTSS/PTG/BFI). RESULTS: Within the PTSS network, strong negative emotions emerged as the strongest influence on the network. Again, in the PTSS and BFI network, strong negative emotions exerted the strongest overall influence in addition to bridging the PTSS and personality domains. In the network with all variables of interest, the PTG domain of new possibilities was the strongest overall influence on the network. Specific relationships between constructs were identified. LIMITATIONS: Limitations of this study include the cross-sectional design and utilization of a sub-threshold PTSD, non-treatment seeking sample. CONCLUSIONS: Overall, nuanced relationships between variables of interest were identified, informing personalized treatment and furthers our understanding of both positive and negative responses to trauma. As the primary influence across two networks, the experience of strong negative emotions appears to be central to the subjective experience of PTSD. This may indicate a need to modify present treatments for PTSD, which conceptualize PTSD as a primarily fear-based disorder.

Food Insecurity and Suicidal Ideation: Results from a National Longitudinal Study of Military Veterans.

OBJECTIVE: Research examining social determinants of suicide risk in veterans suggests a potential link between food insecurity and subsequent suicidal ideation in military veterans. The objective of this study is to investigate, if and how, food insecurity predicts subsequent suicidal ideation in a nationally representative longitudinal survey of veterans. METHODS: A national longitudinal survey was analyzed of participants randomly drawn from over one million U.S. military service members who served after September 11, 2001. N = 1,090 veterans provided two waves of data one year apart (79% retention rate); the final sample was representative of post-9/11 veterans in all 50 states and all military branches. RESULTS: Veterans with food insecurity had nearly four times higher suicidal ideation one year later compared to veterans not reporting food insecurity (39% vs 10%). In multivariable analyses controlling for demographic, military, and clinical covariates, food insecurity (OR = 2.37, p =.0165) predicted suicidal ideation one year later, as did mental health disorders (OR = 2.12, p = .0097). Veterans with both food insecurity and mental health disorders had a more than nine-fold increase in predicted probability of suicidal ideation in the subsequent year compared to veterans with neither food insecurity nor mental health disorders (48.5% vs. 5.5%). CONCLUSION: These findings identify food insecurity as an independent risk marker for suicidal ideation in military veterans in addition to mental disorders. Food insecurity is both an indicator of and an intervention point for subsequent suicide risk. Regularly assessing for food insecurity, and intervening accordingly, can provide upstream opportunities to reduce odds of suicide among veterans.HIGHLIGHTSMilitary veterans with food insecurity were at elevated risk of suicidal ideation.Veterans with mental health disorders had higher odds of suicidal ideation one year later.Food insecurity plus mental health disorders led to a substantial increase in suicidal ideation.

Perceived sleep quality mediates the relationship between posttraumatic stress and somatic symptoms.

OBJECTIVE: Posttraumatic stress symptoms (PTSS) have been associated with increased somatic symptom expression. Sleep concerns have been associated with PTSS and somatic symptoms. Previous research suggests that sleep affects multiple domains of functioning including comorbid psychological and physical health concerns. The current study examines whether perceived sleep quality or sleep efficiency/duration may be mediating the relationship between PTSS and somatic symptoms in a trauma-exposed sample. METHOD: The sample consisted of 864 students, recruited from a large Midwestern university and compensated with research participation credit. Data were collected online over approximately 39 months (October 2015 through January 2019), and the pertinent scales examined in this study included Pittsburgh Sleep Quality Index, Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders, fifth edition, and Screening for Somatoform Symptoms-7. RESULTS: Of the 864 students, 668 participants identified as female (77.3%) and 540 identified as non-Hispanic White (62.5%), with an overall average age of 23.14 years (SD = 6.64). Mediation analyses indicated that the overall model examining global sleep quality complaints as a mechanism of the relationship between PTSS and somatic symptoms was significant, F(3, 860) = 193.97, R² = .40, p < .001, and that perceived sleep quality was found to be the only significant specific mediator (indirect effect = .21). Although females reported greater somatic severity, PTSS, and sleep concerns, models were significant, even after examining the influence of gender. CONCLUSIONS: Global sleep complaints are associated with both PTSS and somatic symptoms. Perceived sleep quality specifically mediated the relationship between PTSS and somatic symptoms, highlighting a potential intervention for improving physical health consequences in trauma-exposed individuals. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Application of Pharmacokinetic/Pharmacodynamic Modeling to Bridge Mouse Antitumor Efficacy and Monkey Toxicology Data for Determining the Therapeutic Index of an Interleukin-10 Fc Fusion Protein.

Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed to quantitatively integrate preclinical pharmacology and toxicology data for determining the therapeutic index (TI) of an interleukin-10 (IL-10) fragment crystallizable (Fc) fusion protein. Mouse Fc fused with mouse IL-10 (mFc-mIL-10) was studied in mice for antitumor efficacy, and the elevation of interleukin-18 (IL-18) was examined as a PD biomarker. The in vivo mFc-mIL-10 EC50 for the IL-18 induction was estimated to be 2.4 nM, similar to the in vitro receptor binding affinity (Kd) of 3.2 nM. The IL-18 induction was further evaluated in cynomolgus monkeys, where the in vivo induction EC50 by a human IL-10 human Fc-fusion protein (hFc-hIL-10) was 0.08 nM vs. 0.3 nM measured as the in vitro Kd. The extent of the IL-18 induction correlated with mouse antitumor efficacy and was used to connect mouse efficacy to that in monkeys. The PD-based efficacious dose projected in monkeys was comparable to the results obtained using a PK-based method in which mouse efficacious exposure was targeted and corrected for affinity differences between the species. Furthermore, PK/PD relationships were developed for anemia and thrombocytopenia in monkeys treated with hFc-hIL-10, with thrombocytopenia predicted to be dose-limiting toxicity. Using quantitative pharmacology and toxicology information obtained through modeling work in the same species, the TI of hFc-hIL-10 in monkeys was determined to be 2.4 (vs. PD-based efficacy) and 1.2-3 (vs. PK-based efficacy), indicating a narrow safety margin. The model-based approaches were proven valuable to the developability assessment of the IL-10 Fc-fusion protein.

The Corpus Callosum and PTSD Severity.

Posttraumatic stress disorder (PTSD) is a chronic, debilitating disorder that is associated with neural alterations in multiple brain regions. Neuroimaging studies have largely focused on gray matter abnormalities in PTSD, with less information known about the integrity of white matter tracts. Prior studies of brain white matter in PTSD have produced mixed results, likely due to differences in neuroimaging sequences and clinical variables. This study addressed this gap by examining the microstructural integrity of the corpus callosum, the largest white matter fiber bundle in the brain, using diffusion tensor imaging (DTI). Sixty adult females diagnosed with PTSD with a history of interpersonal violence were compared with 18 trauma-exposed controls. All participants underwent DTI using 1.5 T. MANOVA revealed significantly higher fractional anisotropy (FA; p = .012) in the genu of the corpus callosum (GCC) compared with the trauma-exposed controls. These results suggest the GCC to relate to PTSD symptomatology. Further studies of this mechanism may provide insight into improving treatment and prevention efforts.

Treatment outcome of posttraumatic stress disorder: A white matter tract analysis.

Despite the development of empirically supported treatments for posttraumatic stress disorder (PTSD), many individuals remain symptomatic following therapy or dropout prematurely. Neuroimaging studies examining PTSD treatment outcome may offer valuable insights into possible mechanisms that may impact treatment efficacy. To date, few studies of PTSD have used neuroimaging to examine symptom change following completed treatment, and most have focused on gray matter. Studies of white matter are equally important, as changes in white matter integrity (WMI) are connected to a host of detrimental outcomes. The current study examined symptom change of 21 women with PTSD as a result of interpersonal violence who received baseline diffusion tensor imaging (DTI) scans and completed 12 weeks of Cognitive Processing Therapy (CPT). After controlling for baseline PTSD severity, fractional anisotropy (FA) in the left internal capsule, posterior limb of the internal capsule, left cingulate gyrus, superior longitudinal fasciculus, and splenium of the corpus callosum was predicted by PTSD symptom change. Results contribute to understanding neural changes within therapy and may assist in predicting individual treatment response. Namely, by identifying areas potentially impacted by PTSD treatment, future studies may be able to connect the function of these white matter areas to better predict patient PTSD treatment outcome.

A network analysis of risk factors for suicide in Iraq/Afghanistan-era veterans.

Suicidal ideation (SI) is a prevalent issue in the veteran population. A number of factors have been identified as risk factors for suicidal ideation (SI) in veterans, including suicide attempts, depression, posttraumatic stress disorder (PTSD), and drug use. However, clinicians' ability to predict suicide is poor, particularly given the interplay between various factors such as previous suicide attempts. As such, there is a gap in our knowledge of which factors most saliently predict suicide risk and which should be targets for interventions designed to lower SI. Network analysis, a method allowing for an examination of how variables relate within the context of a network of factors, may bridge this gap by simultaneously evaluating the interrelationships between risk factors for suicide in veterans. Current study used network analysis and data from 2268 Iraq/Afghanistan-era military veterans to examine the relationships between suicidal ideation and several factors related to suicide risk, such as past suicide attempts, PTSD symptoms, depression, drug use, trauma exposure. Partial correlation network results showed suicidal ideation to be strongly related to depression, with smaller connections to past suicide attempts and anger. Additionally, past suicide attempts was strongly related to history of childhood trauma and weakly related to problematic drug use and PTSD symptoms. These results offer valuable information for both predicting suicide risk and differentiating targets for interventions lowering suicide risk in veterans.

In vitro and in vivo characterization of MDX-1401 for therapy of malignant lymphoma.

PURPOSE: This study was undertaken to evaluate the effects of MDX-1401, a nonfucosylated fully human monoclonal antibody that binds to human CD30, and to determine whether it exhibits greater in vitro and in vivo activity than its parental antibody. EXPERIMENTAL DESIGN: Assays measuring antibody binding to CD30-expressing cells and FcgammaRIIIa (CD16) transfectants as well as antibody-dependent cellular cytotoxicity (ADCC) were conducted. Antitumor activity was determined using a Karpas-299 systemic model. RESULTS: The binding of MDX-1401 to CD30 antigen was identical to fucose-containing parental anti-CD30 antibody (MDX-060). In contrast, MDX-1401 showed increased binding affinity to FcgammaRIIIa-transfected cells resulting in increased effector function. MDX-1401 greatly improved ADCC activity as evidenced by a decrease in half-maximal effective concentration (EC(50)) and an increase in maximum cell lysis when compared with MDX-060. Increased ADCC activity was observed among a panel of cell lines, including one with very low CD30 antigen expression in which parental antibody failed to induce any detectable ADCC. MDX-1401 activity with all FcgammaRIIIa polymorphic variants, including less active Phe/Phe158 and Phe/Val158 effector cells, was shown. Furthermore, MDX-1401 was efficacious in inhibiting tumor growth in CD30(+) lymphoma xenografts. CONCLUSIONS: The low doses of antibody required for ADCC activity irrespective of donor genotype, the ability to mediate ADCC in target cells expressing low levels of CD30, and increased in vivo efficacy support the development of MDX-1401 for treatment of malignant lymphoma.

The effects of bullying in depression on white matter integrity.

Individuals with elevated symptoms of depression exhibit alterations in white matter integrity, including lower fractional anisotropy (FA) evident on diffusion tensor imaging (DTI). Similarly, individuals with a history of early life stress (ELS) exhibit lower FA in the white matter independent of concurrent depression. Prior studies have not determined whether the neuroimaging signature of comorbid ELS and adult depression differs from the pattern of brain white matter changes associated with depression in the absence of self-reported ELS. The current study examined FA in multiple white matter tracts in 186 adults (93 males; 93 females) with a current diagnosis of major depressive disorder, including 88 who reported a history of bullying before the age of 18 (43 males; 45 females). All patients were antidepressant medication free at the time of testing. After adjusting for demographics and other ELS subtypes, participants with a history of bullying exhibited increased FA in the right medial lemniscus (p =.039) and left posterior corona radiata (p =.008) compared to participants with depression but no self-reported history of bullying. Both groups endorsed similar levels of depression. Group differences were most pronounced among individuals who endorsed bullying in late adolescence (14-17 years of age). Results suggest bullying in late adolescence is uniquely related to abnormal brain microstructure among individuals with current diagnoses of depression, possibly due to an overactive fear response. Further work is needed to differentiate why ELS within bullying is associated with higher FA.

Enhanced SLAMF7 Homotypic Interactions by Elotuzumab Improves NK Cell Killing of Multiple Myeloma.

Elotuzumab (Elo) is an IgG1 monoclonal antibody targeting SLAMF7 (CS1, CRACC, and CD319), which is highly expressed on multiple myeloma (MM) cells, natural killer (NK) cells, and subsets of other leukocytes. By engaging with FcγRIIIA (CD16), Elo promotes potent NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) toward SLAMF7+ MM tumor cells. Relapsed/refractory MM patients treated with the combination of Elo, lenalidomide, and dexamethasone have improved progression-free survival. We previously showed that Elo enhances NK cell activity via a costimulation mechanism, independent of CD16 binding. Here, we further studied the effect of Elo on cytotoxicity of CD16-negative NK-92 cells. Elo, but not other SLAMF7 antibodies, uniquely enhanced cytotoxicity mediated by CD16-negative NK-92 cells toward SLAMF7+ target cells. Furthermore, this CD16-independent enhancement of cytotoxicity required expression of SLAMF7 containing the full cytoplasmic domain in the NK cells, implicating costimulatory signaling. The CD16-independent costimulation by Elo was associated with increased expression of NKG2D, ICAM-1, and activated LFA-1 on NK cells, and enhanced cytotoxicity was partially reduced by NKG2D blocking antibodies. In addition, an Fc mutant form of Elo that cannot bind CD16 promoted cytotoxicity of SLAMF7+ target cells by NK cells from most healthy donors, especially if previously cultured in IL2. We conclude that in addition to promoting NK cell-mediated ADCC (CD16-dependent) responses, Elo promoted SLAMF7-SLAMF7 interactions in a CD16-independent manner to enhance NK cytotoxicity toward MM cells.

Targeting DDR2 enhances tumor response to anti-PD-1 immunotherapy.

While a fraction of cancer patients treated with anti-PD-1 show durable therapeutic responses, most remain unresponsive, highlighting the need to better understand and improve these therapies. Using an in vivo screening approach with a customized shRNA pooled library, we identified DDR2 as a leading target for the enhancement of response to anti-PD-1 immunotherapy. Using isogenic in vivo murine models across five different tumor histologies-bladder, breast, colon, sarcoma, and melanoma-we show that DDR2 depletion increases sensitivity to anti-PD-1 treatment compared to monotherapy. Combination treatment of tumor-bearing mice with anti-PD-1 and dasatinib, a tyrosine kinase inhibitor of DDR2, led to tumor load reduction. RNA-seq and CyTOF analysis revealed higher CD8+ T cell populations in tumors with DDR2 depletion and those treated with dasatinib when either was combined with anti-PD-1 treatment. Our work provides strong scientific rationale for targeting DDR2 in combination with PD-1 inhibitors.

Hydrogen/deuterium exchange mass spectrometry and computational modeling reveal a discontinuous epitope of an antibody/TL1A Interaction.

TL1A, a tumor necrosis factor-like cytokine, is a ligand for the death domain receptor DR3. TL1A, upon binding to DR3, can stimulate lymphocytes and trigger secretion of proinflammatory cytokines. Therefore, blockade of TL1A/DR3 interaction may be a potential therapeutic strategy for autoimmune and inflammatory diseases. Recently, the anti-TL1A monoclonal antibody 1 (mAb1) with a strong potency in blocking the TL1A/DR3 interaction was identified. Here, we report on the use of hydrogen/deuterium exchange mass spectrometry (HDX-MS) to obtain molecular-level details of mAb1's binding epitope on TL1A. HDX coupled with electron-transfer dissociation MS provided residue-level epitope information. The HDX dataset, in combination with solvent accessible surface area (SASA) analysis and computational modeling, revealed a discontinuous epitope within the predicted interaction interface of TL1A and DR3. The epitope regions span a distance within the approximate size of the variable domains of mAb1's heavy and light chains, indicating it uses a unique mechanism of action to block the TL1A/DR3 interaction.

Risk factors for concurrent suicidal ideation and violent impulses in military veterans.

Suicide and violence are significant problems in a subset of Iraq/Afghanistan-era veterans. This study investigates how posttraumatic stress disorder (PTSD) and resilience in veterans are associated with suicidal ideation and violent impulses while controlling for known covariates of both adverse outcomes. Structured clinical interviews were conducted of N = 2,543 Iraq/Afghanistan-era U.S. veterans. Compared with veterans denying suicidal ideation or violent impulses (n = 1,927), veterans endorsing both (n = 171) were more likely to meet diagnostic criteria for PTSD, report childhood abuse, combat exposure, physical pain symptoms, and drug misuse, and less likely to endorse self-direction/life purpose. Veterans reporting concurrent suicidal ideation and violent impulses had higher odds of misusing drugs and reporting pain symptoms relative to veterans reporting suicidal ideation only (n = 186) and had lower odds of endorsing self-direction/life purpose compared with veterans reporting violent impulses only (n = 259). The findings underscore the importance of examining drug abuse, physical pain symptoms, and self-direction/life purpose, as well as PTSD and history of trauma, in the context of clinical assessment and empirical research aimed at optimizing risk management of suicide and violence in military veterans. (PsycINFO Database Record

Improving Mental Health Treatment Utilization in Military Veterans: Examining the Effects of Perceived Need for Care and Social Support.

OBJECTIVE: Many veterans with mental health problems do not adequately utilize needed care. Research has focused on identifying barriers to mental health care in veterans. METHOD: The current study adds to existing literature by examining whether perceived need for treatment and social support affect treatment utilization in a national longitudinal survey of Iraq and Afghanistan veterans (n = 1090). RESULTS: The Health Beliefs Model (HBM) postulates that a key reason why patients fail to obtain needed care is their belief "it's up to me to handle my own problems." This view was endorsed by 42% in the current national sample of veterans and was found in multivariate analysis to predict less treatment seeking in the next year. Mediation analysis revealed that veterans with higher ratings of social support were less likely to believe they needed to solve mental health problems on their own, indirectly equating to higher odds of treatment use. Simultaneously, findings indicated that posttraumatic stress disorder (PTSD) had a direct effect on more mental health visits but was also associated with higher endorsement that one needed to handle one's own problems and thus had an indirect effect of reducing mental health visits. CONCLUSION: Both social support and PTSD affected veterans' perceptions of needing to solve one's own problems, significantly predicted follow-up with mental health care. As a result, the findings indicate that clinicians' should explore veterans' belief systems about perceived treatment need as well as investigate the role of social support to improve mental health treatment utilization.

The anti-SLAMF7 antibody elotuzumab mediates NK cell activation through both CD16-dependent and -independent mechanisms.

Elotuzumab is a humanized therapeutic monoclonal antibody directed to the surface glycoprotein SLAMF7 (CS1, CRACC, CD319), which is highly expressed on multiple myeloma (MM) tumor cells. Improved clinical outcomes have been observed following treatment of MM patients with elotuzumab in combination with lenalidomide or bortezomib. Previous work showed that elotuzumab stimulates NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), via Fc-domain engagement with FcγRIIIa (CD16). SLAMF7 is also expressed on NK cells, where it can transmit stimulatory signals. We tested whether elotuzumab can directly activate NK cells via ligation with SLAMF7 on NK cells in addition to targeting ADCC through CD16. We show that elotuzumab strongly promoted degranulation and activation of NK cells in a CD16-dependent manner, and a non-fucosylated form of elotuzumab with higher affinity to CD16 exhibited enhanced potency. Using F(ab')2 or Fc-mutant forms of the antibody, the direct binding of elotuzumab to SLAMF7 alone could not stimulate measurable CD69 expression or degranulation of NK cells. However, the addition of soluble elotuzumab could costimulate calcium signaling responses triggered by multimeric engagement of NKp46 and NKG2D in a CD16-independent manner. Thus, while elotuzumab primarily stimulates NK cells through CD16, it can also transduce effective "trans"-costimulatory signals upon direct engagement with SLAMF7, since these responses did not require direct co-engagement with the activating receptors. Trans-costimulation by elotuzumab has potential to reduce activation thresholds of other NK cell receptors engaging with their ligands on myeloma target cell surfaces, thereby potentially further increasing NK cell responsiveness in patients.