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更新于：2025-03-29
Sym-021
更新于：2025-03-29
概要
基本信息
原研机构 |
非在研机构- |
最高研发阶段临床1期 |
首次获批日期- |
最高研发阶段(中国)- |
特殊审评- |
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关联
7
项与 Sym-021 相关的临床试验ChiCTR2400082600
Cohort study of SABR combined with anti-PD-1 and targeted therapy versus anti-PD-1 and targeted therapy for recurrent or metastatic renal cell carcinoma patients
NCT05162755
A Phase 1a/1b, Open-label, Multicenter Trial Investigating the Safety, Tolerability, and Preliminary Anti-neoplastic Activity of S095029 (Anti-NKG2A) as Monotherapy and in Combination With Sym021 (Anti-PD-1) in Patients With Advanced Solid Tumor Malignancies Followed by an Expansion Part With Triplet Combinations of S095029 and Sym021 and an Anti-HER2 mAb or Anti-EGFR mAbs (Futuximab/Modotuximab) in Patients With Metastatic Gastric or Colorectal Cancers
NCT04195373
A Phase I Open-label, Safety Study of Intra-tumoral Application of TMV-018 in Combination With 5-FC or Anti-PD-1 Therapy in Patients With Tumors of the Gastrointestinal Tract
100 项与 Sym-021 相关的临床结果
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100 项与 Sym-021 相关的转化医学
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100 项与 Sym-021 相关的专利（医药）
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6
项与 Sym-021 相关的文献（医药）2024-09-20Nan fang yi ke da xue xue bao = Journal of Southern Medical University
[High RNF7 expression enhances PD-1 resistance of non-small cell lung cancer cells by promoting CXCL1 expression and myeloid-derived suppressor cell recruitment via activating NF-κB signaling].
Article
作者: Zhong, N ; Geng, B ; Sun, Z ; Zhao, W ; Wang, H
OBJECTIVE:
To investigate the mechanism of RNF7 for regulating myeloid-derived suppressor cells (MDSCs) in nonsmall cell lung cancer (NSCLC).
METHODS:
TIMER2.0 database and immunohistochemistry were used to analyze RNF7 expression level and its correlation with immune cell infiltration in non-small cell lung cancer. The impact of RNF7 expression levels on prognosis of lung cancer patients was analyzed using Kaplan-Meier survival analysis. CMT-167 cells with RNF7 overexpression or knockdown were inoculated subcutaneously in C57BL/6 mice, and the mice in RNF7 knockdown group were treated with anti-PD-1 or IgG isotype control 7 days after the inoculation. The tumor tissues were harvested after 30 days for tumor volume measurement, detection of S100A8+A9 and Gr-1 expressions with immunohistochemistry, and analysis of MDSC infiltration. Gene set enrichment analysis (GSEA) was performed to identify the potential pathways regulated by RNF7 in NSCLC. Western blotting and luciferase assays were used to assess the impact of RNF7 on the NF-κB signaling pathway. ELISA and RT-qPCR were used to measure chemokine (C-X-C motif) ligand 1 (CXCL1) expression.
RESULTS:
RNF7 expression was significantly upregulated in NSCLC, and high RNF7 expression levels were associated with poor prognosis of the patients (P < 0.001). TIMER2.0 analysis revealed a positive correlation between RNF7 expression and MDSC infiltration (P < 0.001). GSEA suggested that RNF7 was enriched in the NF-κB signaling pathway. In NSCLC cells, RNF7 knockdown significantly inhibited NF-κB activation and reduced CXCL1 expression. In the tumor-bearing mice, RNF7 overexpression significantly increased MDSC infiltration in the tumor tissue, and RNF7 knockdown obviously reduced MDSC infiltration and enhanced the efficacy of anti-PD-1 therapy.
CONCLUSION:
High expression of RNF7 in NSCLC cells promotes CXCL1 expression by activating the NF-κB signaling pathway, thus leading to the chemotactic recruitment of MDSCs, which contributes to tumor resistance to antiPD-1 therapy.
2020-12-01Journal of hematology & oncology1区 · 医学
CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer
1区 · 医学
ArticleOA
作者: Dong, Xiaorong ; Wu, Gang ; Chen, Yaobing ; Zhou, Xiaoshu ; Xu, Shuangbing ; Zhang, Tao ; Meng, Rui ; Liu, Li ; Hong, Jiaxin ; Zhang, Sheng ; Zhang, Ruiguang ; Wang, Jian ; Tang, Jing ; Lin, Zhenyu ; Zong, Yan ; Yang, Kunyu ; Xu, Yingzhuo
Abstract:
Background:
The cyclin-dependent kinase 7 (CDK7) subunit of TFIIH regulates RNA polymerase-II-based transcription and promotes tumor progression. However, the mechanisms involved in CDK7-mediated immune evasion are unclear in non-small cell lung cancer (NSCLC).
Methods:
RNA silencing and pharmacologic inhibitors were used to evaluate the functions of CDK7/p38α/MYC/PD-L1 axis in cancer cell proliferation and antiPD-1 therapy resistance. Flow cytometry was performed to detect the status of the immune microenvironment after CDK7 inhibition and antiPD-1 therapy in vivo. CD8 depletion antibodies were used to assess the role of CD8+ T cells in combined CDK7 and PD-1 blockade. The associations among CDK7, p38α, MYC, PD-L1, infiltrating T cells, and survival outcomes were validated in two tissue microarrays and public transcriptomic data of NSCLC.
Results:
High CDK7 mRNA and protein levels were identified to be associated with poor prognosis in NSCLC. CDK7 silencing and CDK7 inhibitor THZ1 elicited apoptosis and suppressed tumor growth. Moreover, CDK7 ablation specifically suppressed p38α/MYC-associated genes, and THZ1 inhibited MYC transcriptional activity through downregulating p38α. CDK7 inhibition sensitized NSCLC to p38α inhibitor. Further, THZ1 suppressed PD-L1 expression by inhibiting MYC activity. THZ1 boosted antitumor immunity by recruiting infiltrating CD8+ T cells and synergized with antiPD-1 therapy. The CDK7/MYC/PD-L1 signature and infiltrating T cell status collectively stratified NSCLC patients into different risk groups.
Conclusion:
These data suggest that the combined CDK7 inhibitor THZ1 and antiPD-1 therapy can be an effective treatment in NSCLC.
2019-05-19mAbs2区 · 医学
Sym021, a promising anti-PD1 clinical candidate antibody derived from a new chicken antibody discovery platform
2区 · 医学
Article
作者: Bouquin, Thomas ; Uhlenbrock, Franziska ; Pedersen, Mikkel W ; Lindsted, Trine ; Kragh, Michael ; Gad, Monika ; Horak, Ivan D ; Fröhlich, Camilla ; Galler, Gunther R ; Dietrich, Nikolaj ; Gjetting, Torben ; Melander, Maria C ; Grandal, Michael M ; Koefoed, Klaus ; Bhatia, Vikram K ; Lantto, Johan ; Strandh, Magnus
Discovery of therapeutic antibodies is a field of intense development, where immunization of rodents remains a major source of antibody candidates. However, high orthologue protein sequence homology between human and rodent species disfavors generation of antibodies against functionally conserved binding epitopes. Chickens are phylogenetically distant from mammals. Since chickens generate antibodies from a restricted set of germline genes, the possibility of adapting the Symplex antibody discovery platform to chicken immunoglobulin genes and combining it with high-throughput humanization of antibody frameworks by "mass complementarity-determining region grafting" was explored. Hence, wild type chickens were immunized with an immune checkpoint inhibitor programmed cell death 1 (PD1) antigen, and a repertoire of 144 antibodies was generated. The PD1 antibody repertoire was successfully humanized, and we found that most humanized antibodies retained affinity largely similar to that of the parental chicken antibodies. The lead antibody Sym021 blocked PD-L1 and PD-L2 ligand binding, resulting in elevated T-cell cytokine production in vitro. Detailed epitope mapping showed that the epitope recognized by Sym021 was unique compared to the clinically approved PD1 antibodies pembrolizumab and nivolumab. Moreover, Sym021 bound human PD1 with a stronger affinity (30 pM) compared to nivolumab and pembrolizumab, while also cross-reacting with cynomolgus and mouse PD1. This enabled direct testing of Sym021 in the syngeneic mouse in vivo cancer models and evaluation of preclinical toxicology in cynomolgus monkeys. Preclinical in vivo evaluation in various murine and human tumor models demonstrated a pronounced anti-tumor effect of Sym021, supporting its current evaluation in a Phase 1 clinical trial. Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; CD, cluster of differentiation; CDC, complement-dependent cytotoxicity; CDR, complementarity determining region; DC, dendritic cell; ELISA, enzyme-linked immunosorbent assay; FACS, fluorescence activated cell sorting; FR, framework region; GM-CSF, granulocyte-macrophage colony-stimulating factor; HRP, horseradish peroxidase; IgG, immunoglobulin G; IL, interleukin; IFN, interferon; mAb, monoclonal antibody; MLR, mixed lymphocyte reaction; NK, natural killer; PBMC, peripheral blood mono-nuclear cell; PD1, programmed cell death 1; PDL1, programmed cell death ligand 1; RT-PCR, reverse transcription polymerase chain reaction; SEB, Staphylococcus Enterotoxin B; SPR, surface Plasmon Resonance; VL, variable part of light chain; VH, variable part of heavy chain.
100 项与 Sym-021 相关的药物交易
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 晚期恶性实体瘤 | 临床1期 | 美国 | 2021-10-15 | |
| 晚期恶性实体瘤 | 临床1期 | 加拿大 | 2021-10-15 | |
| 复发性实体肿瘤 | 临床1期 | 美国 | 2020-10-12 | |
| 复发性实体肿瘤 | 临床1期 | 加拿大 | 2020-10-12 | |
| 复发性实体肿瘤 | 临床1期 | 法国 | 2020-10-12 | |
| 复发性实体肿瘤 | 临床1期 | 西班牙 | 2020-10-12 | |
| 局部晚期恶性实体瘤 | 临床1期 | 美国 | 2017-11-20 | |
| 局部晚期恶性实体瘤 | 临床1期 | 加拿大 | 2017-11-20 | |
| 淋巴瘤 | 临床1期 | 美国 | 2017-11-20 | |
| 淋巴瘤 | 临床1期 | 加拿大 | 2017-11-20 |
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临床结果
临床结果
适应症
分期
评价
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N/A | 复发性头颈部鳞状细胞癌 PD-L1 positive (CPS≥1) | 89 | (irAEs) | 廠鹽觸願衊選鹽範簾襯(衊鬱網網願繭構艱構夢) = 10% 顧艱構鬱壓製艱構艱鹽 (獵壓蓋簾壓繭鏇選願顧 ) 更多 | 积极 | 2024-05-24 | |
(non-irAEs) | |||||||
N/A | 86 | 窪積鹽鬱製膚鹹鹽壓觸(襯衊窪製襯繭鏇構製壓) = 鬱繭遞鏇鹽窪衊憲蓋鹽 願憲壓餘選夢窪膚艱繭 (鏇範憲淵夢齋構蓋夢廠 ) 更多 | 积极 | 2023-05-31 | |||
临床1期 | - | 衊壓鹹窪鬱鏇鏇積艱鹹(繭鹹齋鑰築選夢餘顧範) = Sym021, Sym022 and Sym023 alone and Sym021 in combination with either Sym022 or Sym023 were well tolerated with AE profiles typical of immune checkpoint inhibitors 淵膚壓願願獵衊壓鹽壓 (鹹獵鏇鑰膚範窪鏇糧築 ) | - | 2020-09-20 | |||
N/A | 51 | (HLA-A2 supertype) | 願壓鬱蓋顧製糧簾鏇鬱(憲範願選憲網憲膚獵製) = 範遞膚顧鏇簾鹹鏇簾簾 夢廠餘蓋遞鑰範壓窪膚 (觸襯餘鏇鏇築鏇蓋顧憲 ) | - | 2020-04-01 | ||
(Patients without HLA-A2 supertype) | 願壓鬱蓋顧製糧簾鏇鬱(憲範願選憲網憲膚獵製) = 襯鏇齋鏇簾壓淵醖顧蓋 夢廠餘蓋遞鑰範壓窪膚 (觸襯餘鏇鏇築鏇蓋顧憲 ) | ||||||
N/A | 黑色素瘤 末线 | 200 | 襯遞繭範築廠範鹽願製(選鬱構範膚壓築簾廠繭) = 繭蓋獵衊願蓋蓋夢夢齋 鹹艱壓網遞鏇艱膚鑰願 (鬱廠選餘網鑰鏇網構窪 ) 更多 | - | 2019-09-30 | ||
N/A | - | aPD1 | 淵築網鹹積艱築範糧鬱(顧醖艱鏇壓鏇艱醖壓襯) = 網遞糧憲鏇遞範餘鬱襯 衊選網網夢鹽願糧襯壓 (範觸範衊製壓襯蓋鹹淵 ) 更多 | - | 2017-05-30 | ||
aPD1 + IPI | 膚築壓窪餘齋廠衊淵製(構鬱獵觸壓簾齋壓獵遞) = 艱鹽獵鏇夢齋獵範製窪 製鏇糧構鹽構憲遞鏇網 (糧鏇觸簾簾獵窪襯糧製 ) 更多 | ||||||
N/A | 64 | aPD1 + aCTLA4 | 襯網夢壓糧艱範簾衊鹹(醖鑰醖遞觸淵憲選願襯) = One death from irAEs occurred related to Toxic Epidermal Necrolysis (TEN) 製鑰齋膚壓壓襯鬱衊糧 (衊製鏇夢壓選衊範製鑰 ) 更多 | 积极 | 2017-05-30 |
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