mAb Group Research Articles

Pooled analysis of the MANTICO2 and MONET randomized controlled trials comparing drug efficacy for early treatment of COVID-19 during Omicron waves

BackgroundThe clinical effectiveness of early therapies for mild-to-moderate COVID-19, comparing antivirals and monoclonal antibodies (mAbs) during the Omicron era, has not been conclusively assessed through a post-approval comparative trial. We present a pooled analysis of two randomized clinical trials conducted during Omicron waves. Methods The MANTICO2/MONET trial is a pooled analysis of two multicentric, independent, phase-4, three-arm, superiority, randomized, open-label trials. Nonhospitalized patients with early mild-to-moderate COVID-19 (≤5 days after symptoms’ onset) and at least one risk factor for disease progression were randomized 1:1:1 to receive 500mg of intravenous sotrovimab (SOT) or 600mg of intramuscular tixagevimab/cilgavimab (TGM/CGM) or oral 5-days course of nirmatrelvir/ritonavir (NMV/r) 300/100mg BID. Primary outcome was COVID-19-related hospitalization or death within 29 days after randomization. Fisher’s exact test for pooled data and incidence of failure was reported as overall and by arm with respective 95% CI.Pairwise comparisons across the arms were conducted using unadjusted exact logistic regression. An analysis by means of a doubly robust marginal model using augmented inverse probability weighting (AIPW) was also conducted to estimate the potential outcomes (Pom) in each treatment group and their difference by the average treatment effect (ATE). Analysis of symptom persistence within 30 days after randomization was performed using a 2-level hierarchical mixed-effects logistic model with a random intercept at the patient’s level. Point estimates and 95% confidence intervals were adjusted for age and sex and calculated using ANOVA-like methods for the mixedeffects logistic model. These trials are registred with the European Clinical Trials Database, EudraCT2021-002612-31 (MANTICO2) and EudraCT2021-004188-28 (MONET) and ClinicalTrials.gov, NCT05321394 (MANTICO2) Findings Between March 2022 and February 2023, 991 patients (SOT=332, TGM/CGM =327, NMV/r=332) were enrolled in 15 Italian centersThe overall mean age was 66 years; 482 participants (48.80%) were male and 856 vaccinated with at least a primary course ( 86%). Among the 8/991 hospitalizations observed, one resulted in death. The overall estimate of failure was 0.81% (95%CI; 0.35-1.58%). The odds ratio (OR) for the primary outcome in the NMV/r arm compared to the TGM/CGM and SOT arms was 8.41 (95% CI 1.21 to infinity; p=0.015) and 2.42 (95% CI 0.19 to infinity; p=0.499), respectively. No significant difference was observed between SOT and TGM/CGM (OR 0.32; 95% CI 0.032-1.83; p=0.174). Results were similar when we applied the marginal weighted model accounting for potential residual confounding bias. There was no evidence for a difference in the prevalence of symptoms between treatment groups, except for cough, which was higher in the SOT group compared to the other two groups at the 21-day follow-up (P=0.039) and a higher prevalence of nausea at the 7-day follow-up in the NMV/r group compared to the mAbs group (p=0.036). Interpretation NMV/r was superior to TGM/CGM in reducing hospital admission or death in clinical vulnerable patients with SARS-CoV-2 infection treated within 5 days of symptoms’ onset. No significant difference in symptom prevalence over time across the arms was found. Funding: The trials were funded by the Italian Agency of Drugs (AIFA) in 2021.

Effect of amubarvimab-romlusevimab for treatment of severe COVID-19 in intensive care units: A retrospective cohort study

Amubarvimab-romlusevimab is a commonly recommended antiviral treatment in China for adult patients with mild or moderate SARS-CoV-2 infections, especially for patients with a high risk factor for progression to severe COVID-19. However, its exact efficacy in patients with severe Covid-19 is not yet known.This is a single-center retrospective cohort study, in which we collected the general data, laboratory tests, radiological characteristics, viral conversion status, and prognosis of the disease from patients with COVID-19 hospitalized, from December 2022 to March 2023 in the Department of Critical Care Medicine. The amubarvimab-romlusevimab therapy can reduce the 28-day mortality (29.79 % vs 51.35 %, p = 0.02), and ICU mortality (29.79 % vs 55.41 %, p = 0.006) of severe COVID-19.A 1:1 PSM (Propensity Score Matching) was performed to reduce bias, in order to ensure the two groups were balanced and comparable. In the matched population (n = 47), there were no statistically significant differences between the mAbs (monoclonal antibody)group and the Non-antiviral group in 28-day, and thromboembolic events in COVID-19 patients. The 40-day survival analysis shows that mAbs therapy can improve patient prognosis (HR = 0.45, 95%CI = 0.26–0.76, p = 0.008). However, no significant intergroup difference in the 40-day cumulative viral conversion rate. In a univariate Cox regression analysis, The Amubarvimab - romlusevimab therapy(HR:0.464; CI:[0.252–0.853]; p:0.013) is a protective factor and CRP, PCT, PLT, Lactate, PT, PT-INR, and pt% level at admission were risk factors for clinical prognosis. After including the above covariates, Multifactorial COX regression shows that the Amubarvimab - romlusevimab therapy(HR:0.392; CI:[0.211–0.729]; p:0.003), CRP, Lactate and PT-INR at admission are independent factors for mortality of severe COVID-19. Based on the current data, we conclude that amubarvimab-romlusevimab therapy is beneficial for patients with severe COVID-19.

Abstract PO5-18-07: A Humanized Monoclonal Antibody to Secreted Frizzled-Related Protein 2 Inhibits TNBC Lung Metastases

Abstract Introduction: A promising novel target for breast cancer is secreted frizzled-related protein 2 (SFRP2). SFRP2 protects tumors against apoptosis, promotes T-cell exhaustion, and induces angiogenesis. SFRP2 is expressed in breast cancer but has not been specifically evaluated in triple negative breast cancer. We previously developed a humanized monoclonal antibody to SFRP2, (hSFRP2 mAb) that inhibits primary breast cancer growth in mice without toxicity. The purpose of this study is to establish the presence of SFRP2 in human TNBC, evaluate the efficacy of hSFRP2 mAb in metastatic TNBC in vivo, and in a cell line resistant to chemotherapy. Methods: Immunohistochemistry (IHC) with SFRP2 antibody on a human TNBC tissue microarray (TMA) containing 88 FFPE cores. After IHC with primary antibody to SFRP2, the TMA was scanned and staining intensity was quantified using spatial analysis. Results for SFRP2 staining were analyzed as previously described for analyses of estrogen and progesterone receptor positivity; categories are: 0-absence of staining; low positive (0-10%), and positive >10%. Development of a doxorubicin (dox)-resistant cell line and induction of apoptosis with hSFRP2 mAb. MDA-MB-231 cells were treated with 4nM dox and increased 2nM at a time until the cells were resistant to 10µM dox after 12 months. WT and dox-resistant cells were treated for 4 hours with either hSFRP2 mAb (10uM,) or IgG control (10uM) (n=6). Apoptosis was detected with Promokine Apoptosis/Necrosis/Healthy cells kit. Cells were imaged using the EVOS FLc and counted using Imagej software. Differences between treated and control were compared with two-tailed T-test. hSFRP2 mAb treatment of mice with metastatic TNBC. PY8119 and E0771 TNBC murine cells (5 × 105/100 μL) were injected iv into 6–8-week-old C57BL/6 female mice. The next day the mice were treated with IgG1 control 8 mg/kg iv or hSFRP2 mAb 8 mg/kg iv every 3 days. After four weeks, the lungs were resected, and surface metastases were counted. Differences between treated and control were compared with Poisson distributions. FFPE sections of lungs were stained with ApopTag kit. Three metastases per lung were counted at 20 X, and the difference between IgG1 and hSFRP2 mAb groups compared with two-tailed T-test. Results: SFRP2 protein is present in human TNBC. Out of 88 cores, 83 cores (94%) were positive, 4 cores (4.5%) were minimally positive, and 1 core (1.1%) was negative for SFRP2. Development of a doxorubicin (dox)-resistant cell line and induction of apoptosis with hSFRP2 mAb treatment in vitro. The number of apoptotic cells in IgG1 control-treated MDA-MB-231 cells was 11.5 ± 3.7, and 76.6 ± 5.0 for hSFRP2 mAb-treated tumors (p< 0.001, n=9). The mean number of apoptotic MDA-MB-231 dox-resistant cells in IgG1 control was 16.7 ± 6.0, and 68.4 ± 6.4 for hSFRP2 mAb-treated tumors, (p< 0.001, n=9). hSFRP2 mAb inhibits the growth of metastatic TNBC in vivo and increases apoptosis. For E0771, the number of surface metastases was 8.9 ±2.8 in the IgG1 control group and 4.9 ± 1.1 in the hSFRP2 mAb treated group (p< 0.05, n=15). The number of apoptotic cells/HPF was 9.8 ± 1.8 for the IgG1 control group and 21.0 ± 4.6 for the hSFRP2 mAb group (n=15, p< .01). For Py8119 tumors there were 6.4 ± 1.0 metastases in the IgG1 control group and 3.6 ± 0.9 in the hSFRP2 mAb group (p< 0.05, n=11). The number of apoptotic cells/HPF was 6 ± 1.8 for the IgG1 control group and 14 ±1.3 for the hSFRP2 mAb group (n=10, p< 0.001). Conclusions: SFRP2 protein is abundantly expressed in human TNBC. A humanized monoclonal antibody to SFRP2 reduces TNBC lung metastases growth in two in vivo models and increases tumor apoptosis. TNBC resistant to doxorubicin remains sensitive to apoptosis induced by the hSFRP2 mAb. Citation Format: Lillian Hsu, Patrick Nasarre, Julie Siegel, Eleanor Hilliard, Rupak Mukherjee, Nancy Klauber-Demore. A Humanized Monoclonal Antibody to Secreted Frizzled-Related Protein 2 Inhibits TNBC Lung Metastases [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-07.

Alterations in the fecal microbiota of methamphetamine users with bad sleep quality during abstinence

BackgroundMethamphetamine (MA) abuse has resulted in a plethora of social issues. Sleep disturbance is a prominent issue about MA addiction, which serve as a risk factor for relapse, and the gut microbiota could play an important role in the pathophysiological mechanisms of sleep disturbances. Therefore, improving sleep quality can be beneficial for treating methamphetamine addiction, and interventions addressing the gut microbiota may represent a promising approach.MethodWe recruited 70 MA users to investigate the associations between sleep quality and fecal microbiota by the Pittsburgh Sleep Quality Index (PSQI), which was divided into MA-GS (PSQI score < 7, MA users with good sleep quality, n = 49) and MA-BS group (PSQI score ≥ 7, MA users with bad sleep quality, n = 21). In addition, we compared the gut microbiota between the MA-GS and healthy control (HC, n = 38) groups. 16S rRNA sequencing was applied to identify the gut bacteria.ResultThe study revealed that the relative abundances of the Thermoanaerobacterales at the order level differed between the MA-GS and MA-BS groups. Additionally, a positive correlation was found between the relative abundance of the genus Sutterella and daytime dysfunction. Furthermore, comparisons between MA users and HCs revealed differences in beta diversity and relative abundances of various bacterial taxa.ConclusionIn conclusion, the study investigated alterations in the gut microbiota among MA users. Furthermore, we demonstrated that the genus Sutterella changes may be associated with daytime dysfunction, suggesting that the genus Sutterella may be a biomarker for bad sleep quality in MA users.

Effects of prophylactic drug therapies and anti-calcitonin peptide-related monoclonal antibodies on subjective sleep quality: An Italian multicenter study

Objective/backgroundsleep alterations strongly influence migraine severity. Prophylactic therapies have a major impact on migraine frequency and associated symptoms. The study purpose was to compare the impact of oral drug therapies or gene-related anti-calcitonin monoclonal antibodies (anti-CGRP mAbs) on sleep alterations. We also evaluated which drug therapies are more effective on sleep quality and the different impact on migraine frequency and life quality. Patients/methodsthis is a multicenter, prospective study conducted in three specialized headache centers (Marche Polytechnic University, Ancona; University of Palermo, Palermo; Fondazione Policlinico Campus Bio-Medico, Rome). At baseline, we assigned migraine patients to preventive therapy with first-line drugs or anti-CGRP mAbs. The Pittsburgh Sleep Quality Index (PSQI) and Migraine Disability Assessment (MIDAS) scales were administered. After three months, we re-evaluated the patients with the same scales. Results214 patients were enrolled. Any prophylaxis was significantly associated with a reduction in PSQI score (mean difference 1.841; 95%CI:1.413–2.269; p < 0.0001), most significantly in the anti-CGRP mAb group (mean difference 1.49; 95%CI:2.617-0.366; p = 0.010). Anti-CGRP mAbs resulted in significant improvement in migraine severity and MIDAS scores. Among oral therapies, calcium antagonists and antidepressants were the most effective in reducing PSQI score between T0 and T1 (p = 0.042; p = 0.049; p < 0.0001, respectively). Conclusionsanti-CGRP mAbs revitalized the management of migraine with stable and well-documented efficacy. Our data also suggest that anti-CGRP mAbs result in a positive effect on sleep quality, with a significant improvement in PSQI scores. Knowing the relevant impact of sleep disruption on migraine severity, these data could help for the management of migraine patients.

Efficacy and Safety of PSCK9 Inhibitors on Patients with Acute Coronary Syndrome: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

PCSK9 MaB (Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor) may reduce the occurrence of major adverse cardiovascular events (MACEs) in patients diagnosed with acute coronary syndrome (ACS). In this meta-analysis, we conducted a thorough compilation of evidence from established clinical studies to evaluate PCSK9 MaB's capacity to control blood lipid levels and prevent MACEs in ACS patients. We conducted searches on Pubmed, Embase, the Cochrane Library, and Web of Science to identify relevant articles. Data from ACS patients were extracted using a standardized format for aggregating data. We calculated the risk ratio (RR) for MACE and assessed changes in blood lipid parameters. All statistical analyses were performed using RevMan. 11 articles representing 5 trials were included in our systematic review and meta-analysis. When compared to a placebo, PCSK9 MaB significantly reduced the risk of MACEs ( = 0%, p = 0.63, RR [95% CI] = 0.88 [0.81, 0.97], p 0.01) and the recurrence rate of ACS ( = 45%, p = 0.18, RR [95% CI] = 0.89 [0.83, 0.95], p 0.01). Additionally, PCSK9 MaB notably reduced low-density lipoprotein cholesterol (LDL-C) levels (SMD [95% CI] = -2.12 [-2.32, -1.92], p 0.01) and Apolipoprotein B (ApoB) levels (SMD [95% CI] = -1.83 [-2.48, -1.18], p 0.01). Importantly, there were no significant differences in adverse reactions between the PCSK9 MaB group and the control group. PCSK9 MaB, whether used as a standalone treatment or in combination with other therapies, can effectively inhibit PCSK9. It substantially lowers key blood lipid parameters, including low-density lipoprotein (LDL), ApoB, and triglycerides, all without giving rise to notable safety concerns.

Mechanism exploration of Zoledronic acid combined with PD-1 in the treatment of hepatocellular carcinoma

How to increase the response of immune checkpoint inhibitors (ICIs) is a challenge. In clinical, we found that Zoledronic acid (ZA) may increase the anti-tumor effect of immunotherapy for hepatocellular carcinoma (HCC). To explore the underlying mechanism, we established a mouse model of HCC by subcutaneously injecting Hepa1-6 cell line. The result showed that the tumor volume in the ZA plus anti-PD-1 monocloning antibody (anti-PD-1 mAb) treatment groups was significantly smaller than that of control group, and the onset time of tumor inhibition was even shorter than that of the anti-PD-1 mAb group. Using flow cytometry (FC) to detect the proportion of major immune cell subsets in tumor tissues of each group of mice, we found that the synergistic anti-tumor effect of ZA and anti-PD-1 mAb may be related to ZA-induced polarization of macrophages toward the M1 phenotype. Next, we performed bulk RNA sequencing on tumor samples from different groups to obtain differentially expressed genes (DEGs), which were then input DEGs into pathway enrichment analysis. Data indicated that ZA participated in the M1-type polarization via ferroptosis-related pathways. Our results revealed how ZA involves in the anti-tumor effect of PD-1 monoclonal antibody and provided a potential therapeutic candidate for patients with HCC.

Monoclonal Antibody Infusions for Outpatient Management of Mild-Moderate COVID-19.

The COVID-19 pandemic has led to a rapid, exponential increase in hospitalizations and morbidity/mortality. In November 2020, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) permitting administration of the first monoclonal antibodies (mAb) for outpatient treatment of COVID-19. Early data showed a reduction in COVID-19-related hospitalizations with few adverse events. However, since these treatments are only authorized under an EUA, real-world data are minimal. To assess efficacy and safety of mAbs in a veteran population. This retrospective study analyzed veterans at the Ralph H. Johnson Veterans Affairs Health Care System with mild-moderate COVID-19 and screened for mAb eligibility between December 1, 2020, and October 31, 2021. The primary outcome was hospitalizations and/or emergency department (ED) visits within 30 days. Secondary outcomes included 30-day mortality and post-COVID-19 conditions. Adverse events were also evaluated. Outcomes were compared between mAb-treated patients and eligible veterans who were not treated. There were 296 and 275 veterans in the mAb and control groups, respectively. No statistically significant difference was found for the primary outcome overall (25.7% vs 25.1%; P = 0.87), nor for COVID-19-related return visits or hospitalizations (13.9% v. 16%; P = 0.4). However, the mAb group had more return ED visits (P = 0.35), and the control group had significantly more hospitalizations (P = 0.02). Vaccinated veterans who received an mAb had fewer return visits and hospitalizations (P = 0.01). More mAb-treated veterans experienced post-COVID-19 conditions. No difference in mortality was found. Four nonsevere adverse events occurred after the mAb therapy. Overall, the mAbs appeared safe and effective. Sicker, higher-risk mAb-treated veterans faired similarly to less-sick, high-risk veterans not treated. Those who were vaccinated seemed to benefit the most from mAb therapy. Future prospective studies with more matched groups are needed to assess full benefits and risks of mAbs shown to neutralize the predominant variants.

Pharmacological inhibition of ICOS attenuates the protective effect of exercise on cardiac fibrosis induced by isoproterenol

AimsTo investigate the cardioprotective mechanism of exercise or exercise combined with inducible costimulatory molecules (ICOS) monoclonal antibody (mAb) therapy against isoproterenol (ISO)-induced cardiac remodeling. Main methodsTotally 24 male C57BL/6J mice were randomly divided into four groups: the control group (normal saline treatment), ISO group (subcutaneous injection of isoproterenol, 10 mg/kg/day, once daily for 5 consecutive days), the exercise with subcutaneous ISO injection group (EPI), and the exercise with injected with ISO and ICOS mAb group (EPII). The mice in EPI and EPII group were trained on a small animal treadmill for 4 weeks (13 m/min, 0% grade, 60min/day). Key findingsExercise significantly attenuated CD45+, Mac-2 inflammatory cell infiltration, cardiac fibrosis and inhibited the RIPK1/RIPK3/MLKL/CaMKII and cardiomyocyte pyroptosis pathways to counter ISO-induced severe cardiac injury. The administration of the ICOS mAb may inhibit the cardioprotection of exercise against ISO-induced heart damage. Compared to those in EPI, our data showed that the increasing levels of myocardial fibrosis, the leukocyte infiltration of cardiac tissue and proteins expression of cardiac myocyte necrosis and pyroptosis signaling pathways in the EPII group. SignificanceOur results demonstrated that exercise decreased leukocyte infiltration in heart, inhibited the cardiomyocyte pyroptosis and necroptosis signaling pathways, and attenuated inflammatory responses to alleviate ISO-induced cardiac fibrosis. However, the antifibrotic effects of combined treatment with exercise and ICOS mAb intervention did not exhibit synergistic enhancement.

Clinical Characteristics and Treatment Outcomes of Pulmonary Diseases Caused by Coinfections With Multiple Nontuberculous Mycobacterial Species.

Coinfections with multiple nontuberculous mycobacterial (NTM) species have not been widely studied. We aimed to evaluate the clinical characteristics and treatment outcomes in patients with NTM-pulmonary disease (PD) caused by coinfection with multiple NTM species. We retrospectively reviewed patients with NTM-PD at a tertiary referral hospital in Korea between March 2012 and December 2018. Coinfection was defined as two or more species of NTM pathogens isolated from the same respiratory specimen or different specimens within three months. Among 1,009 patients with NTM-PD, 147 (14.6%) NTM coinfections were observed (average age 64.7 years, 69.4% women). NTM species were identified more frequently (median 6 vs. 3 times, P < 0.001) in the coinfection group than in the single species group, and follow-up duration was also longer in the coinfection group (median 44.9 vs. 27.1 months, P < 0.001). Mycobacterium avium complex (MAC) and M. abscessus and M. massiliense (MAB) were the dominant combinations (n = 71, 48.3%). For patients treated for over six months in the MAC plus MAB group (n = 31), sputum culture conversion and microbiological cure were achieved in 67.7% and 41.9% of patients, respectively. We divided the MAC plus MAB coinfection group into three subgroups according to the target mycobacteria; however, no statistical differences were found in the treatment outcomes. In NTM-PD cases, a significant number of multiple NTM species coinfections occurred. Proper identification of all cultured NTM species through follow-up is necessary to detect multispecies coinfections. Further research is needed to understand the nature of NTM-PD in such cases.

Alternative Pathway Masp-3 Inhibitor OMS906 Effectively and Potently Inhibits Complement-Mediated Hemolysis in Preclinical Models Mechanistically Similar to Paroxysmal Nocturnal Hemoglobinuria

Introduction: Mannan-binding lectin-associated serine protease-3 (MASP-3) activates pro-complement Factor D (CFD) to form mature CFD, a rate-limiting enzyme in the alternative pathway (AP) of the complement system. CFD controls cleavage of complement Factor B (CFB) to form AP C3 convertase, which drives an amplification loop of protease complexes that activates both C3b-mediated opsonization and the terminal pathway. OMS906 is a humanized IgG4 monoclonal antibody (mAb) that binds to and inhibits MASP-3, thereby blocking maturation of CFD and downstream AP activity. Data from mice and monkeys demonstrated that OMS906 is highly selective and effectively inhibits AP activity. MASP-3 inhibition could provide therapeutic benefit in a variety of AP-mediated diseases, such as paroxysmal nocturnal hemoglobinuria (PNH). In PNH, a rare and life-threatening disorder, red blood cells (RBCs) lacking CD59 and CD55 regulatory surface proteins are targeted for rapid clearance via intravascular hemolysis and extravascular hemolysis, due to AP dysregulation. Clinical efficacy of OMS906 in a study of patients with PNH has been reported. To provide mechanistic support, we conducted in vitro and in vivo studies using preclinical models of complement-mediated hemolysis that have mechanistic overlap with PNH. Methods: In vitro potency of OMS906 was assessed using RBCs deficient in CD55 and CD59 to mimic the physiological effect of PNH. Healthy human donor RBCs were treated with inhibitory CD55 and CD59 antibodies, then incubated under AP assay conditions with human serum (diluted to 50%) containing OMS906, anti-C5 IgG4 mAb, or an isotype mAb control. The potency of OMS906, expressed as the half-maximal inhibitory concentration (IC 50), was assessed based on prevention of hemolysis of the PNH-like RBCs in vitro. Lysis was quantified by measuring hemoglobin released into sample supernatants using spectrophotometric absorbance. The in vivo effect of OMS906 on survival of murine RBCs prone to rapid clearance was assessed using RBCs from Crry -/- mice, which lack a rodent-specific complement regulatory protein that blocks AP activation. C57BL/6J male mice were intravenously injected with fluorescent labelled Crry -/- RBCs and received OMS906 or isotype mAb control via subcutaneous injection, or anti-CFB mAb via intraperitoneal injection. Blood samples were taken daily until Day 14 and the remaining number of Crry -/- RBCs measured by flow cytometry. Results: In vitro, OMS906 inhibited terminal cell lysis in human PNH-like RBCs more potently than a C5 inhibitor. Comparison of representative drug concentration-response showed that the average functional potency was 58-fold greater with OMS906 (IC 50: 0.8 μg/mL; 3 experiments; 12 total RBC donors) than with anti-C5 mAb (IC 50: 46.2 μg/mL; 2 experiments; 4 total RBC donors). In addition, the maximal extent to which lysis was inhibited was consistently greater with OMS906 than with anti-C5 mAb. In vivo, the rate of decline in number of Crry -/- RBCs was significantly slowed in mice treated with OMS906, in contrast to the rapid loss observed in isotype mAb control-treated mice ( Figure). OMS906 recipients showed a rate of Crry -/- RBC survival similar to the anti-CFB mAb group. Conclusion: OMS906 inhibited RBC lysis more potently than a C5 inhibitor, providing evidence that MASP-3 inhibition blocks downstream terminal activity and thus intravascular hemolysis. In addition, OMS906 improved survival of Crry -/- RBCs comparably to a CFB inhibitor, indicating that MASP-3 inhibition prevents the AP-mediated destruction of RBCs predictive of extravascular hemolysis. OMS906 is currently in clinical development for the treatment of PNH.

Delivery of α-Particles By a Human-Rat Chimeric CD82 Monoclonal Antibody Potently Inhibits the Proliferation of CD82-Expressing Acute Myeloid Leukemia Cells in a Murine Xenograft Model

[Background] We previously found that acute myeloid leukemia (AML) cells aberrantly express CD82, a member of the tetraspanin family, on their surface. Functional analyses of CD82 by either depletion or forced expression of CD82 revealed that CD82 plays a role in the adhesion of AML cells to the bone marrow microenvironment in association with the inhibition of matrix metallopeptidase 9 (IJC 2013). In addition, CD82 transactivates several signaling pathways and upregulates anti-apoptotic Bcl-2L12 molecules in AML cells (Ikezoe T, et al. Int J Cancer. 2014;134:55, PLoS One. 2015;10: e0125017, Leukemia 2015;29:2296, Canc Sci. 2017;108:685). Alpha particle-emitting radionuclides are very attractive for cancer therapy, especially for micrometastases and isolated cancer cells commonly observed in leukemia, because of their high linear energy transfer and short effective path length in tissues. Astatine-211 ( 211At), with an appropriate half-life (7.2 hours), emits α-particles with higher energy in a shorter distance than ß-particles. It is ideal for cancer therapy through targeting tumor cells with α-particles by breaking double-stranded DNA while minimizing damage to normal cells. We have recently generated 211At-labeled human-rat chimeric CD82 monoclonal antibody ( 211At-h/r CD82 mAb) to deliver α-particles to CD82-expressing AML cells. [Aims] We conducted this study to evaluate the efficacy of a treatment strategy targeting CD82-expressing AML cells with 211At-h/r CD82 mAb. [Methods] Immunohistochemical staining was conducted to evaluate the binding of h/r CD82 mAb to U937 AML cells. 211At was produced by 209Bi(α, 2n) 211At nuclear reactions using an cyclotron (MP-30, Sumitomo Heavy Industries Ltd., Tokyo, Japan) at our institution, and h/r CD82 mAb was radiolabeled as described in our previous report (Oriuchi N, et al. Sci Rep. 2020;10:6810). A high-level CD82-expressing human AML cells xenograft (U937) was established in nude mice. In the biodistribution study, the mice were intravenously injected with 0.25 MBq of 211At-h/r CD82 mAb, and sacrificed at 1 min, 1, 3, 6, and 24 h after the injections (n=3 in each group). Blood, organs, and tumor tissues were collected, weighed, and measured for radioactivity using a gamma counter. The radioactivities of the blood, organs, and tumor tissues are presented as percent injected radioactivity dose per gram (%ID/g). In the treatment study, the mice were randomly divided into a nontreated (control, n=3) and two treated groups after the formation of palpable tumors. The mice in the treated groups were intravenously injected with either non-radiolabeled h/r CD82 mAb (h/r CD82 mAb, n=5) or 63.6 MBq of 211At-h/r CD82 mAb (n=4) on day 0. The tumor size of each mouse was measured daily until day 40 treatment. When the surface of the tumor tissue ruptured or the tumor diameter exceeded 20 mm, the tumor size measurement was stopped, and the mice were euthanized. [Results] Dense staining of CD82 by h/r CD82 mAb in a block of U937 cells was confirmed by immunohistochemical staining. The uptake levels of 211At-h/r CD82 mAb in the tumor significantly increased over time, which were 1.3 ± 0.3%ID/g, 6.3 ± 0.4%ID/g, 8.4 ± 2.0%ID/g, and 8.7 ± 0.8%ID/g at 1 min, and 1, 3, and 6 h after the injection, respectively. The highest tumor uptake level was achieved 6 h after the injection. This study revealed that the tumor volume significantly increased over time in the control and h/r CD82 mAb groups (from 106.9±36.6 mm 3 on day 0 to 4195 ± 1359.7 mm 3 on day16 in the control group, p&amp;lt;0.001; from 115.5 ± 11.7 on day 0 to 4045.5 ± 1912.1 mm 3 on day16 in the h/r CD82 mAb group, p&amp;lt;0.001). There was no significant difference in tumor volume between the control and h/r CD82 mAb groups. In contrast, the tumor volume significantly decreased over time after treatment with 211At-h/r CD82 mAb until day 10 (from 200.9±44.4 mm 3 on day 0 to 45.0 ± 60.5 mm 3 on day10, p&amp;lt;0.001 vs control and h/r CD82 mAb groups). Notably, two mice had no palpable tumor on day 45, indicating complete elimination of AML cells. [Conclusion] Delivery of α-particles by h/r CD82 mAb to CD82-expressing AML cells may be a promising strategy to overcome this lethal disease.

Influence of socioeconomic status on the presence of obstructive coronary artery disease and cardiovascular outcomes in patients undergoing invasive coronary angiography

Abstract Background Although it has been documented that low socioeconomic status (SES) is associated with increased risk of mortality and cardiovascular disease (CVD), this issue has not been addressed in patients at high CVD risk. This study was performed to investigate the association of the patient’s SES with the presence of obstructive coronary artery disease (CAD) and long-term cardiovascular outcomes who undergo invasive coronary angiography (ICA). Methods A total of 9,530 patients who underwent ICA for the evaluation and treatment of CAD (66.0 ± 12.3 years and 60.2% male) were retrospectively reviewed. The patients were divided into two groups according to the health insurance type: those with low SES who had the Medical aid program (Medical aid beneficiary [MAB] group; n = 1,436) and those with high SES who had the National Health Insurance program (National Health Insurance beneficiary [NHIB] group; n = 8,094). The primary outcome was a composite of cardiac death, acute myocardial infarction, coronary revascularization, and ischemic stroke. Results Of the study patients, 1,436 (15.1%) were in the MAB group. The prevalence of cardiovascular risk factors was higher in the MAB group compared to the NHIB group. However, the prevalence of obstructive CAD was similar between the two groups (62.8% vs. 64.2%; p = 0.306). During a median follow-up period of 3.5 years (interquartile range, 1.0-5.9 years), the incidence of the composite cardiovascular event was significantly higher in the MAB group than in the NHIB group (20.2% vs. 16.2%, p &amp;lt; 0.001). In multivariable Cox regression analysis, compared to the NHIB group, the MAB group was independently associated with worse clinical outcomes even after controlling for potential confounders (adjusted odds ratio, 1.28; 95% confidence interval, 1.07-1.54; p = 0.006). Conclusions Although CAD prevalence was similar, MABs showed an increased risk of composite cardiovascular events than NHIBs in Korean adults undergoing ICA. This provides additional evidence for the association between low SES and an increased risk of CVD, even in high-risk subjects.

CEA dynamics for predicting response after anti-EGFR monoclonal antibody treatment in metastatic colorectal cancer

Carcinoembryonic antigen (CEA) is the most widely used tumor marker in metastatic colorectal cancer (mCRC). However, its potential as a predictive marker of progression in mCRC during systemic chemotherapy, particularly in patients receiving monoclonal antibodies as a combination therapy, has remained of interest. Herein, we investigated whether CEA changes could predict disease progression and clinical outcomes in patients with mCRC cotreated with systemic chemotherapy and/or biologic agents. A total of 1261 patients with mCRC undergoing a first-line systemic treatment were included in this retrospective study. We analyzed the optimal cut-off value for CEA changes to predict progression at the first response evaluation by the treatment arm (chemotherapy alone, chemotherapy plus anti-vascular endothelial growth factor (VEGF) monoclonal antibody [mAb], and chemotherapy plus anti-epidermal growth factor receptor [EGFR] mAb). These cut-off values were then used to predict overall survival (OS) and progression-free survival (PFS). When stratified by their treatment arm, 891 (70.6%), 266 (21.0%), and 104 (8.2%) of the study patients were included in the chemotherapy alone-, anti-VEGF mAb, and anti-EGFR mAb groups, respectively. The optimal CEA cut-off values were 16.5% and 38.9% increase in the whole cohort and anti-EGFR mAb group, respectively, and these values showed high sensitivity and specificity for predicting disease progression. The patients in the entire population and anti-EGFR mAb group with CEA changes below these cut-off values showed significantly better OS and PFS outcomes compared those whose changes were above cut-off values. Among the patients with mCRC treated with anti-VEGF mAb, no associations were found between OS or PFS outcomes and CEA changes. CEA is potentially a good surrogate marker for predicting disease progression and survival outcomes in patients with mCRC receiving first-line systemic chemotherapy alone or chemotherapy with anti-EGFR mAb, whereas it is less effective in those treated with anti-VEGF mAb.

Noninvasive Imaging OX40+ Activated T Cells Provides Early Warning of Rheumatoid Arthritis

PurposeThe goal of this study was to develop an imaging probe—IRDye-680RD-OX40 mAb—that can be used for noninvasive imaging and optical imaging of rheumatoid arthritis (RA). OX40/OX40 ligand (OX40L) interactions have been shown to exert potent costimulatory effects on T cell activation. Detectable change in T cell activation profiles was observed in early RA.MethodsOX40 expression pattern was analyzed by flow cytometry. N-hydroxysuccinimide (NHS) esters are used to label proteins selectively on free amino groups of OX40 monoclonal antibody (mAb). Characterization of IRDye-680RD-OX40 mAb was measured and a fluorescence spectrum gathered. Cell binding assay was also performed between activated and naïve murine T cells. Longitudinal near-infrared fluorescence (NIRF) imaging of the probe was performed on day 8, day 9, day 10, and day 11 of adjuvant-induced arthritis (AIA) mouse model. Paw thickness and body weight were compared between the OX40 mAb and IgG injection groups.ResultsNIRF imaging with IRDye-680RD-OX40 mAb revealed strong OX40-positive responses with high specificity. Flow analysis showed that OX40 was specifically expressed on the surface of T cells in RP and spleen of AIA model. The AIA group was significantly differentiated from the control group at all time points with imaging monitoring. The region of interest (ROI) was in line with ex vivo imaging and biodistribution study. This study highlights the potential utility of the OX40 NIRF imaging as a new strategy for RA prediction and T cell monitoring.ConclusionThe results provide evidence that IRDye-680RD-OX40 mAb detects organized T cells activation in early RA. The optical probe was capable of detection of RA pathogenesis. It identified transcriptional responses to RA that mediate its immune functions. Thus, it may be an ideal probe for RA imaging.Graphical

SOX plus bevacizumab versus SOX plus cetuximab as initial treatment of recurrent advanced colorectal cancer with wild-type KRAS (MCSGO-1107 study): A phase II randomized study.

136 Background: Although clinical outcomes of chemotherapy in patients with locally advanced or metastatic colorectal cancer (CRC) have improved over the last decade, the standard-of-care chemotherapy regimens for patients with unresectable RAS wild-type CRC remain to be discussed. The aim of this study was to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated, unresectable, locally advanced, or metastatic CRC with wild-type KRAS. Methods: This phase II, randomized, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated, unresectable, locally advanced, or metastatic CRC with wild-type KRAS. Forty-five patients were enrolled in this study between February 2012 and October 2016. Results: The overall response rate (ORR) for the SOX+B-mab group was 59.1%, whereas that for the SOX+C-mab group was 43.5% (p = 0.29). The disease control rate (DCR) for the SOX+B-mab group was 90.9%, whereas that of the SOX+C-mab group was 91.3% (p = 0.96). For all patients, median OS were 25.3 months (95% CI: 16.5–39.4 months) in the SOX+B-mab group and 15.5 months (95% CI: 7.30–30.4 months, p = 0.167) in the SOX+C-mab group. Median PFS were 11.7 months (95% CI: 7.37–18.2 months) in the SOX+B-mab group and 5.5 months (95% CI: 3.36–10.1 months, p = 0.077) in the SOX+C-mab group. In the SOX+B-mab group, OS and PFS were not significantly different with and without early tumor shrinkage (ETS). However, in the SOX+C-mab group, patients with ETS had significantly better OS (30.4 months [95% CI: 8.0–44.3 months, p = 0.032]) and PFS (12.0 months [95% CI: 5.1–19.7 months, p = 0.003]) than those without ETS. Conclusions: The safety and efficacy of SOX+B-mab and SOX+C-mab as initial treatment for unresectable CRC with wild-type KRAS were almost the same. ETS was more correlated with PFS in the SOX+C-mab group than in the SOX+B-mab group, suggesting consideration of treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen. Clinical trial information: UMIN000006706 .

Anti-VEGF and Anti-EGFR Antibody Therapy on T-Cell Infiltration and TCR Variation in Metastatic Colorectal Cancer.

Chemotherapy combined with anti-EGFR or anti-VEGF monoclonal antibodies (mAb) is widely used to treat patients with metastatic colorectal cancer (mCRC). Here, we investigated the effects of these antibodies on T-cell infiltration and T-cell receptor (TCR) repertoire variation in CRC liver metastases. Ten patients with mCRC received chemotherapy in combination with anti-EGFR (n=6) or anti-VEGF (n=4) mAb. T-cell infiltration was examined for CD3 and CD8 by carrying out immunohistochemistry on biopsy or surgical specimens from liver metastases before and after treatment. TCR repertoire analysis was carried out on specimens with post-treatment CD3+ T-cell infiltration. T-cell infiltrations were approximately 83% (5/6) and 50% (2/4), following treatment with anti-EGFR or anti-VEGF mAb, respectively. TCR repertoire analysis revealed higher clonality and lower diversity of TCR alpha and beta (TRA and TRB) in the anti-VEGF mAb group than that in the anti-EGFR group mAb. Furthermore, the percentage of the common TCR clones between infiltrating T cells and T cells in peripheral blood was significantly lower in the anti-VEGF mAb group compared to that in the anti-EGFR mAb group. The population of T cells infiltrating liver metastases in the anti-VEGF mAb group differed from that in the anti-EGFR mAb group.

Lung Ultrasound Is Useful for Evaluating Lung Damage in COVID-19 Patients Treated with Bamlanivimab and Etesevimab: A Single-Center Pilot Study

Background and Objectives: COVID-19 induces massive systemic inflammation. Researchers have spent much time and effort finding an excellent and rapid image tool to evaluate COVID-19 patients. Since the pandemic's beginning, lung ultrasound (LUS) has been identified for this purpose. Monoclonal antibodies (mAb) were used to treat mild patients and prevent respiratory disease worsening. Materials and Methods: We evaluated 15 Caucasian patients with mild COVID-19 who did not require home oxygen, treated with Bamlanivimab and Etesevimab (Group 1). A molecular nose-throat swab test confirmed the diagnosis. All were office patients, and nobody was affected by respiratory failure. They were admitted to receive the single-day infusion of mAb treatment in agreement with the Italian Drug Agency (AIFA) rules for approval. LUS was performed before the drug administration (T0) and after three months (T1). We compared LUS at T1 in other outpatients who came for follow-up and were overlapping at the time of diagnosis for admittance criteria to receive mAb (Group 2). Results: Our COVID-19 outpatients reported no hospitalization in a follow-up visit after recovery. All patients became SARS-CoV-2 negative within one month since T0. LUS score at T0 was 8.23 ± 6.46. At T1 we found a significant decrease in Group 1 LUS score (5.18 ± 4.74; p < 0.05). We also found a significant decrease in the LUS score of Group 1 T1 compared to Group2 T1 (5.18 ± 4.74 vs 7.82 ± 5.21; p < 0.05). Conclusion: Early treatment of the SARS-CoV-2 virus effectively achieves a better recovery from disease and reduces lung involvement after three months as evaluated with LUS. Despite extrapolation to the general population may be done with caution, based on our data this ultrasound method is also effective for evaluating and following lung involvement in COVID-19 patients.

878. Association between Anterior Nasal and Plasma SARS-CoV-2 RNA Levels and Hospitalization or Death for Non-Hospitalized Adults with Mild-to-Moderate COVID-19

Abstract Background Data are currently limited on the performance of SARS-CoV-2 RNA levels as predictors or surrogate markers for clinical outcomes in outpatients with mild-to-moderate COVID-19. Methods This exploratory analysis used data from 2205 non-hospitalized adults who enrolled between August 2020 and July 2021 and participated in placebo-controlled evaluations of two monoclonal antibody (mAb) agents (bamlanivimab [n=317] or amubarvimab/romlusevimab [n=837]), and an open-label cohort of bamlanivimab recipients [n=1051] as part of the ACTIV-2/A5401 platform trial. SARS-CoV-2 RNA levels were measured in anterior nasal (AN) swabs and plasma at day 0 (pre-treatment) and AN at day 3. We fit regression models to estimate the association between RNA level or detection and subsequent hospitalization/death within 28 days of enrollment. Results One-hundred four participants (53/571 [9%] on placebo and 51/1634 [3%] on mAb) died or were hospitalized through day 28. Median AN RNA levels were lower at day 3 compared to day 0 in both placebo (2.5 vs 4.0 log10 copies/mL [cp/mL]) and mAb (2.3 vs 4.9) groups. For placebo recipients, higher Day 0 AN RNA was associated with an increasing risk of hospitalization/death, ranging from 3% to 16% for &amp;lt; 2 and ≥ 6 log10 cp/mL, respectively. Although only 1% had quantifiable plasma SARS-CoV-2 RNA, there was a similar trend for day 0 plasma RNA: 5% hospitalizations/death for undetectable RNA, 16% for detectable but not quantifiable RNA, and 80% for ≥ 2 log10 cp/mL. Among 485 placebo recipients with days 0 and 3 AN RNA results, the risk of subsequent hospitalization/death was highest among those with ≥ 5.0 log10 cp/mL at both days [8/78; 10%] and lowest for those with unquantifiable levels at both days [0/124; 0%]. Higher AN RNA at day 3 (adjusted for day 0 RNA) was associated with subsequent hospitalization/death among placebo recipients (relative risk (RR): 1.4 per log10 cp/mL; 95%CI: 1.0, 2.1), but not mAb recipients (RR: 1.0; 95%CI: 0.7, 1.6). Conclusion These findings suggest that AN and plasma SARS-CoV-2 RNA levels are predictive of hospitalization/death in the natural history setting. However, different associations for mAb and placebo recipients raises concerns for using AN RNA as a surrogate for clinical outcomes in mAb trials. Disclosures Kara W. Chew, M.D., M.S., Merck Sharp &amp; Dohme: Grant/Research Support|Pardes Bioscences: Advisor/Consultant Joseph J. Eron, MD, GSK: Advisor/Consultant|Merck: Advisor/Consultant Jonathan Z. Li, MD, MMSc, Abbvie: Advisor/Consultant|Merck: Grant/Research Support William A. Fischer, II, MD, Janssen: Adjudication Committee (Influenza)|Merck: Advisor/Consultant|Ridgeback Biopharmaceuticals: Research funding provided to the University of North Carolina|Roche: Advisor/Consultant|Syneos: Adjudication committee (Influenza) Paul Klekotka, MD, PhD, Eli Lilly: Employee|Eli Lilly: Stocks/Bonds David A. Margolis, MD MPH, Brii Biosciences: Stocks/Bonds David A. Wohl, M.D., Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Lilly: Grant/Research Support|ViiV: Advisor/Consultant|ViiV: Grant/Research Support Eric S. Daar, M.D., Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Merck: Advisor/Consultant|ViiV: Advisor/Consultant|ViiV: Grant/Research Support Davey M. Smith, M.D., M.A.S., Arena Pharmaceuticals: Advisor/Consultant|Bayer Pharmaceuticals: Advisor/Consultant|Brio Clinical.: Advisor/Consultant|Fluxergy: Advisor/Consultant|Kiadis: Advisor/Consultant|Linear Therapies: Advisor/Consultant|Matrix BioMed: Advisor/Consultant|Model Medicines: Advisor/Consultant|Signant Health: Advisor/Consultant|VxBiosciences: Advisor/Consultant Judith S. Currier, M.D., MSc, Merck: Advisor/Consultant.

Nasal Symptoms in Asthmatic Patients under Treatment with Anti-IL-5 Monoclonal Antibodies. A Real-Life Cohort Study.

We carried out an observational study in adults (≥18 years) on anti-IL-5 mAb treatment. Variables included ACT and SNOT-22 questionnaires, nasal polyps score, blood total IgE levels and blood eosinophil count. Overall, 38 participants were included in the study; 19 patients received mepolizumab, 17 were treated with benralizumab and 2 patients were given reslizumab. There was a statistically significant difference in the ACT and SNOT-22 scores before and after mAb treatment. ACT score increased from 11.05 to 21.5 after treatment (p &lt; 0.001). SNOT-22 decreased from 57 to 37.3 after treatment (p = 0.004). No statistically significant differences between mAb groups were observed regarding the ACT or the SNOT-22 (p = 0.775) response (p = 0.775). In addition, 60.53% of patients obtained a minimal clinically important difference (MCID) in SNOT-22. A significant clinical response based on SNOT-22 score evolution after anti-IL-5 mAb treatment was observed. This study also demonstrated that blood eosinophil count, rather than serum total IgE levels, is the best predictor of asthma symptom improvement, which was assessed through the ACT and SNOT-22 questionnaires.