A5065658092- Monoclonal and Polyclonal Antibodies Research
- Cytokine Signaling Pathways and Interactions
- HER2/EGFR in Cancer Research
- T-cell and B-cell Immunology
- Rheumatoid Arthritis Research and Therapies
- Chronic Lymphocytic Leukemia Research
- Immunotherapy and Immune Responses
- Nicotinic Acetylcholine Receptors Study
- Protein purification and stability
- Crystallization and Solubility Studies
- Folate and B Vitamins Research
- X-ray Diffraction in Crystallography
- Lymphoma Diagnosis and Treatment
- Vagus Nerve Stimulation Research
- Receptor Mechanisms and Signaling
- Immune Response and Inflammation
- Archaeological Research and Protection
- Systemic Lupus Erythematosus Research
- Immune Cell Function and Interaction
- Toxin Mechanisms and Immunotoxins
- Pharmacogenetics and Drug Metabolism
- Biochemical and Molecular Research
- Cell Adhesion Molecules Research
- Estrogen and related hormone effects
- Hemoglobinopathies and Related Disorders
AbbVie (United States)
2018-2025
Centre Hospitalier Régional et Universitaire de Nancy
2021-2023
Abbott (United States)
2009-2012
Établissement Français du Sang
2008
Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration limited because severe side effects. We therefore sought to identify an approach selectively target GCs inflamed tissue. Previous work identified that anti–tumor necrosis factor (TNF) antibodies bind transmembrane TNF undergo internalization; therefore, anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could...
Glucocorticoid receptor modulators (GRM) are the first-line treatment for many immune diseases, but unwanted side effects restrict chronic dosing. However, targeted delivery of a GRM payload via an immunology antibody-drug conjugate (iADC) may deliver significant efficacy at doses that do not lead to effects. We initiated our α-TNF-GRM ADC project focusing on identifying optimal and linker afforded stable attachment both antibody, resulting in identification synthetically accessible...
Using a convergent synthetic route to enable multiple points of diversity, series glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties in vitro. Despite covering large range profiling the nonconjugated small molecule was suboptimal they conjugated mouse antitumor necrosis factor (TNF) antibody using MP-Ala-Ala linker. Screening resulting drug conjugates (ADCs) provided better assessment efficacy physical properties, reinforcing need...
To facilitate subcutaneous dosing, biotherapeutics need to exhibit properties that enable high-concentration formulation and long-term stability in the buffer. For antibody–drug conjugates (ADCs), introduction of drug-linkers can lead increased hydrophobicity higher levels aggregation, which are both detrimental required for dosing. Herein we show how physicochemical ADCs could be controlled through drug-linker chemistry combination with prodrug payload, optimization these combinations...
Stable attachment of drug-linkers to the antibody is a critical requirement, and for maleimide conjugation cysteine, it achieved by ring hydrolysis succinimide ring. During ADC profiling in our in-house property screening funnel, we discovered that open form equilibrium with closed succinimide. Bromoacetamide (BrAc) was identified as optimal replacement, affords stable drug-linker while completely removing undesired open-closed equilibrium. Additionally, BrAc also offers multiple benefits...
Abstract The Bcl-2 family of proteins plays a critical role in controlling immune responses by regulating the expansion and contraction activated lymphocyte clones apoptosis. ABT-737, which was originally developed for oncology, is potent inhibitor Bcl-2, Bcl-xL, Bcl-w protein function. There evidence that Bcl-2–associated dysregulation apoptosis may contribute to pathogenesis autoimmunity lead development autoimmune diseases. In this study, we report ABT-737 treatment resulted inhibition...
T-helper 17 (Th17) cells produce homodimeric IL17A/A and IL17F/F cytokines as well the heterodimeric IL17A/F isoform, all having known roles in defense against extracellular pathogens including fungal infection. Antibodies targeting IL17A (such secukinumab ixekizumab) have been approved to treat psoriasis, psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis are under further investigation therapies inflammatory disorders such hidradenitis suppurativa giant cell arteritis....
Bruton's tyrosine kinase (BTK) is a non-receptor required for intracellular signaling downstream of multiple immunoreceptors. We evaluated ABBV-105, covalent BTK inhibitor, using in vitro and vivo assays to determine potency, selectivity, efficacy validate the therapeutic potential ABBV-105 inflammatory disease.ABBV-105 potency selectivity were enzymatic cellular assays. The impact on B cell function was assessed mechanistic models antibody production. Efficacy chronic disease animal...
Tumor necrosis factor α (TNFα) is a soluble cytokine that directly involved in systemic inflammation through the regulation of intracellular NF-κB and MAPK signaling pathways. The development biologic drugs inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis other chronic autoimmune diseases; however, proven be difficult drug small molecules. Herein, we present two-phase, fragment-based discovery (FBDD) effort which first identified isoquinoline...
We describe the discovery of a thioester-containing glucocorticoid receptor modulator (GRM) payload and corresponding antibody-drug conjugate (ADC). Payload
Background: Glucocorticoids (GC) are potent drugs used for treating many inflammatory diseases. While GCs effective in immune diseases, dose and duration of administration is limited due to significant side effects. Resting cells have very little TNF expression on the cell surface it only an activated state that upregulated. Upon stimulation, upregulated although a amount cleaved from cell, portion remains surface. We observed anti-TNF antibodies bind transmembrane (tmTNF) undergo...
Nuclear factor (erythroid-derived 2) like 2 (NRF2) is a nuclear transcription activated in response to oxidative stress that induces gene program dampens inflammation and can limit cell damage perpetuates the inflammatory response. We have identified A-1396076, potent selective NRF2 activator with demonstrated KEAP1 binding modulation of cellular mediated effects. In vivo administration A-1396076 inhibits across several rodent models autoimmunity when administered at or before time antigen...
Objective Janus kinase family members are essential for signaling by multiple cytokines, including many implicated in systemic lupus erythematosus (SLE) pathogenesis. To test whether inhibition of JAK1 can be efficacious SLE, we used a JAK1‐selective inhibitor (ABT‐317) and evaluated its ability to ameliorate disease murine SLE. Methods Efficacy ABT‐317 was using NZB/W‐F 1 mice treated prophylactically therapeutically. Primary endpoints were proteinuria, survival, saliva production. Other...
Pharmacokinetic variability in drug plasma exposure between different studies within the same species is not unexpected due to a variety of factors (such as differences formulation, active pharmaceutical ingredient salt form and solid-state, genetic strain, sex, environmental, disease status, bioanalysis methods, circadian rhythms, etc.) although from research group typically does occur great degree because these variables are commonly controlled. Surprisingly, pharmacology proof concept...
Topic: 27. Thalassemias Background: Endocrinopathies remain the main complication of iron overload in Transfusion Dependent Thalassemia (TDT), hypogonadism, generally due to oxidative stress related pituitary damage, being most frequent and often earliest manifestation. A well-managed chelation therapy initiated during infancy reduces risk pubertal delay hypogonadism. Few data about current development TDT patients receiving DFX are available literature. Aims: The aim this national study was...
Abstract Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation, swelling, and destruction of joints. In this study we used intra-articular lavage the knee joint to easily rapidly assess kinetics cellular infiltration cytokine production within local synovial environment during in rodent models arthritis. collagen induced rats, knees arthritic animals had increased cellularity composed neutrophils, monocytes T cells as well marked increases pro-inflammatory...
Abstract Rheumatoid Arthritis is characterized by chronic inflammation and synovial hyperplasia which leads to the destruction of cartilage bone. We have shown earlier (Wu et al, 2007) that blocking IL1α/β provides better efficacy than monotherapy in a CIA model when treatment begins at first clinical sign but not necessarily bone loss (therapeutic mode). These studies describe late therapeutic mCIA mode designed evaluate anti-inflammatory drugs on animals with established lesions. To define...