Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex–mediated immune responses

The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.

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633. Preliminary Results from a Phase 1 Single Ascending-Dose Study Assessing Safety, Serum Viral Neutralizing Antibody Titers (sVNA), and Pharmacokinetic (PK) Profile of ADG20: an Extended Half-Life Monoclonal Antibody Being Developed for the Treatment and Prevention of Coronavirus Disease (COVID-19)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.831 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S420-S420

Author(s):

Helen Paguntalan ◽

Zoltán Magyarics ◽

Lynn E Connolly ◽

Ellie Hershberger ◽

Kristin Narayan ◽

...

Keyword(s):

Monoclonal Antibody ◽

Half Life ◽

Phase 1 ◽

Neutralizing Antibody ◽

Post Dose ◽

Treatment And Prevention ◽

Dose Study ◽

Antibody Titers ◽

Single Ascending Dose Study ◽

Ongoing Phase

Abstract Background ADG20 is a fully human IgG1 monoclonal antibody engineered to have high potency and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like CoVs with pandemic potential by binding to a highly conserved epitope in the receptor-binding domain (RBD) of the spike protein. The Fc region of ADG20 has been modified to provide an extended half-life. ADG20 is in clinical development for the treatment and prevention of COVID-19. Methods This is an ongoing Phase 1, randomized, placebo (PBO)-controlled, single ascending-dose study of ADG20 administered intramuscularly (IM) or intravenously (IV) to healthy adults aged 18–50 years with no evidence of prior or current SARS-CoV-2 infection. Participants were randomized 8:2 in 3 cohorts (N=10/cohort: n=8 ADG20, n=2 PBO): ADG20 300 mg IM, 500 mg IV, and 600 mg IM. Safety, tolerability, PK, and sVNA titers were assessed up to 3 months post dose. Serum ADG20 concentrations were measured with a validated hybrid ligand binding liquid chromatography–mass spectrometry (MS)/MS assay. sVNA titers against authentic SARS-CoV-2 were determined by a plaque reduction neutralization assay. Results Overall, 30 participants received ADG20 (n=24) or PBO (n=6). Blinded safety data for all cohorts and PK/sVNA titer data for the 300 mg IM cohort are reported. Through a minimum of 10 weeks post dose, no study drug-related adverse events (AEs), serious AEs, injection site reactions, or hypersensitivity reactions were reported. The observed preliminary PK profile was dose proportional, consistent with an extended half-life monoclonal antibody, and well predicted by translational physiologically-based PK modeling. The measured 50% sVNA titer (MN50; geometric mean [coefficient of variation, %]) was 1382 (32.7%) 13 days after a single 300 mg IM dose. These values are within the range of peak serum neutralizing antibody titers reported for COVID-19 mRNA vaccines. Conclusion A single dose of ADG20, up to 600 mg IM, was well tolerated. Preliminary PK and sVNA titer profiles support the ongoing Phase 2/3 trials of ADG20 at a 300 mg IM dose for the prevention of COVID-19 (EVADE: NCT04859517) and treatment of ambulatory patients with mild to moderate COVID-19 (STAMP: NCT04805671). Disclosures Helen Paguntalan, MD, Adagio Therapeutics, Inc. (Scientific Research Study Investigator) Zoltán Magyarics, MD, PhD, Adagio Therapeutics, Inc. (Consultant) Lynn E. Connolly, MD, PhD, Adagio Therapeutics, Inc. (Employee) Ellie Hershberger, PharmD, Adagio Therapeutics, Inc. (Employee) Kristin Narayan, PhD, Adagio Therapeutics, Inc. (Employee) Deepali Gupta, BS, Adagio Therapeutics, Inc. (Employee) Paul G. Ambrose, PharmD, Adagio Therapeutics, Inc. (Employee) Frank Engler, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Ed Campanaro, BSN, MSHS, Adagio Therapeutics, Inc. (Employee) Anita F. Das, PhD, Adagio Therapeutics, Inc. (Consultant) Pete Schmidt, MD, Adagio Therapeutics, Inc. (Employee)

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MO258SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF VIS649, AN APRIL-NEUTRALIZING IGG2 MONOCLONAL ANTIBODY, IN HEALTHY VOLUNTEERS: PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE ASCENDING DOSE STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab104.0016 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Yusuke Suzuki ◽

Mohit Mathur ◽

Jonathan Barratt ◽

Frank Engler ◽

Jill Yarbrough ◽

...

Keyword(s):

Phase 1 ◽

Study Drug ◽

Dependent Manner ◽

Double Blind ◽

Serum Iga ◽

Dose Study ◽

Dose Response Effect ◽

Japanese Descent ◽

Dose Dependent ◽

Single Ascending Dose Study

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy (IgAN) is a glomerulonephritis characterized by the presence of circulating and glomerular immune complexes containing galactose-deficient (Gd) IgA1. A proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor superfamily of ligands, is thought to play a key role in the pathogenesis of IgAN by virtue of its role in class-switching to IgA production. VIS649, a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of APRIL, is in clinical development as a potential treatment for IgAN. The primary objective of this first-in-human study was to evaluate the safety and tolerability of VIS649 in healthy volunteers. Secondary objectives included characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of VIS649. Method This was a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study of VIS649 in healthy adult male and female volunteers (ClinicalTrials.gov identifier: NCT03719443). The study was conducted in sequential dosing cohorts. The first four cohorts (0.5, 2.0, 6.0, and 12.0 mg/kg, respectively) each enrolled 9 participants (4 of Japanese descent and 5 of non-Japanese descent) who were randomized to VIS649 or placebo in a ratio of 7:2. In addition, a fifth cohort enrolled 15 adults randomized to receive VIS649 6.0 mg/kg or placebo (10:5), followed by tetanus/diphtheria vaccine challenge after 28 days (TENIVAC®, Sanofi Pasteur Limited; the effect of APRIL inhibition on vaccine response is described in a companion abstract). Participants received intravenous administration of study drug on Day 1, were discharged from the institution on Day 2, and were followed for 16–24 weeks on an outpatient basis. Standard safety assessments and blood sampling for PK and PD were performed at regular intervals. Results 51 participants were randomized and dosed with study drug, of whom 47 (92.2%) completed the study. VIS649 was well tolerated, with no serious adverse events (AEs) or AEs that led to study discontinuation. Most treatment-emergent AEs (TEAEs) were mild; the incidence and severity of TEAEs were not dose dependent. One participant in the 2.0 mg/kg group experienced a severe TEAE of syncope following phlebotomy that the investigator considered unlikely to be related to study drug. There was no clinically relevant effect of treatment on laboratory tests, vital signs, electrocardiogram parameters, or physical examinations. VIS649 had non-linear PK: half-life (t½) increased with dose, while drug exposure (AUC) increased in a greater than dose proportional manner. Serum IgA, Gd-IgA1, IgG, and IgM were reversibly suppressed in a dose-dependent manner following VIS649 administration. The maximum mean percentage reductions from baseline occurred at Week 12 for the 12.0 mg/kg dose: IgA, -57.2% (Figure); Gd-IgA1, -71.6% (Figure); IgG, -33.6%; and IgM, -67.2%. These reductions were reversible and showed a dose-response effect with respect to time-to-recovery. Mean free (non-VIS649 bound) serum APRIL levels decreased to the lower limit of quantification (50 pg/mL) for all VIS649 doses at Week 1, and also showed a dose-response effect with respect to time-to-recovery. No depletions in circulating lymphocyte populations were observed. There were no significant PK or PD differences between Japanese and non-Japanese participants. Conclusion A single dose of VIS649, up to 12.0 mg/kg, was safe and well tolerated in healthy adults and was able to suppress free serum APRIL to the lower level of quantification. Serum Gd-IgA1 decreased in parallel with total serum IgA and recovered in a dose-dependent manner following reappearance of free APRIL in serum. These data support the further clinical development of VIS649 as a potential treatment for IgAN.

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NDI-010976, A Potent, Liver-Directed, Oral Inhibitor of Acetyl Coa Carboxylase for Non-Alcoholic Steatohepatitis: A Phase 1 Single Ascending Dose Study in Healthy Volunteers

Journal of Hepatology ◽

10.1016/s0168-8278(16)00866-7 ◽

2016 ◽

Vol 64 (2) ◽

pp. S501-S502 ◽

Cited By ~ 1

Author(s):

W.F. Westlin ◽

G. Harriman ◽

H.J. Harwood ◽

R. Kapeller ◽

S. Lennon ◽

...

Keyword(s):

Healthy Volunteers ◽

Phase 1 ◽

Acetyl Coa Carboxylase ◽

Acetyl Coa ◽

Alcoholic Steatohepatitis ◽

Dose Study ◽

Single Ascending Dose Study

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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00279-17 ◽

2017 ◽

Vol 61 (8) ◽

Cited By ~ 5

Author(s):

Jeremy J. Lim ◽

Michael A. Derby ◽

Yaping Zhang ◽

Rong Deng ◽

Richard Larouche ◽

...

Keyword(s):

Adverse Events ◽

Phase 1 ◽

Influenza B Virus ◽

Influenza B ◽

Double Blind ◽

Double Blind Placebo ◽

B Virus ◽

Dose Study ◽

Single Ascending Dose Study ◽

Dose Proportional

ABSTRACT Influenza B can cause significant morbidity and mortality. MHAB5553A, a human monoclonal immunoglobulin G1 (IgG1) antibody that binds to a highly conserved region of the hemagglutinin protein of influenza B virus, is being examined as a novel therapeutic for the treatment of influenza B patients with severe disease. This phase 1, randomized, double-blind, placebo-controlled, single-ascending-dose study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of MHAB5553A. Twenty-six healthy male and female volunteers of >18 years of age were randomized into five cohorts receiving a single intravenous (i.v.) dose of 120, 1,200, 3,600, 8,400, or 10,800 mg MHAB5553A or placebo (four active:one placebo, except for the 120-mg cohort [4:2]). Subjects were followed for 120 days after dosing. No subject discontinued the study, no dose-limiting adverse events or serious adverse events were reported, and a maximum tolerated dose (MTD) was not defined. The most commonly reported adverse events were cold symptoms and headache; most were mild and occurred at a similar rate across all cohorts. MHAB5553A showed no relevant time- or dose-related changes in laboratory values or vital signs compared to the placebo. The observed serum PK was linear and generally dose proportional, and the observed nasal PK was nonlinear and generally non-dose proportional. MHAB5553A is generally well tolerated in healthy volunteers up to at least a single i.v. dose of 10,800 mg and demonstrated linear serum PK consistent with those of a human IgG1 antibody lacking known endogenous targets in humans. (This study has been registered at ClinicalTrials.gov under registration no. NCT02528903.)

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The Generation and Regulation of Tissue-Resident Tregs and Their Role in Autoimmune Diseases

Journal of Immunology Research ◽

10.1155/2020/8815280 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Shuang Wang ◽

Xueyang Zou ◽

Yi Zhang ◽

Xiaoya Wang ◽

Wei Yang ◽

...

Keyword(s):

Skeletal Muscle ◽

T Cells ◽

Immune Responses ◽

Autoimmune Diseases ◽

Hot Spot ◽

Exploratory Stage ◽

And Function

Regulatory T cells (Tregs), as an important subset of T cells, play an important role in maintaining body homeostasis by regulating immune responses and preventing autoimmune diseases. In-depth research finds that Tregs have strong instability and plasticity, and according to their developmental origin, Tregs can be classified into thymic-derived Tregs (tTregs), endogenous-induced Tregs (pTregs), which are produced by antigen-stimulated T cells in the periphery in vivo, and induced Tregs (iTregs), which differentiate from naïve T cells in vitro. In recent years, studies have found that Tregs are divided into lymphatic and tissue-resident Tregs according to their location. Research on the generation and function of lymphoid Tregs has been more comprehensive and thorough, but the role of tissue Tregs is still in the exploratory stage, and it has become a research hot spot. In this review, we discuss the instability and plasticity of Tregs and the latest developments of tissue-resident Tregs in the field of biology, including adipose tissue, colon, skeletal muscle, and other Tregs that have been recently discovered as well as their production, regulation, and function in specific tissues and their role in the pathogenesis of autoimmune diseases.

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LB793 A phase 1, open-Label, single ascending dose study in healthy subjects of the safety, tolerability and pharmacokinetics of ASLAN004, a novel IgG anti-IL-13 receptor alpha 1 Inhibitor

Journal of Investigative Dermatology ◽

10.1016/j.jid.2021.07.123 ◽

2021 ◽

Vol 141 (9) ◽

pp. B19

Author(s):

L. Lee ◽

H. Hajireen ◽

A. Ward ◽

C. Firth

Keyword(s):

Healthy Subjects ◽

Phase 1 ◽

Open Label ◽

Receptor Alpha ◽

Dose Study ◽

Single Ascending Dose Study

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Suppressor T Cells in Human Diseases

Journal of Experimental Medicine ◽

10.1084/jem.20040812 ◽

2004 ◽

Vol 200 (3) ◽

pp. 273-276 ◽

Cited By ~ 112

Author(s):

Clare Baecher-Allan ◽

David A. Hafler

Keyword(s):

T Cells ◽

Infectious Diseases ◽

Immune Responses ◽

Autoimmune Diseases ◽

Peripheral Tolerance ◽

Human Diseases ◽

Suppressor T Cells ◽

Wide Range ◽

Human Immune

Although central and peripheral tolerance are important for the regulation of human immune responses to self- and microbial antigens, an important role of suppressor CD4+ CD25+ T cells is suggested from the recent investigations of human autoimmune diseases and HIV. These new data provide increasing evidence that altered function of CD4+ CD25+ T cells may be an important factor in a wide range of human inflammatory and infectious diseases.

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Advantages of Extracellular Ubiquitin in Modulation of Immune Responses

Mediators of Inflammation ◽

10.1155/2016/4190390 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Rusudan Sujashvili

Keyword(s):

Immune Responses ◽

Autoimmune Diseases ◽

B Lymphocytes ◽

Ubiquitin Proteasome System ◽

Cellular Processes ◽

Immune Mediated ◽

Ubiquitin Proteasome ◽

Good Potential ◽

Hematopoietic Cell Lines

T and B lymphocytes play a central role in protecting the human body from infectious pathogens but occasionally they can escape immune tolerance, become activated, and induce autoimmune diseases. All deregulated cellular processes are associated with improper functioning of the ubiquitin-proteasome system (UPS) in eukaryotic cells. The role of ubiquitin in regulation of immune responses and in autoimmune diseases is only beginning to emerge. Ubiquitin is found in intra- and extracellular fluids and is involved in regulation of numerous cellular processes. Extracellular ubiquitin ascribed a role in lymphocyte differentiation. It regulates differentiation and maturation of hematopoietic cell lines. Ubiquitination is involved in initiation, propagation, and termination of immune responses. Disrupted ubiquitination can lead to autoimmunity. Recent observations showed that it can suppress immune response and prevent inflammation. Exogenous ubiquitin may provide good potential as a new tool for targeted therapy for immune mediated disorders of various etiologies.

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