A5031662196- Monoclonal and Polyclonal Antibodies Research
- T-cell and B-cell Immunology
- Cancer Immunotherapy and Biomarkers
- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- Immunodeficiency and Autoimmune Disorders
- CAR-T cell therapy research
- Systemic Lupus Erythematosus Research
- Dermatology and Skin Diseases
- Herbal Medicine Research Studies
- Chronic Lymphocytic Leukemia Research
- Cytokine Signaling Pathways and Interactions
- Immune Response and Inflammation
- Psoriasis: Treatment and Pathogenesis
- Ocular Diseases and Behçet’s Syndrome
- Microscopic Colitis
- Glycosylation and Glycoproteins Research
- Exercise and Physiological Responses
- Peptidase Inhibition and Analysis
- Hypothalamic control of reproductive hormones
- NF-κB Signaling Pathways
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Cancer Research and Treatments
- Chemokine receptors and signaling
- Whipple's Disease and Interleukins
Alpine Immune Sciences (United States)
2018-2024
Bristol-Myers Squibb (United States)
2013-2017
Bristol-Myers Squibb (Germany)
2016
Institut thématique Immunologie, inflammation, infectiologie et microbiologie
2007
The proinflammatory cytokines IL-17A and IL-17F have a high degree of sequence similarity share many biological properties. Both been implicated as factors contributing to the progression inflammatory autoimmune diseases. Moreover, reagents that neutralize significantly ameliorate disease severity in several mouse models human disease. mediates its effects through interaction with cognate receptor, IL-17 receptor (IL-17RA). We report here IL-17RA-related molecule, IL-17RC is for IL-17F....
Members of the CD28 family play important roles in regulating T-cell functions and share a common gene structure profile. We have identified VSTM3 as protein whose matches that other members. This (also known TIGIT WUCAM) has been previously shown to affect immune responses is expressed on NK cells, activated memory T Tregs. The nectin-family proteins CD155 CD112 serve counter-structures for VSTM3, also bind activating receptor CD226 cells cells. Hence, this group interacting forms network...
Objective Dysregulated APRIL/BAFF signaling is implicated in the pathogenesis of multiple autoimmune diseases, including systemic lupus erythematosus and nephritis. We undertook this study to develop evaluate a high‐affinity antagonist overcome clinical limitations existing B cell inhibitors. Methods A variant TACI‐Fc generated by directed evolution showed enhanced binding for both APRIL BAFF was designated povetacicept (ALPN‐303). Povetacicept compared wild‐type (WT) related molecules vitro...
Recent advances in cancer treatment with checkpoint blockade of receptors such as CTLA-4 and PD-1 have demonstrated that combinations agents complementary immunomodulatory effects the potential to enhance antitumor activity compared single agents. We investigated efficacy immune-modulatory interleukin-21 (IL-21) combined several syngeneic mouse tumor models. After establishment, mice were administered recombinant IL-21 (mIL-21) alone or combination blocking monoclonal antibodies against...
Corticotroph-derived glycoprotein hormone (CGH), also referred to as thyrostimulin, is a noncovalent heterodimer of alpha 2 (GPHA2) and beta 5 (GPHB5). Here, we demonstrate that both subunits CGH are expressed in the corticotroph cells human anterior pituitary, well skin, retina, testis. activates TSH receptor (TSHR); (125)I-CGH binding expressing TSHR saturable, specific, high affinity. In competition studies, unlabeled potent competitor for (125)I-TSH binding, whereas does not compete...
Abstract Background Overexpression or administration of interleukin 31 ( IL ‐31) has been shown to induce a profound itch response in mice and dogs. The chronic pruritus observed mouse ‐31 transgenic results the development skin lesions alopecia through excoriation from excessive scratching, condition similar that patients with atopic dermatitis AD ). Objective To test whether induces non‐human primates and, if so, treatment an anti‐ neutralizing monoclonal antibody mA b) can block response....
Despite the recent clinical success of T cell checkpoint inhibition targeting CTLA-4 and PD-1 pathways, many patients either fail to achieve objective responses or they develop resistance therapy. In some cases, poor blockade have been linked suboptimal CD28 costimulation inability generate maintain a productive adaptive anti-tumor immune response. To address this, here we utilize directed evolution engineer CD80 IgV domain with increased PD-L1 affinity fuse this an immunoglobulin Fc domain,...
Bispecific antibodies (bsAbs) present an attractive opportunity to combine the additive and potentially synergistic effects exhibited by combinations of monoclonal (mAbs). Current challenges for engineering bsAbs include retention binding affinity parent mAb or antibody fragment, ability bind both targets simultaneously, matching valency with biology. Other factors consider structural stability expression recombinant molecule, which may have significant impact on its development as a...
The disease state can modulate the penetration of large antibody-sized therapeutic molecules into affected tissues. Suitable bioanalytical methods are required for quantitative analysis drug tissue levels to enable a better understanding parameters influencing and target engagement.Described is sensitive selective LC-MS/MS assay quantification human mAb in mouse By homogenizing tissues directly serum, common serum calibration curve be used multiple A generic procedure was affinity...
Abstract Binding of Ag-Ab immune complexes to cellular FcγR promotes cell activation, release inflammatory mediators, and tissue destruction characteristic autoimmune disease. To evaluate whether a soluble could block the proinflammatory effects complexes, recombinant human (rh) versions FcγRIA, FcγRIIA, FcγRIIIA were prepared. rh-FcγRIA IgG was high affinity (KD = 1.7 × 10−10 M), whereas rh-FcγRIIA rh-FcγRIIIA bound with low 0.6–1.9 10−6 M). All rh-FcγR reduced complex precipitation,...
Binding of immune complexes to cellular FcgammaRs can promote cell activation and inflammation. In previous studies, a recombinant human (rh) soluble FcgammaR, rh-FcgammaRIA (CD64A), was shown block inflammation in passive transfer models complex-mediated disease. To assess whether could T cell- B cell-dependent model disease, the efficacy collagen-induced arthritis evaluated. Mice with established were treated single s.c. injection (0.2-2.0 mg/dose) given every other day for 11 days....
Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). CD146 and CCR5 are proteins that mark activated T helper 17 (Th17) cells. The Th17 phenotype is promoted by the interaction receptor ICOS on cells with ligand (ICOSL) dendritic (DCs). We performed multiparametric flow cytometry in cohort 156 HCT recipients conducted experiments aGVHD murine models to understand role ICOSL+ DCs. observed an increased frequency...
CD28 and inducible T cell costimulator (ICOS) appear to have nonredundant roles in activation adaptive immunity. We undertook this study characterize vitro vivo the therapeutic potential of acazicolcept (ALPN-101), an Fc fusion protein a human variant ICOS ligand (ICOSL) domain designed inhibit both costimulation, inflammatory arthritis.Acazicolcept was compared with inhibitors either or pathways (abatacept belatacept [CTLA-4Ig], prezalumab [anti-ICOSL monoclonal antibody]) receptor binding...
To explore the role of BAFF and APRIL cytokines in pathogenesis anti-N-methyl-D-aspartate receptor (NMDAR) autoimmune encephalitis.
Immunoglobulin superfamily member (IgSF) proteins play a significant role in regulating immune responses with surface expression on all cell subsets, making the IgSF an attractive family of for therapeutic targeting human diseases. We have developed directed evolution platform capable engineering domains to increase affinities cognate ligands and/or introduce binding non-cognate ligands. Using this scientific platform, ICOSL been derived enhanced ICOS and additional high-affinity receptor,...
3019 Background: Interleukin 21 (IL-21), a γc chain family cytokine, is produced primarily by CD4+ T cells and has many effects on immune cells, including enhancing CD8+ cell NK proliferation cytotoxicity. Recombinant IL-21 (rIL-21) therapy resulted in objective responses ~20% of melanoma renal carcinoma patients. In mouse models, monoclonal antibody (mAb) blockade CTLA-4 prolongs antigen-specific responses, while programmed death 1 (PD-1) reverses tumor induced suppression. Ipilimumab,...
<h3>Objective</h3> BAFF and APRIL signal through TACI, BCMA, and/or BAFF-R, play important roles in the activation, differentiation, survival of B cells, particularly antibody-secreting as well T cells innate immune cells. Therapeutic agents targeting have demonstrated promising clinical potential systemic lupus erythematosus (SLE), nephritis (LN), other cell-related diseases; however, these inhibit only BAFF, APRIL, or predominantly more potent inhibition both cytokines is likely required...
<h3>Background:</h3> Povetacicept (ALPN-303; TACI vTD-Fc)[1] is an enhanced, high affinity dual antagonist of BAFF (B cell activating factor) and APRIL (a proliferation inducing ligand), cytokines that play key roles in the pathogenesis multiple autoimmune diseases via their activation, differentiation, and/or survival B cells, including antibody-secreting as well T lymphocytes innate immune cells. Other therapeutic agents targeting APRIL, wild-type (WT) TACI-Fc fusion proteins, have...
Purpose: Combined inhibition of CD28 and inducible T cell costimulator (ICOS) pathways with acazicolcept (ALPN-101) represents a potential new treatment for uveitis. Here, we evaluate preclinical efficacy using experimental autoimmune uveitis (EAU) in Lewis rats. Methods: Efficacy was tested 57 rats treated either systemic (subcutaneous) or local (intravitreal) administration compared to matched Fc-only control corticosteroid. Impact on assessed clinical scoring, optical coherence tomography...
Background: BAFF and APRIL are TNF superfamily members that form homo- heteromultimers bind TACI BCMA on B cells; also binds BAFF-R. support cell development, differentiation, survival, particularly for plasmablasts plasma cells, play critical roles in the pathogenesis of cell-related autoimmune diseases. In nonclinical models, inhibition either or alone mediates relatively modest effects, whereas their co-neutralization dramatically reduces function, including antibody production. Fc...
Background/Purpose: Despite many recent advances in immunotherapy, graft versus host disease (GvHD), which reflects immune-mediated attack of recipient tissue by donor T cells, remains the major cause morbidity and nonrelapse mortality after hematopoietic stem cell transplantation (HCT). The immunoglobulin superfamily (IgSF) is a large, diverse family proteins that includes several key cell-expressed members such as CD28, inducible costimulator (ICOS), PD-1, CTLA-4. CD28 ICOS particular play...
BackgroundALPN-101 (ICOSL vIgD-Fc) is an Fc fusion protein of a human ICOSL variant immunoglobulin domain (vIgD™) designed to simultaneously inhibit the ICOS and CD28 costimulatory pathways. bind CD80/CD86, respectively, play critical roles in T cell activation adaptive immunity. ALPN-101 has demonstrated preliminary efficacy model graft versus host disease (GvHD) (2018 BMT abstract #244). Here we examined its efficacy, exposure, pharmacodynamics preparation for upcoming clinical...