更新于：2024-11-21

Atrosab

更新于：2024-11-21

概要

研发状态

概要

基本信息

药物类型

单克隆抗体

别名

Anti-TNF-receptor-1 monoclonal antibody、atrosab-MS

靶点

TNFR1

作用机制

TNFR1抑制剂(肿瘤坏死因子受体1型抑制剂)

治疗领域

消化系统疾病免疫系统疾病感染+ [1]

在研适应症

非酒精性脂肪性肝炎强直性脊柱炎银屑病关节炎+ [2]

非在研适应症-

原研机构

Celonic AG

在研机构

Baliopharm AG

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

序列信息

Sequence Code 69458VL

Sequence Code 53372CDR3-L

Sequence Code 316745546CDR2-H

Sequence Code 53352CDR3-H

Sequence Code 121255CDR1-L

Sequence Code 146758CDR1-H

Sequence Code 69454VH

Sequence Code 149729CDR2-L

关联

100 项与 Atrosab 相关的临床结果

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100 项与 Atrosab 相关的转化医学

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100 项与 Atrosab 相关的专利（医药）

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项与 Atrosab 相关的文献（医药）

2024-03-20·Science Translational Medicine1区 · 医学

An anti–TNF–glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases

1区 · 医学

Article

作者: Jia, Ying ; Wang, Zhi ; Mathieu, Suzanne ; Pang, Yinuo ; Wang, Ce ; Phillips, Lucy ; McPherson, Michael J. ; Hernandez, Axel ; Wang, Lu ; Tian, Yu ; Pitney, Victoria ; Brown, Nathan J. ; Kang, Bit Na ; Ruzek, Melanie ; Oh, Jason Z. ; Schmidt, Diana ; Shi, Dan ; Stoffel, Robert ; Zheng, Pingping ; Goess, Christian ; Xu, Jianwen ; Zhu, Haizhong ; McCarthy, Kimberley ; Parmentier, Julie ; Hayes, Martin E. ; Hobson, Adrian D. ; Qiu, Wei ; D’Cunha, Ronilda R. ; Bi, Yingtao ; Waegell, Wendy ; Longenecker, Kenton L. ; Bryant, Shaughn ; Marvin, Christopher C. ; Graff, Candace ; Liu, Wei

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti–tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti–TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti–TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti–TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti–TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

2022-12-08·Journal of Medicinal Chemistry1区 · 医学

Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate

1区 · 医学

Article

作者: Hobson, Adrian D. ; Randolph, John T. ; Yu, Yajie ; Santora, Ling C. ; Sun, Liang ; Bryant, Shaughn H. ; Mathieu, Suzanne L. ; McPherson, Michael J. ; Yang, Jindong ; Shrestha, Anurupa ; Zhou, Jian ; Fettis, Margaret M. ; Qu, Pei ; Li, Xiaofeng ; Wang, Zhi ; Wang, Zhongyuan ; Fitzgibbons, Julia ; Patel, Meena V. ; Hernandez, Axel ; Tian, Yu ; Bischoff, Agnieszka K. ; Henry, Rodger F. ; Li, Tongmei ; Li, Xiang ; Marvin, Christopher C. ; Wang, Lu ; Hayes, Martin E. ; Aguirre, Ana L. ; Yang, Shi ; Zhang, Qiang ; Graff, Candace ; Schmidt, Diana L. ; Goess, Christian

Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties in vitro. Despite covering a large range of diversity, profiling the nonconjugated small molecule was suboptimal and they were conjugated to a mouse antitumor necrosis factor (TNF) antibody using the MP-Ala-Ala linker. Screening of the resulting antibody drug conjugates (ADCs) provided a better assessment of efficacy and physical properties, reinforcing the need to conduct structure-activity relationship studies on the complete ADC. DAR4 ADCs were screened in an acute mouse contact hypersensitivity model measuring biomarkers to ensure a sufficient therapeutic window. In a chronic mouse arthritis model, mouse anti-TNF GRM ADCs were efficacious after a single dose of 10 mg/kg i.p. for over 30 days. Data on the unconjugated payloads and mouse surrogate anti-TNF ADCs identified payload 17 which was conjugated to a human anti-TNF antibody and advanced to the clinic as ABBV-3373.

2022-06-15·American Journal of Respiratory and Critical Care Medicine

CD4⁺T-Cell Dysfunction in Severe COVID-19 Disease Is Tumor Necrosis Factor-α/Tumor Necrosis Factor Receptor 1–Dependent

Article

作者: Snyder, Mark E. ; Iasella, Carlo J. ; Bhatt, Payal ; Popescu, Iulia ; Brown, Mark J. ; McDyer, John F. ; Koshy, Ritchie ; Chen, Kong ; Lendermon, Elizabeth A. ; Sembrat, John C. ; An, Xiaojing ; Wells, Alan H. ; Alder, Jonathan K. ; Konstantinidis, Ioannis ; Das, Antu ; Hannan, Stefanie J. ; Kass, Daniel J. ; Johnson, Bruce ; Kiss, Joseph E. ; Morris, Alison ; Chen, Bill B. ; McVerry, Bryan J. ; Burke, Robin ; Kitsios, Georgios ; Kilaru, Silpa ; Saul, Melissa ; Chen, Xiaoping ; Pilewski, Joseph M. ; Sanchez, Pablo G. ; Linstrum, Kelsey ; Lyons, Emily J. ; Deng, Evan ; Lieber, Sophia C. ; McMahon, Deborah K. ; Triulzi, Darrell J.

Rationale: Lymphopenia is common in severe coronavirus disease (COVID-19), yet the immune mechanisms are poorly understood. As inflammatory cytokines are increased in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a role in contributing to reduced T-cell numbers. Objectives: We sought to characterize the functional SARS-CoV-2 T-cell responses in patients with severe versus recovered, mild COVID-19 to determine whether differences were detectable. Methods: Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort. Measurements and Main Results: In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4⁺ lymphopenia predominated, with lower CD4⁺/CD8⁺ ratios in severe COVID-19 compared with patients with mild disease (P < 0.0001). In severe disease, immunodominant CD4⁺ T-cell responses to Spike-1 (S1) produced increased in vitro TNF-α (tumor necrosis factor-α) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4⁺TNF-α⁺ T-cell responses inversely correlated with absolute CD4⁺ counts from patients with severe COVID-19 (n = 76; R = -0.797; P < 0.0001). In vitro TNF-α blockade, including infliximab or anti-TNF receptor 1 antibodies, strikingly rescued S1-specific CD4⁺ T-cell proliferation and abrogated S1-specific activation-induced cell death in peripheral blood mononuclear cells from patients with severe COVID-19 (P < 0.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NFκB signaling in S1-stimulated CD4⁺ cells with infliximab treatment. We also evaluated BAL and lung explant CD4⁺ T cells recovered from patients with severe COVID-19 and observed that lung T cells produced higher TNF-α compared with peripheral blood mononuclear cells. Conclusions: Together, our findings show CD4⁺ dysfunction in severe COVID-19 is TNF-α/TNF receptor 1-dependent through immune mechanisms that may contribute to lymphopenia. TNF-α blockade may be beneficial in severe COVID-19.

100 项与 Atrosab 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
非酒精性脂肪性肝炎	临床前	瑞士	Baliopharm AG	2023-06-28
强直性脊柱炎	药物发现	瑞士	Baliopharm AG	2023-06-28
银屑病关节炎	药物发现	瑞士	Baliopharm AG	2023-06-28
斑块状银屑病	药物发现	瑞士	Baliopharm AG	2023-06-28
类风湿关节炎	药物发现	瑞士	Baliopharm AG	2023-06-28