Preclinical safety and efficacy of the recombinant CR1 drug product CSL040 in rats and cynomolgus monkeys DOI Creative Commons

Tanja Ruthsatz,

Sandra Wymann,

Elena Velkoska

и другие.

Toxicology and Applied Pharmacology, Год журнала: 2024, Номер 495, С. 117191 - 117191

Опубликована: Дек. 7, 2024

CSL040 is a soluble, recombinant fragment of the complement receptor 1 (CR1) extracellular domain that acts as an inhibitor all three pathways system. Systemic toxicity, toxicokinetics (TK), and pharmacodynamics (PD) were assessed in two-week intravenous (IV) bolus studies Han Wistar rats cynomolgus monkeys. Recovery from any effects was evaluated during four-week recovery period. Daily repeat-dose administration for 2 weeks at doses up to 500 mg/kg IV well tolerated monkeys, leading no observed adverse effect level (NOAEL) both species. Safety pharmacology parameters such electrophysiology heart, blood pressure, heart rate, respiratory rate measurements, general toxicological readouts considered unaffected by treatment. Anti-drug antibodies (ADAs) monkeys some highest dose CSL040, but with on pharmacokinetics (PK), supportive adequate exposure levels required safety assessment. All inhibited dose-dependently CSL040. Additionally, cytokine detected vitro using release assay. These non-clinical demonstrated PD activity consistent its mode action, PK properties, profile supporting phase clinical strategy. A small follow-up study comparing PK/PD following subcutaneous (SC) also suggested latter route might be viable alternative administration.

Язык: Английский

Complement in human disease: approved and up-and-coming therapeutics DOI Creative Commons
Erin E. West, Trent M. Woodruff, Véronique Frémeaux‐Bacchi

и другие.

The Lancet, Год журнала: 2023, Номер 403(10424), С. 392 - 405

Опубликована: Ноя. 15, 2023

Язык: Английский

Процитировано

67
Contemporary review of IgA nephropathy DOI Creative Commons
Edward J. Filippone, Rakesh Gulati,

John L. Farber

и другие.

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Авг. 12, 2024

IgA nephropathy (IgAN) is considered the most common primary glomerulonephritis worldwide with a predilection for Asian-Pacific populations and relative rarity in those of African descent. Perhaps 20%–50% patients progress to kidney failure. The pathogenesis incompletely understood. Mesangial deposition immune complexes containing galactose-deficient IgA1 complexed anti-glycan IgG or antibodies results mesangial cell activation proliferation, inflammatory recruitment, complement activation, podocyte damage. Diagnosis requires biopsy interpreted by Oxford criteria. Additional pathologic features include podocytopathy, thrombotic microangiopathy, C4d staining. Biomarkers predicting adverse outcomes proteinuria, reduced GFR, hypertension, pathology. Acceptable surrogate endpoints therapeutic trials ongoing proteinuria rate eGFR decline. significance persisting hematuria remains uncertain. mainstay therapy supportive, consisting lifestyle modifications, renin–angiotensin inhibition (if hypertensive proteinuric), sodium-glucose-transporter 2 GFR endothelin-receptor antagonism proteinuric). Immunosuppression should be at high risk after maximal supportive care. Corticosteroids are controversial positive observed Chinese. They carry serious side effects. Similarly, mycophenolate may effective Other immunosuppressants uncertain benefit. Tonsillectomy appears efficacious Japanese. Active areas investigation B-cell agents targeting survival factors BAFF APRIL alternate pathway (Factors B D), lectin (MASP-2), (C3 C5). Hopefully soon, who how immunosuppression will clarified, failure can forestalled.

Язык: Английский

Процитировано

7
Paroxysmal nocturnal hemoglobinuria: Where we stand DOI Creative Commons
Jens Panse

American Journal of Hematology, Год журнала: 2023, Номер 98(S4)

Опубликована: Янв. 3, 2023

Abstract For the last 20 years, therapy of paroxysmal nocturnal hemoglobinuria (PNH) relied—up until recently—on antibody based terminal complement inhibitionon. PNH pathophysiology—a mutational defect leading to partial or complete absence complement‐regulatory proteins on blood cells—leads intravascular hemolysis and consequences such as thrombosis other sequelae. A plethora new drugs interfering with proximal cascade are under recent development first “proof‐of‐pinciple” inhibitor targeting C3 has been approved in 2021. “PNH: where we stand” will try give a brief account came from stand focusing therapeutic options. The associated improvements well potential actual future treatments their impact disease continue necessitate academic scientific focus improving treatment options side effects outcomes relevant individual patient lives circumstances order develop effective, safe, available for all hemolytic patients globally.

Язык: Английский

Процитировано

16
Reeling in complement in transplant‐associated thrombotic microangiopathy: You're going to need a bigger boat DOI Creative Commons
Sonata Jodele, Anthony Sabulski

American Journal of Hematology, Год журнала: 2023, Номер 98(S4)

Опубликована: Фев. 7, 2023

Over the last decade there have been numerous advances in both diagnosis and treatment of transplant-associated thrombotic microangiopathy (TA-TMA). These are largely result an improved understanding complement activation TA-TMA ability to prevent end organ injury death with timely initiation complement-blocking therapies. In this article, we review our current pathophysiology TA-TMA, particularly as it pertains activation, endothelial injury, clinical management. We then novel therapies that currently under investigation for use well discuss special considerations therapy hematopoietic stem cell transplant recipients. Through these reviews aim answer or at least provide educated discussion on most commonly posed management questions dilemmas.

Язык: Английский

Процитировано

14
GSK3 inhibition reduces ECM production and prevents age-related macular degeneration–like pathology DOI Creative Commons

Sophia M. DiCesare,

Antonio Ortega, Gracen E. Collier

и другие.

JCI Insight, Год журнала: 2024, Номер 9(15)

Опубликована: Авг. 7, 2024

Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD) is an age-related macular degeneration–like (AMD-like) caused by autosomal dominant R345W mutation in the secreted glycoprotein, fibulin-3 (F3). To identify new small molecules that reduce F3 production pigmented epithelium (RPE) cells, we knocked-in a luminescent peptide tag (HiBiT) into endogenous locus enabled simple, sensitive, and high-throughput detection of protein. The GSK3 inhibitor, CHIR99021 (CHIR), significantly reduced burden (expression, secretion, intracellular levels) immortalized RPE non-RPE cells. Low-level, long-term CHIR treatment promoted remodeling extracellular matrix, reducing sub-RPE deposit-associated proteins (e.g., amelotin, complement component 3, collagen IV, fibronectin), while increasing differentiation factors tyrosinase, pigment epithelium-derived factor). In vivo, 8-month-old R345W+/+ knockin mice with (25 mg/kg i.p., 1 mo) was well tolerated F3-associated AMD-like basal laminar deposit number size, thereby preventing main pathological feature these mice. This important demonstration molecule–based prevention pathology ML/DHRD may herald rejuvenation interest inhibition for degenerative diseases, including potentially AMD itself.

Язык: Английский

Процитировано

4
Cryo-EM analysis of complement C3 reveals a reversible major opening of the macroglobulin ring DOI
Trine A.F. Gadeberg, Martin Høgholm Jørgensen, Heidi Gytz Olesen

и другие.

Nature Structural & Molecular Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 23, 2025

Язык: Английский

Процитировано

0
Modulating the complement system through epitope-specific inhibition by complement C3 inhibitors DOI Creative Commons
Zhidong Chen,

M. Wang,

Wenqian Duan

и другие.

Journal of Biological Chemistry, Год журнала: 2025, Номер unknown, С. 108250 - 108250

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Enhanced renal ischemia/reperfusion injury repair potential of exosomes derived from B7-H1high mesenchymal stem cells DOI Creative Commons
Jiahui He, Yongming Yao, Ruiyan Wang

и другие.

Frontiers in Genetics, Год журнала: 2025, Номер 16

Опубликована: Апрель 2, 2025

Two subgroups with high expression of B7-H1 and low were successfully isolated from primitive human umbilical cord mesenchymal stem cells. And exosomes isolated. In comparison to the sham-operated group, mice in IRI group demonstrated elevated serum levels blood urea nitrogen (BUN) creatinine (Scr), accompanied by a more pronounced degree renal tissue damage. The administration via tail vein markedly accelerated recovery function mice, therapeutic effect beingmore those treated B7-H1high-Exo. Moreover RNA sequencing mouse kidney B7-H1high-Exo B7-H1low-Exo showed that eight genes (C3, IRF7, AREG, CXCL10, Aldh1l2, Fnip2, Vcam1, St6galnac3) involved pathophysiological process ischemia-reperfusion injury. vitro vivo experiments level C3 protein was significantly decreased, which indicated played role down-regulating C3.

Язык: Английский

Процитировано

0
Tissue-targeted regulators of complement for amelioration of human disease: rationale and novel therapeutic strategies DOI Creative Commons
Fei Liu, Stefan Wawersik, Stephen Tomlinson

и другие.

The Journal of Immunology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 21, 2025

Abstract The complement system is an essential part of innate immunity, and dysregulated underlying driver in many inflammatory autoimmune diseases. Currently approved complement-focused therapeutics rely on systemic blockade activation, but a major challenge with this approach that components exist high abundance undergo rapid turnover, creating large pharmacologic sink. To improve the arsenal therapies, tissue-targeting has emerged as strategy to re-regulate diseased tissue, while limiting blockade. This approach, which based directing modulators tissues through recognition tissue-fixed activated fragments, tissue-specific epitopes, or injury-associated neoepitopes, potential for enhanced potency durability reduced infection risk. In review, we discuss rationale tissue-targeted strategies taken achieve local regulation, current state preclinical clinical stage therapeutics, future directions.

Язык: Английский

Процитировано

0
Activation of the complement system by nanoparticles and strategies for complement inhibition DOI Creative Commons
Hajira Haroon,

Elisha Dhillon,

Z. Shadi Farhangrazi

и другие.

European Journal of Pharmaceutics and Biopharmaceutics, Год журнала: 2023, Номер 193, С. 227 - 240

Опубликована: Ноя. 8, 2023

The complement system is a multicomponent and multifunctional arm of the innate immune system. Complement contributes to non-specific host defence maintains homeostasis through multifaceted processes pathways, including crosstalk with adaptive system, contact (coagulation) kinin systems, alarmin high-mobility group box 1. also present intracellularly, orchestrating wide range housekeeping physiological in both nonimmune cells, thus showing its more sophisticated roles beyond immunity, but are still controversial. Particulate drug carriers nanopharmaceuticals typically architectures surface patterns that trigger different ways, resulting beneficial adverse responses depending on extent activation regulation as well pathophysiological circumstances. Here we consider role regulations evaluate mechanisms by which nanoparticles modulate responses. Effective strategies for prevention nanoparticle-mediated introduced discussed.

Язык: Английский

Процитировано

6