BACKGROUND:Electronic medical record database studies suggest that underlying allergic diathesis is a risk factor for COVID-19 but may attenuate outcomes. OBJECTIVE:To evaluate the effect of background atopic conditions on outcomes across clinical trials in patients with and without COVID-19 treated with casirivimab plus imdevimab (CAS + IMD). METHODS:This analysis included 4057 outpatients with acute COVID-19. Supplementary analyses involved 2652 patients without COVID-19, investigating prevention in the home or community settings. Participants were randomized to CAS + IMD or placebo. Participants with atopic conditions were identified by medical history and categorized as follows: (1) any atopic condition; (2) atopic conditions excluding asthma; (3) asthma excluding other atopic conditions; and (4) no atopic conditions. Assessments included time to hospitalization/death and change in viral load from baseline to day 7 analyzed using adjusted regression methodologies. RESULTS:Among placebo subjects, the adjusted risk of hospitalization/death was 52% lower in those with an atopic background without asthma vs those without atopy (hazard ratio [HR]: 0.48; 95% CI, 0.31-0.74; P < .001). The adjusted risk of hospitalization/death in patients receiving placebo was 2.90 times higher for those with asthma only vs those without atopic conditions (HR, 2.90; CI, 1.55-5.48; P < .001). The HR for hospitalization/death for CAS + IMD vs placebo was 0.26 for patients without atopy (CI, 0.12-0.58; P < .001), 0.17 (CI, 0.06-0.49; P < .001) for patients with atopic conditions excluding asthma, and 0.32 (CI, 0.16-0.63; P < .001) for those with asthma only. In the prevention studies, unvaccinated subjects with atopic conditions excluding asthma exhibited more than 2-fold increase in the rate of contracting COVID-19 vs those without atopy (HR, 2.10; CI, 1.05-4.21; P = .037). Adjustment for imbalance in antihistamine use had little effect on estimates. CONCLUSION:In COVID-19 prevention and treatment, atopic disease was associated with heightened susceptibility to infection but better clinical outcomes. CAS + IMD improved clinical outcomes in both cases.

REGN17092 is a human IgG 1 monoclonal antibody which includes a YTE modification in the Fc portion to extend the half-life. It targets severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study is a randomized, double-blind, placebo-controlled, single ascending dose study to evaluate the safety, tolerability and pharmacokinetics of REGN17092 in healthy subjects (18-60 yrs of age). The study consisted of 5 study cohorts evaluating intravenous (lV) dosing (300mg, 1200mg and 2400mg) and subcutaneous (SC) dosing (300mg and 1200mg) of REGN17092. The primary end point was safety and tolerability. Secondary end points included pharmacokinetics and anti-drug antibodies. Between Nov 2023 and Feb 2024, a total of 78 participants screened; 40 subjects were randomized. Clinical adverse events were reported by 34/40 (85%) subjects. Most frequently reported adverse events, assessed as related by the investigator, in ≥3 participants included injection site reactions (ISR) (17.5%) and headache (10%).). Most clinical adverse events were mild to moderate in intensity. Infusion related reactions (all mild) occurred in 9 subjects (4 headache, 2 diastolic hypotension, 1 blood pressure increase, 1 dysgeusia, 1 migraine). Injection site reactions (all mild) occurred in 13 subjects. Most frequent injection site reaction symptoms reported include erythema, edema and pain. There were 2 serious adverse events (atrial fibrillation and cholecystectomy), neither were deemed related to investigational product. The REGN17092 exhibited an extended half-life of greater than 70 days. REGN17092 is well tolerated in healthy adults. The pharmacokinetic analyses suggest the REGN17092 maintains high plasma concentrations for several months after a single subcutaneous administration. Flonza Isa, MD, Regeneron Pharmaceuticals, Inc.: Stocks/Bonds (Public Company) Ashley Sconzo, MS, Regeneron Pharmaceuticals, Inc.: Stocks/Bonds (Public Company) Yogesh Patel, PhD, Regeneron Pharmaceuticals, Inc.: Stocks/Bonds (Public Company) Maria Rosario, PhD, Regeneron Pharmaceuticals, Inc.: Stocks/Bonds (Public Company) Kenneth C. Turner, PhD, Regeneron Pharmaceuticals, Inc.: Stocks/Bonds (Public Company) Oleg Milberg, PhD, Regeneron Pharmaceuticals, Inc.: Stocks/Bonds (Public Company) Ana Gonzalez Ortiz, MD, PhD, Regeneron Pharmaceuticals, Inc.: Stocks/Bonds (Public Company) Lori Faria, BS, Regeneron Pharmaceuticals, Inc.: Stocks/Bonds (Public Company) Ingeborg Heirman, PhD, Regeneron Pharmaceuticals, Inc.: Stocks/Bonds (Public Company) Alina Baum, PhD, Regeneron Pharmaceuticals, Inc.: Stocks/Bonds (Public Company) Thomas Norton, MD, Regeneron Pharmaceuticals, Inc.: Stocks/Bonds (Public Company) Veronica Mas Casullo, MD, Regeneron Pharmaceuticals, Inc.: Stocks/Bonds (Public Company) Boaz Hirshberg, MD, MBA, Regeneron Pharmaceuticals, Inc.: Stocks/Bonds (Public Company)

Immune Aplastic Anemia (AA) is an autoimmune disease where hematopoietic stem and progenitor cells (HSPC) are destroyed by cytotoxic CD8+ T cells, resulting in peripheral cytopenias, i.e. anemia, thrombocytopenia and neutropenia. Most compelling evidence that HSPC destruction is immune-mediated is that two-thirds of severe AA patients demonstrate hematologic improvement in response to immunosuppressive therapy consisting of anti-thymocyte globulin and cyclosporin A. Interferon γ (IFNγ) and tumor necrosis factor α (TNFα) have both been implicated as critical effector molecules involved in the destruction of bone marrow HSPCs in AA. Furthermore, mRNA expression of the inflammatory chemokine receptor CXCR3 and the chemokine CCL20, a ligand of CCR6, has been shown to be elevated in peripheral blood and bone marrow mononuclear cells, suggesting a role for T helper/cytotoxic (Th/c) 1 and Th/c17 cells in the pathobiology of AA. To further elucidate the pathobiology of AA, we conducted a comprehensive multiproteomic analysis of adult AA patients eligible for bone marrow transplant ([BMT]; n=20; samples pre-BMT) and matched healthy controls (n=20). We performed plasma proteomic analyses using Olink and conducted high-dimensional immunophenotyping by flow cytometry using peripheral blood mononuclear cells (PBMCs). Using Olink proteomic analysis, we observed that, relative to healthy controls, plasma from AA patients exhibited significantly higher levels of several hematopoietic growth factors, including thrombopoietin (TPO), erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) and Fms-like tyrosine kinase 3 ligand (FLT3LG), indicating that an AA disease signature is reflected in circulation. Furthermore, we observed that AA patients had significant (Bonferroni corrected) elevations in interleukin 15 (IL15), a cytokine that plays a crucial role in T cell activation and effector functions. Thus, we looked at other T cell-associated molecules and observed trends towards elevations in several other cytokines in plasma of AA patients, including IFNγ, IL17A, IL17F, and interleukin 2 receptor α (IL2Rα). Interestingly, there was also a trend towards an increase in plasma CCL20 in AA patients, as previously reported. Using high-dimensional flow cytometry immunophenotyping on PBMCs, we observed an increase in the percentage of circulating T cells, both CD4+ and CD8+ T cells, in PBMCs from AA patients. These T cells exhibited an activated phenotype with increased surface expression of the costimulatory receptor 4-1BB. Profiling of both CD4+ and CD8+ T cell subsets revealed a T helper 17 (Th17) and T cytotoxic 1 (Tc1) cell enrichment with increased proportions in overall Th17 (both Th1.17 and Th17.22 cells) and Tc1 cells (both Tc1 and Tc1.17 cells). While antigen presentation plays a critical role in initiating immune responses in autoimmune diseases, little is known about the role of antigen presenting cells (APCs) in AA pathobiology. Here, we showed that, while the percentage of professional APCs, i.e., B cells, monocytes and dendritic cells, was reduced in blood of AA patients, these cells presented an activated phenotype characterized by significant upregulation of the costimulatory receptor 4-1BB at their surface. In addition, B cells from AA patients exhibited higher surface expression of the inflammatory chemokine receptor CCR6 and the antigen presentation molecule HLA-DR, while monocytes expressed higher level of CCR7, a chemokine receptor essential for cell migration to lymph nodes.Conclusion: In this study, we confirmed that AA is characterized by significant increases in several hematopoietic growth factors in the periphery, which may reflect compensatory mechanisms that counterbalance the lack of blood cell production in the bone marrow. Furthermore, we demonstrated that AA is an autoimmune disease characterized by an inflammatory phenotype biased towards a Th/c1.17 immune response and increased circulating Th1 and Th17 cytokines (e.g. IFNγ and IL17A/F). Finally, we showed that multiple APCs may participate in antigen presentation in AA, as both B cells and monocytes/DCs exhibit an activated phenotype with increased expression of chemokine receptors and major histocompatibility complex class II molecules. Overall, our data suggest that broad APC activation and pathogenic Th/c1.17 immune responses contribute to AA pathobiology.

Background: Aplastic anemia (AA) is considered a T cell-mediated autoimmune disease where hematopoietic stem and progenitor cells are destroyed by cytotoxic T cells, resulting in peripheral cytopenias (neutropenia, anemia, thrombocytopenia). For patients in whom hematologic stem cell transplantation is not available or suitable as a treatment option, T cell-targeted immunosuppressive therapy (IST) is standard of care. However, current IST options (eg, anti-thymocyte globulin and cyclosporine) are limited by toxicities. Given that lymphocyte development, proliferation, and activity are mediated in large part by gamma chain (gc) cytokines (IL2, IL4, IL7, IL9, IL15, IL21), which share a common receptor subunit (interleukin 2 receptor subunit gamma; IL2RG), IL2RG blockade may provide an novel means to suppress pathogenic T cell responses in T cell-mediated diseases, like AA. In nonhuman primates, IL2RG blockade profoundly decreases NK cells and reduces T cells by ~50%, with no impact on neutrophils or platelets, supporting its potential utility in AA. Methods: REGN7257, a human monoclonal antibody that binds IL2RG, inhibiting signaling of all gc cytokines, was evaluated in a phase 1, multinational, open-label, first-in-human study involving patients with severe aplastic anemia (SAA) that is refractory to or relapsed on standard of care IST. Seventeen participants were enrolled across 4 dose levels: 5 mg/kg (n=3), 10 mg/kg (n=6), 20 mg/kg (n=4), and 40 mg/kg (n=4), administered as a single IV infusion. The primary endpoint was the incidence of adverse events (AEs) and serious adverse events (SAEs) up to 12 months post-treatment. Adverse events of interest (AEIs) were defined as any non-hematologic grade 3 or above AE (excluding febrile neutropenia or typical infections that occur in the neutropenic patient), opportunistic infections, or evidence of potential liver impairment. Secondary endpoints included changes in blood lymphocyte counts, serum pharmacokinetics (PK), and hematologic response rates. Exploratory analyses included changes in serum cytokines. Results: Observed AEs were generally consistent with underlying SAA. Eighty-eight AEs were reported across 16 of the 17 participants; most (85%) were non-serious. Seven participants (41%) experienced at least 1 SAE; most (86%) were related to febrile neutropenia/infectious events or hospitalizations for transfusions to address anemia or thrombocytopenia. All SAEs were considered by the investigator as not related to study drug. No AEIs were reported. Two participants with profound neutropenia (neutrophils ≤20 cells/µL) at baseline experienced multiple infectious AEs and died after early termination from the study. Both deaths were assessed by the investigator as not related to study drug. Two participants experienced infusion-related reactions (1 in the 5 mg/kg dose group, 1 in the 40 mg/kg dose group); both received the full dose of REGN7257 and both events were considered non-serious. REGN7257 exhibited nonlinear PK, with greater than dose-proportional increases in exposure with increasing dose. Treatment induced transient increases in NK and CD8 T cell counts across all dose levels, followed by reductions to below baseline at doses ≥10 mg/kg in some patients. Transient increases in gc cytokines in serum were observed, consistent with target engagement. Transient reductions in inflammatory/effector molecules in serum were also observed. One patient with IST-relapsed SAA who received a single dose of 20 mg/kg achieved a partial hematologic response. Improvement in peripheral cytopenias correlated contemporaneously with reduction in lymphocyte counts and serum hematopoietic growth factors. The hematologic response was lost as drug cleared but returned with a repeat dose (40 mg/kg). Conclusion: Data from this first-in-human evaluation of REGN7257 in patients with IST-refractory or IST-relapsed SAA show that IL2RG blockade was generally well-tolerated with observed AEs being generally consistent with the underlying disease. Reductions in lymphocytes and changes in serum cytokines and inflammatory/effector molecules were consistent with drug activity. One patient achieved a partial hematologic response that waned as drug cleared, but returned with retreatment. Taken together, REGN7257's acceptable safety profile and biologic activity in AA support its continued development, as well as its potential utility in less severe T cell-mediated diseases.

Background: Acute graft-versus-host disease (aGvHD) is a severe immune complication that can occur following allogeneic hematopoietic stem cell transplantation (HSCT). aGvHD arises when T cells from the donor graft recognize the recipient's tissues as foreign and initiate an immune response against the recipient. This attack typically occurs within the first 100 days post-transplant, leading to tissue damage in various organs, including the skin, gastrointestinal tract and liver. Methods: To further elucidate the pathobiology of aGvHD and response to corticosteroid (CS) treatment, we conducted a comprehensive multiproteomic analysis of HSCT recipients who developed aGvHD post-transplantation (n=10; samples collected pre-HSCT, at time of aGvHD onset and 30 days after the onset of aGvHD) and healthy controls (n=10). All aGvHD patients received CS as first-line treatment, and 8 of 10 patients achieved clinical remission (median of 16 days from aGvHD onset to remission [range: 7-56 days]). We performed plasma proteomic analyses using Olink and conducted immunophenotyping by flow cytometry using peripheral blood mononuclear cells (PBMCs). Results: Immunophenotyping of PBMCs from HSCT recipients at onset of aGvHD showed a significant increase in the percentage of circulating monocytes and monocyte-derived dendritic cells (mDCs) compared to pre-HSCT, and those populations were normalized with CS treatment by 30 days post aGvHD onset. Deeper phenotypic analysis of monocytic cells at aGVHD onset revealed that circulating monocytes, and to a lesser extent mDCs, exhibited an activated phenotype with increased expression of CCR7 (a chemokine receptor essential for cell migration to lymph nodes), CD38 (involved in tissue recruitment) and components of the receptor for IL15 (IL2Rγ and IL15Rα). This phenotypic change at aGvHD onset was accompanied by increased plasma levels of macrophage colony-stimulating factor (M-CSF), as well as APRIL and BAFF, which are two cytokines primarily expressed by monocytes and DCs. Intriguingly, CS treatment only partially reverted the overall activation of monocytic cells, with surface IL15Rα remaining elevated on both monocytes and mDCs at day 30 post aGvHD onset. Similarly, APRIL plasma levels remained significantly elevated in CS-treated patients. Reductions in the percentage of circulating T cells at aGvHD onset compared to pre-HSCT were also observed, consistent with delayed reconstitution of adaptive immunity compared to innate immunity post-HSCT. Despite these relative reductions, extensive phenotypic analysis showed that CD8+ T cells, and to a lesser extent CD4+ T cells, were highly proliferative and presented with an effector phenotype (e.g. increased surface expression of CD38, CD95 [Fas], IL2Rβ and IL15Rα). Granzyme B expression was also highly expressed in CD8+ T cells at aGvHD onset. These phenotypic changes were associated with increased plasma levels of the effector molecules Granzyme B, IFNγ and IFNγ-induced chemokines (CXCL9 and CXCL10), as well as multiple γ chain (γc) cytokines and soluble receptors (IL2, IL2Rα, IL7 and IL15Rα). As expected, CS treatment partially reduced T cell proliferation and activation. However, Granzyme B expression in CD8+ T cells was remarkably unaffected by CS treatment. Similarly, other cell surface (e.g. IL15Rα) and plasma (e.g. CXCL10) markers remained elevated at day 30 post aGvHD onset.Conclusion: We demonstrated that aGvHD onset is characterized by relative increases in circulating monocytic cells displaying an activated phenotype. Despite relative reductions in circulating T cells, both CD4+ and CD8+ T cells also exhibited a highly activated and proliferative phenotype. As expected, the overall activation state associated with aGvHD was reduced by CS treatment, and this was associated with clinical response, as most of the patients (8/10) were steroid-sensitive and achieved remission. However, several activation markers associated with both T cells and monocytic cells remained elevated in CS-treated aGvHD patients at day 30 post aGvHD diagnosis (e.g. plasma APRIL and CXLC10; IL15Rα on both T and monocytic cells, and Granzyme B in CD8+ T cells). Our data suggest that aGvHD onset involves innate cell activation followed by an adaptive response that is partially resistant to CS, with underlying inflammation persisting in treated patients.

Background While immunotherapy has been highly successful for the treatment of some cancers, for others, the immune response to tumor antigens is weak leading to treatment failure. The resistance of tumors to checkpoint inhibitor therapy may be caused by T cell exhaustion resulting from checkpoint activation.Methods In this study, lentiviral vectors that expressed T cell epitopes of an experimentally introduced tumor antigen, ovalbumin, or the endogenous tumor antigen, Trp1 were developed. The vectors coexpressed CD40 ligand (CD40L), which served to mature the dendritic cells (DCs), and a soluble programmed cell death protein 1 (PD-1) microbody to prevent checkpoint activation. Vaccination of mice bearing B16.OVA melanomas with vector-transduced DCs induced the proliferation and activation of functional, antigen-specific, cytolytic CD8 T cells.Results Vaccination induced the expansion of CD8 T cells that infiltrated the tumors to suppress tumor growth. Vector-encoded CD40L and PD-1 microbody increased the extent of tumor growth suppression. Adoptive transfer demonstrated that the effect was mediated by CD8 T cells. Direct injection of the vector, without the need for ex vivo transduction of DCs, was also effective.Conclusions This study suggests that therapeutic vaccination that induces tumor antigen-specific CD8 T cells coupled with a vector-expressed checkpoint inhibitor can be an effective means to suppress the growth of tumors that are resistant to conventional immunotherapy.

Objectives There is limited qualitative research on patients’ experiences with long COVID-19, and how specific symptoms impact their daily lives. The study aimed to understand patients’ lived experiences of long COVID-19 and to develop a conceptual model representing the symptoms and their impact on overall quality of life.Setting Qualitative study consisting of a comprehensive literature review, and in-depth clinician and patient semistructured interviews.Participants Forty-one adult patients with long COVID-19, of whom 18 (44%) were recruited through Regeneron Pharmaceuticals’s clinical trials and 23 (56%) through recruitment agencies; 85.4% were female and 73.2% were White. Five independent clinicians treating patients with long COVID-19 were interviewed. Concept saturation was also assessed.Primary and secondary outcomes Interview transcripts were analysed thematically to identify concepts of interest spontaneously mentioned by patients, including symptoms and their impacts on daily life, to guide the development of the conceptual model.Results Findings from the literature review and clinician and patient interviews resulted in the development of a conceptual model comprising two overarching domains: symptoms (upper respiratory tract, lower respiratory tract, smell and taste, systemic, gastrointestinal, neurocognitive and other) and impacts (activities of daily living, instrumental activities of daily living, physical impacts, emotional, social/leisure activities and professional impacts). Saturation was achieved for the reported impacts. The symptoms reported were heterogenic; neurocognitive symptoms, such as numbness, ringing in ears, haziness, confusion, forgetfulness/memory problems, brain fog, concentration, difficulties finding the right word and challenges with fine motor skills, were particularly pertinent for several months.Conclusion The conceptual model, developed based on patient experience data of long COVID-19, highlighted numerous symptoms that impact patients’ physical and mental well-being, and suggests humanistic unmet needs. Prospective real-world studies are warranted to understand the pattern of long COVID-19 experienced in larger samples over longer periods of time.

This study aimed to assess the effects of a monoclonal antibody (mAb) combination on symptoms, daily function, and overall health-related quality of life. We analyzed patient-reported outcomes data from symptomatic outpatients in a phase 1/2/3 trial. Patients with confirmed SARS-CoV-2 infection and ≥ 1 risk factor for severe COVID-19 received mAb treatment (casirivimab plus imdevimab 1200 mg) or placebo. Prespecified exploratory assessments included time to sustained symptoms resolution, usual health, and return to usual activities (assessed daily for 29 days). The trial was conducted from September 2020 to February 2021, prior to widespread COVID-19 vaccination programs and Omicron-lineage variants against which casirivimab + imdevimab is not active. In this analysis 736 outpatients received mAb and 1341 received placebo. Median time to sustained symptoms resolution was consistently shorter with mAb versus placebo (≥ 2 consecutive days: 14 vs 17 days, [nominal p = 0.0017]; ≥ 3 consecutive days: 17 vs 21 days, [nominal p = 0.0046]). Median time to sustained return to usual health and usual activities were both consistently shorter with mAb versus placebo (≥ 2 consecutive days: 12 vs 15 days [nominal p = 0.0001] and 9 vs 11 days [nominal p = 0.0001], respectively; ≥ 3 consecutive days: 14 vs 18 days [nominal p = 0.0003] and 10 vs 13 days [nominal p = 0.0041], respectively). mAb treatment against susceptible SARS-CoV-2 strains improved how patients feel and function, as evidenced by shortened time to sustained symptoms resolution and return to usual health and activities. Future studies are warranted to assess the patient experience with next generation mAbs. Registration number, NCT04425629; Submission date June 11, 2020.

The safety of casirivimab + imdevimab (CAS + IMD) (anti-severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] monoclonal antibodies [mAbs]) in pediatric outpatients with coronavirus disease 2019 (COVID-19) was evaluated in a randomized phase 1/2/3 trial. Consistent with adults, CAS + IMD was generally well tolerated with low drug-induced immunogenicity rates. The findings support the development of next-generation anti-SARS-CoV-2 mAbs for at-risk pediatric patients. Casirivimab and imdevimab (CAS + IMD) treatment was well-tolerated in pediatric outpatients with >= 1 risk factor for severe coronavirus disease 2019 (COVID-19), with similar safety and pharmacokinetic profiles as observed in adults. CAS + IMD was associated with low rates of COVID-19-related medically attended visits.

Abstract Background The field of long COVID research is rapidly evolving, however, tools to assess and monitor symptoms and recovery of the disease are limited. The objective of the present study was to develop a new patient-reported outcomes instrument, the Symptoms Evolution of Long COVID‑19 (SE-LC19), and establish its content validity. Methods The 40-item SE-LC19 instrument was developed based on patient-relevant empirical evidence from scientific literature and clinical guidelines that reported symptoms specific to long COVID. A 2-part mixed-method approach was employed. Part 1: Qualitative interviews with a purposive sample of 41 patients with confirmed long COVID were conducted for the content validation of SE-LC19. During cognitive debriefing interviews, patients were asked to describe their understanding of the instrument’s instructions, specific symptoms, response options, and recall period to ensure its relevance and comprehensiveness. Five clinicians of different medical specialties who regularly treated patients with long COVID were also interviewed to obtain their clinical expert opinions on SE-LC19. Part 2: Exploratory Rasch Measurement Theory (RMT) analysis was conducted to evaluate the psychometric properties of the SE-LC19 data collected during the interviews. Results Overall, patients reported that the instructions, questions, recall period, and response options for SE-LC19 were comprehensive and relevant. Minor conceptual gaps reported by patients captured nuances in the experience of some symptoms that could be considered in future studies. Some patients suggested a revision of the recall period from 24 h to 7 days to be able to capture more symptoms given the waxing and waning nature of some symptoms. Clinicians found the instrument comprehensive with minimal suggestions regarding its content. Exploratory RMT analyses provided evidence that the SE-LC19 questionnaire performed as intended. Conclusion The present mixed-methods study in patients with confirmed long COVID supports the content validity and applicability of the SE-LC19 instrument to evaluate the symptoms of patients with long COVID. Further research is warranted to explore the psychometric properties of the instrument and refine a meaningful and robust patient-relevant endpoint for use in different settings such as clinical trials and clinical practice to track the onset, severity, and recovery of long COVID.

Objective Pregnant women with COVID-19 are at elevated risk for severe outcomes, but clinical data on management of these patients are limited. Monoclonal antibodies, such as casirivimab plus imdevimab (CAS+IMD), have proven effective in treating non-pregnant adults with COVID-19, prompting further evaluation in pregnant women.Methods A phase 3 portion of an adaptive, multicentre, randomised, double-blind, placebo-controlled trial evaluated the safety, clinical outcomes, pharmacokinetics and immunogenicity of CAS+IMD (1200 mg or 2400 mg) in the treatment of pregnant outpatients with COVID-19 (NCT04425629). Participants were enrolled between December 2020 and November 2021, prior to the emergence of Omicron-lineage variants against which CAS+IMD is not active. Safety was evaluated in randomised participants who received study drug (n=80); clinical outcomes were evaluated in all randomised participants (n=82). Only two pregnant participants received placebo, limiting conclusions regarding treatment effect. Infants born to pregnant participants were followed for developmental outcomes ≤1 year of age.Results In pregnant participants, CAS+IMD was well tolerated, with no grade ≥2 hypersensitivity or infusion-related reactions reported. There were no participant deaths, and only one COVID-19–related medically attended visit. Although two pregnancies (3%) reported issues in the fetus/neonate, they were confounded by maternal history or considered to be due to an alternate aetiology. No adverse developmental outcomes in infants ≤1 year of age were considered related to in utero exposure to the study drug. CAS+IMD 1200 mg and 2400 mg rapidly and similarly reduced viral loads, with a dose-proportional increase in concentrations of CAS+IMD in serum. Pharmacokinetics were consistent with that reported in the general population. Immunogenicity incidence was low.Conclusion CAS+IMD treatment of pregnant outpatients with COVID-19 showed similar safety, clinical outcomes and pharmacokinetic profiles to that observed in non-pregnant adults. There was no evidence of an impact on developmental outcomes in infants ≤1 year of age.Trial registration number NCT04425629.

Increased use of antiviral monoclonal antibodies (mAbs) for treatment and prophylaxis necessitates better understanding of their impact on endogenous immunity to vaccines and viruses. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic presented an opportunity to study immunity in individuals who received antiviral mAbs and were subsequently immunized with vaccines encoding the mAb-targeted viral spike antigen. Here, we describe the impact of administration of an antibody combination, casirivimab plus imdevimab (CAS+IMD), on immune responses to subsequent SARS-CoV-2 vaccination in humans, nonhuman primates, and mice. The presence of CAS+IMD at the time of vaccination led to a specific diminishment of vaccine-elicited pseudovirus neutralizing antibody titers without overall dampening of spike protein-directed immune responses, including antibody, B cell, and T cell responses. The impact on pseudovirus neutralizing titers extended to other therapeutic anti-spike protein antibodies when used as either monotherapy or combination therapy. The specific reduction in pseudovirus neutralizing titers was the result of epitope masking, a phenomenon where specific epitopes are bound by high-affinity antibodies and blocked from B cell recognition. Encouragingly, this reduction in pseudovirus neutralizing titers was reversible with additional booster vaccination. Moreover, by assessing the antiviral immune response in SARS-CoV-2-infected individuals treated therapeutically with CAS+IMD, we demonstrated alteration of antiviral humoral immunity in those who had received mAb therapy, but only in those individuals who had yet to start mounting their natural immune response at the time of mAb treatment. Together, these data demonstrate that antiviral mAbs can alter endogenous humoral immunity during vaccination or infection.

Severe, protracted symptoms are associated with poor outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In a placebo-controlled study of casirivimab and imdevimab (CAS + IMD) in persons at high risk of severe coronavirus disease 2019 (COVID-19; n = 3816), evolution of individual symptoms was assessed for resolution patterns across risk factors, and baseline SARS-CoV-2-specific antibody responses against S1 and N domains. CAS + IMD versus placebo provided statistically significant resolution for 17/23 symptoms, with greater response linked to absence of endogenous anti–SARS-CoV-2 immunoglobulin (Ig)G, IgA, or specific neutralizing antibodies at baseline, or high baseline viral load. Resolution of five key symptoms (onset days 3–5)—dyspnea, cough, feeling feverish, fatigue, and loss of appetite—independently correlated with reduced hospitalization and death (hazard ratio range: 0.31–0.56; P < 0.001–0.043), and was more rapid in CAS + IMD-treated patients lacking robust early antibody responses. Those who seroconverted late still benefited from treatment. Thus, highly neutralizing COVID-19-specific antibodies provided by CAS + IMD treatment accelerated key symptom resolution associated with hospitalization and death in those at high risk for severe disease as well as in those lacking early, endogenous neutralizing antibody responses.

The common γ chain (γc; IL-2RG) is a subunit of the interleukin (IL) receptors for the γc cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The lack of appropriate neutralizing antibodies recognizing IL-2RG has made it difficult to thoroughly interrogate the role of γc cytokines in inflammatory and autoimmune disease settings. Here, we generated a γc cytokine receptor antibody, REGN7257, to determine whether γc cytokines might be targeted for T cell-mediated disease prevention and treatment. Biochemical, structural, and in vitro analysis showed that REGN7257 binds with high affinity to IL-2RG and potently blocks signaling of all γc cytokines. In nonhuman primates, REGN7257 efficiently suppressed T cells without affecting granulocytes, platelets, or red blood cells. Using REGN7257, we showed that γc cytokines drive T cell-mediated disease in mouse models of graft-versus-host disease (GVHD) and multiple sclerosis by affecting multiple aspects of the pathogenic response. We found that our xenogeneic GVHD mouse model recapitulates hallmarks of acute and chronic GVHD, with T cell expansion/infiltration into tissues and liver fibrosis, as well as hallmarks of immune aplastic anemia, with bone marrow aplasia and peripheral cytopenia. Our findings indicate that γc cytokines contribute to GVHD and aplastic anemia pathology by promoting these characteristic features. By demonstrating that broad inhibition of γc cytokine signaling with REGN7257 protects from immune-mediated disorders, our data provide evidence of γc cytokines as key drivers of pathogenic T cell responses, offering a potential strategy for the management of T cell-mediated diseases.

The common γ chain cytokine receptor (γc; IL2RG) family of cytokines includes interleukin 2 (IL2), IL4, IL7, IL9, IL15, and IL21. This set of cytokines exhibits broad pleiotropic actions on both the innate and adaptive immune system with each cytokine sharing the IL2RG chain as part of its signaling receptor complex. Mutations in the IL2RG gene result in X-linked severe combined immunodeficiency (XSCID) in humans, whereby patients present with dramatically diminished numbers of T-cells and NK-cells, and dysfunctional B-cells. Given the crucial role for γc cytokines in the development and function of lymphocytes, modulating their activities may offer therapeutic potential in a range of immune-mediated diseases. To understand the effects of γc cytokine blockade on immune cells including T-cell subsets, we utilized REGN7257, a fully human IL2RG monoclonal antibody that inhibits γc cytokine-induced signaling, and tested its ability to suppress immune cell populations and their functions in cynomolgus monkey and human. Mixed lymphocyte reaction assays were performed to look at the impact of γc cytokine signaling blockade on activation/proliferation of human T-cells. To further analyze the contribution of γc cytokines to T-cell differentiation and function, we performed in vitro transcriptomic studies on human peripheral blood mononuclear cells stimulated with anti-CD3/CD28 beads. In addition, we assessed the effects of γc cytokine signaling blockade on both human T-cell and NK-cell effector functions in target cell killing assays. Finally, we evaluated the effects of γc cytokine signaling blockade with REGN7257 on immune cell populations and their activation/proliferation status in cynomolgus monkeys by flow cytometry. γc cytokine signaling blockade with REGN7257 demonstrated potent inhibition of allogeneic responses in mixed human lymphocyte reaction assays, by preventing T-cell activation and proliferation. Two-tailed gene set enrichment analysis identified 4 distinct patterns of significantly enriched gene sets that were impacted by γc cytokine signaling upon CD3/CD28-induced activation of human T-cells: gene sets involved in inflammatory responses, differentiation and proliferation, activation and immune responses, as well as those related to adhesion and migration. These signatures were blocked with REGN7257 treatment. In addition, REGN7257 potently blocked activation (i.e. IFNG production) and cytotoxic activity of both human T-cells and NK-cells in in vitro target cell killing assays. Finally, the impact of γc cytokine signaling blockade on lymphocyte populations in vivo were investigated in cynomolgus monkeys in a single dose pharmacokinetic/pharmacodynamic study and a repeat-dose toxicology study. Inhibition of γc cytokine signaling with REGN7257 in cynomolgus monkeys reduced circulating T-cells and NK-cells, without impacting B-cells, granulocytes, platelets or red blood cells. γc cytokine signaling blockade led to a reduction in both peripheral CD4+ and CD8+ T-cell counts with effector memory T-cells being the most impacted T-cell population studied. Similarly to that observed in human T-cell MLR assays, both activated and proliferating T-cells were reduced in monkeys dosed with REGN7257. Taken together, these pharmacological observations highlight the major role for γc cytokine signaling in maintenance of lymphocyte populations (i.e. NK-cells and T-cells), but not other immune cell populations, such as granulocytes, platelets and red blood cells. Furthermore, our data highlight the importance of γc cytokines in driving functions of cynomolgus monkeys and human effector NK and T-cells, opening a potential new route for the management of immune-mediated diseases.

IMPORTANCE The monoclonal antibody combination of casirivimab and imdevimab reduced viral load, hospitalization, or death when administered as a 1200-mg or greater intravenous (IV) dose in a phase 3 COVID-19 outpatient study. Subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients. OBJECTIVE To assess the virologic efficacy of casirivimab and imdevimab across different IV and SC doses compared with placebo. DESIGN, SETTING, AND PARTICIPANTS This phase 2. randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study included outpatients with SARS-CoV-2 infection at 47 sites across the United States. Participants could be symptomatic or asymptomatic; symptomatic patients with risk factors for severe COVID-19 were excluded. Data were collected from December 15, 2020, to March 4, 2021. INTERVENTIONS Patients were randomized to a single IV dose (523 patients) of casirivimab and imdevimab at 300, 600, 1200, or 2400 mg or placebo; or a single SC dose (292 patients) of casirivimab and imdevimab at 600 or 1200 mg or placebo. MAIN OUTCOMES AND MEASURES The primary end point was the time-weighted average daily change from baseline (TWACB) in viral load from day 1 (baseline) through day 7 in patients seronegative for SARS-CoV-2 at baseline. RESULTS Among 815 randomized participants, 507 (282 randomized to IV treatment, 148 randomized to SC treatment, and 77 randomized to placebo) were seronegative at baseline and included in the primary efficacy analysis. Participants randomized to IV had a mean (SD) age of 34.6 (9.6) years (160 [44.6%] men; 14 [3.9%] Black; 121 [33.7%] Hispanic or Latino; 309 [86.1%] White); those randomized to SC had a mean age of 34.1(10.0) years (102 [45.3%] men; 75 [34.7%] Hispanic or Latino; 6 [2.7%] Black; 190 [84.4%] White). All casirivimab and imdevimab treatments showed significant virologic reduction through day 7. Least-squares mean differences in TWACB viral load for casirivimab and imdevimab vs placebo ranged from -0.56 (95% CI; -0.89 to -0.24) log(10), copies/mL for the 1200-mg IV dose to -0.71(95% CI, -1.05 to -0.38) logo copies/mL for the 2400-mg IV dose. There were no adverse safety signals or dose-related safety findings, grade 2 or greater infusion-related or hypersensitivity reactions, grade 3 or greater injection-site reactions, or fatalities. Two serious adverse events not related to COVI D-19 or the study drug were reported. CONCLUSIONS AND RELEVANCE In this randomized clinical trial including outpatients with asymptomatic and low-risk symptomatic SARS-CoV-2, all IV and SC doses of casirivimab and imdevimab comparably reduced viral load.

Lentiviral vector–based dendritic cell vaccines induce protective T cell responses against viral infection and cancer in animal models. In this study, we tested whether preventative and therapeutic vaccination could be achieved by direct injection of antigen-expressing lentiviral vector, obviating the need for ex vivo transduction of dendritic cells. Injected lentiviral vector preferentially transduced splenic dendritic cells and resulted in long-term expression. Injection of a lentiviral vector encoding an MHC class I–restricted T cell epitope of lymphocytic choriomeningitis virus (LCMV) and CD40 ligand induced an antigen-specific cytolytic CD8+ T lymphocyte response that protected the mice from infection. The injection of chronically infected mice with a lentiviral vector encoding LCMV MHC class I and II T cell epitopes and a soluble programmed cell death 1 microbody rapidly cleared the virus. Vaccination by direct injection of lentiviral vector was more effective in sterile alpha motif and HD-domain containing protein 1–knockout (SAMHD1-knockout) mice, suggesting that lentiviral vectors containing Vpx, a lentiviral protein that increases the efficiency of dendritic cell transduction by inducing the degradation of SAMHD1, would be an effective strategy for the treatment of chronic disease in humans.

Pathogenic immune cell responses in inflammatory and autoimmune diseases can be driven by cytokines of the common gamma chain (γc) cytokine family (IL2, IL4, IL7, IL9, IL15, and IL21). γc cytokines signal through their corresponding receptors, expressed primarily on immune cells, that share a common coreceptor, interleukin 2 receptor subunit gamma (IL2RG) that is required for signaling. To understand the roles of γc cytokines in driving inflammatory and autoimmune diseases, we generated REGN7257, a fully human IL2RG monoclonal antibody that inhibits γc cytokine-induced signaling, and we tested its ability to suppress pathogenic immune cell responses in mouse models of graft-versus-host disease (GVHD), immune aplastic anemia and multiple sclerosis (MS). We first evaluated the efficacy of REGN7257 in xenogeneic and allogeneic mouse models of GVHD. In the xenogeneic model, immunodeficient NOD-scid-IL2RGnull mice were engrafted with human peripheral blood mononuclear cells (huPBMC). In the allogeneic GVHD model, irradiated BALB/c mice were engrafted with bone marrow cells and splenocytes from Il2rghu/hu mice. In the xenogeneic GVHD mouse model, we also analyzed the effects of γc cytokine signaling blockade with REGN7257 on inflammation and immune cell infiltration into tissues (e.g. liver, bone marrow), as well as liver fibrosis. Finally, we assessed the effects of IL2RG blockade on pathogenic immune cell responses in an experimental autoimmune encephalomyelitis (EAE) model of MS, looking at immune cell infiltration into the central nervous system (CNS) and associated demyelination. In both xenogeneic and allogeneic models of GVHD, prophylactic γc cytokine signaling blockade with REGN7257 effectively protected mice from weight loss and resulted in improved survival, by reducing T-cell expansion in blood and production of pro-inflammatory cytokines in serum. Similarly, in the xenogeneic GVHD model, dosing with REGN7257 starting 3 weeks after huPBMC administration effectively protected mice from weight loss and death. Consistent with the classic pathology of GVHD, tissues of control mice were highly infiltrated by immune cells, including CD4+ and CD8+ T-cells, while γc cytokine signaling blockade strongly reduced immune cell infiltration, with reduced tissue levels of pro-inflammatory cytokines. Blockade of γc cytokine signaling also led to a reduction in the severity of chronic GVHD, with decreased macrophage infiltration in liver and associated hepatic fibrosis. In this xenogeneic model of GVHD, hemoglobin levels and platelet numbers in blood were both reduced, indicating anemia and thrombocytopenia, respectively, which are two complications associated with aplastic anemia. In addition to peripheral pancytopenia, recipient mice that were engrafted with huPBMC also showed severe marrow aplasia. Importantly, this phenotype of aplastic anemia was prevented by blockade of γc cytokine signaling. Finally, in an EAE mouse model of MS, inhibition of γc cytokine signaling with REGN7257 alleviated disease progression and significantly prolonged survival. This was associated with reduced inflammation and infiltration by immune cells (CD4+ T-cells, CD8+ T-cells, B-cells and monocytic cells) in the CNS, as well as decreases in myelin oligodendrocyte glycoprotein-specific antibody production. We showed that REGN7257 treatment efficiently protected the spinal cord from demyelination, which was associated with decreased oligodendrocyte injury and neuron protection. Blockade of γc cytokine signaling with REGN7257 protected mice against immune cell-mediated pathology in multiple disease models: an EAE model of MS, an allogeneic GVHD model, and a xenogeneic GVHD model that uniquely presents hallmarks of both acute and chronic GVHD as well as immune aplastic anemia. These data provide evidence of γc cytokines as key drivers of pathogenic immune cell responses, offering a potentially novel strategy for the management of inflammatory and autoimmune diseases, such as GVHD, immune aplastic anemia and MS.