更新于：2024-11-01

PD-1 x BCMA x IL-21R

更新于：2024-11-01

基本信息

关联

项与 PD-1 x BCMA x IL-21R 相关的药物

CD003

靶点

BCMA x IL-21R x PD-1

作用机制

BCMA抑制剂 [+2]

在研机构

乘典（苏州）生物医药有限公司

原研机构

乘典（苏州）生物医药有限公司

在研适应症

多发性骨髓瘤

非在研适应症-

最高研发阶段早期临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 PD-1 x BCMA x IL-21R 相关的临床试验

ChiCTR2300078977 / Recruiting早期临床1期IIT

Single-arm clinical study of PD-1Ab21-BCMACAR-T cells (CD003) in the treatment of refractory and relapsed multiple myeloma

开始日期2023-05-23

申办/合作机构-

100 项与 PD-1 x BCMA x IL-21R 相关的临床结果

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100 项与 PD-1 x BCMA x IL-21R 相关的转化医学

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0 项与 PD-1 x BCMA x IL-21R 相关的专利（医药）

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项与 PD-1 x BCMA x IL-21R 相关的文献（医药）

2022-07-19·Proceedings of the National Academy of Sciences1区 · 综合性期刊

Aging-associated and CD4 T-cell–dependent ectopic CXCL13 activation predisposes to anti–PD-1 therapy-induced adverse events

1区 · 综合性期刊

Article

作者: Miura, Yuji ; Fujiwara, Yukio ; Kamba, Tomomi ; Tomita, Yusuke ; Motoshima, Takanobu ; Komohara, Yoshihiro ; Oshiumi, Hiroyuki ; Imamura, Kosuke ; Ikeda, Tokunori ; Tsukamoto, Hirotake ; Sakagami, Takuro ; Yano, Hiromu ; Kimura, Toshiki

Clinical success of immune-checkpoint blockade (ICB) cancer immunotherapy is compromised by increased risk of immune-related adverse events (irAEs). However, mechanistic action(s) of immune responses underlying development of irAE remain not fully explored. Here, we found that in tumor-bearing aged, but not young, mice, antiprogrammed death receptor (PD)-1 therapy elicited irAE-like multiorgan dysfunctions with ectopic accumulation of T and B cells in damaged organs. In this preclinical model, the organ toxicities were mediated by immunoglobulin G (IgG) deposition because administration of IG from ICB-treated aged mice induced the pathogenicity specifically in naïve aged hosts. Mechanistically, CD4 T-cell–derived interleukin (IL)-21 upregulated B-cell–homing chemokine, CXCL13, preferentially in irAE organs from aged mice treated with anti–PD-1 therapy. The ICB-induced pathogenicity was alleviated by B-cell depletion or by blockade of IL-21 or CXCL13 activity. These results suggest that age-associated immune regulatory milieu contributes to the formation of tertiary lymphoid structure-like lymphocytic aggregates in irAE organs and irAE-related toxicity employing IL-21-CXCL13-auto-antibody axis. Supporting this, a systemic increase in CXCL13 and Il21 expression in CD4 T cells correlated with irAE incidence in ICB-treated patients. These findings provide rationale for therapeutic usefulness of CXCL13 in irAE management.

2022-01-01·Arthritis & Rheumatology1区 · 医学

Effect of Clonally Expanded PD‐1^highCXCR5–CD4+ Peripheral T Helper Cells on B Cell Differentiation in the Joints of Patients With Antinuclear Antibody–Positive Juvenile Idiopathic Arthritis

1区 · 医学

Article

作者: Fischer, Jonas ; Girschick, Hermann ; Dirks, Johannes ; Hofmann, Christine ; Hackenberg, Stephan ; Haase, Gabriele ; Klaussner, Julia ; Holl‐Wieden, Annette ; Morbach, Henner

ObjectiveAntinuclear antibody (ANA)–positive juvenile idiopathic arthritis (JIA) is characterized by synovial B cell hyperactivity, but the precise role of CD4+ T cells in promoting local B cell activation is unknown. This study was undertaken to determine the phenotype and function of synovial CD4+ T cells that promote aberrant B cell activation in JIA.MethodsFlow cytometry was performed to compare the phenotype and cytokine patterns of PD‐1highCD4+ T cells in the synovial fluid (SF) of patients with JIA and T follicular helper cells in the tonsils of control individuals. TCRVB next‐generation sequencing was used to analyze T cell subsets for signs of clonal expansion. The functional impact of these T cell subsets on B cells was examined in cocultures in vitro.ResultsMultidimensional flow cytometry revealed the expansion of interleukin‐21 (IL‐21) and interferon‐γ (IFNγ)–coexpressing PD‐1highCXCR5–HLA–DR+CD4+ T cells that accumulate in the joints of ANA‐positive JIA patients. These T cells exhibited signs of clonal expansion with restricted T cell receptor clonotypes. The phenotype resembled peripheral T helper (Tph) cells with an extrafollicular chemokine receptor pattern and high T‐bet and B lymphocyte–induced maturation protein 1 expression, but low B cell lymphoma 6 expression. SF Tph cells, by provision of IL‐21 and IFNy, skewed B cell differentiation toward a CD21low/–CD11c+ phenotype in vitro. Additionally, SF Tph cell frequencies correlated with the appearance of SF CD21low/–CD11c+CD27–IgM– double‐negative (DN) B cells in situ.ConclusionClonally expanded CD4+ Tph cells accumulate in the joints of ANA‐positive JIA patients and, in particular, promote CD21low/–CD11c+ DN B cell differentiation. The expansion of Tph cells and DN B cells might reflect the autoimmune response in the joints of ANA‐positive JIA patients.

2021-06-01·Immunity, Inflammation and Disease4区 · 医学

Disease‐duration based comparison of subsets of immune cells in SARS CoV‐2 infected patients presenting with mild or severe symptoms identifies prognostic markers for severity

4区 · 医学

ArticleOA

作者: Kulkarni‐Munje, Archana ; Shrivastava, Shubham ; Arankalle, Vidya A. ; Lalwani, Sanjay ; Mishra, Akhilesh C. ; Palkar, Sonali

AbstractIntroductionInfection with SARS‐CoV‐2 leads to a spectrum of symptoms. Understanding the basis for severity remains crucial for better management and therapy development. So far, older age, associated‐comorbidities, and IL‐6 have been associated with severity/mortality.Materials and MethodologyAs a primary step, we analyzed the frequency and functional profile of innate immune cells (NK cells/dendritic cells/monocytes) and adaptive immunity‐driving lymphocytes (B cells/T cells/follicular T helper cells) by flow cytometry. Sixty cases of SARS CoV‐2 infection (25 severe, 35 mild) and ten healthy subjects without SARS CoV‐2 IgG were included. Disease‐duration based analysis of immune profile was explored for early events differentiating the two disease forms. Neutralizing antibody titers were determined by PRNT.Results and ConclusionDisease severity was found to be associated with impaired maturation of mDCs and hyperactivation of NK, follicular T helper cells, and CD8 T cells. Lower IL‐21 receptor expression on memory B cells indicated an imbalance in IL‐21/IL‐21 R ratio. Lower BCMA positive plasmablast cells in severe cases did suggest a probable absence of long‐term humoral immunity. Multivariate analysis revealed a progressive association of PD‐1+CD4 T cells with PRNT50 titers. Thus, in addition to identifying probable prognostic markers for severity, our study emphasizes the definite need for in‐depth viral antigen‐specific functional analyses in a larger patient cohort and with multiple sampling.