[Translation] A randomized, double-blind, placebo-controlled Phase I clinical study to evaluate the safety and tolerability of KPG-818 capsules after multiple oral administration in healthy Chinese subjects, as well as the pharmacokinetic characteristics and food effect test

评估KPG-818胶囊在中国健康受试者中多次口服给药后KPG-818及代谢物KPG-818H的药代动力学特征。评估KPG-818胶囊在中国健康受试者中多次口服给药后的安全性和耐受性。评估食物对KPG-818胶囊在中国健康受试者中单次口服给药后PK的影响。

[Translation]

To evaluate the pharmacokinetic characteristics of KPG-818 and its metabolite KPG-818H after multiple oral administration of KPG-818 capsules in healthy Chinese subjects. To evaluate the safety and tolerability of KPG-818 capsules after multiple oral administration in healthy Chinese subjects. To evaluate the effect of food on the PK of KPG-818 capsules after a single oral administration in healthy Chinese subjects.

Start Date11 Apr 2024

Sponsor / Collaborator

Kangpu Biopharmaceuticals Ltd.

CTR20233129

/ RecruitingPhase 1

一项评价SM17在中国健康受试者和中重度特应性皮炎患者中的随机双盲、安慰剂对照的I期临床研究

[Translation] A randomized, double-blind, placebo-controlled Phase I clinical study evaluating SM17 in healthy subjects and patients with moderate to severe atopic dermatitis in China

第一部分：Ia期健康受试者研究主要目的：评估SM17在中国健康成人受试者中单次及多次给药的安全性和耐受性。次要目的：评估SM17在中国健康受试者中单次及多次给药后的药代动力学（PK）特征。评估SM17在中国健康受试者中的免疫原性。第二部分：Ib期成年中重度特应性皮炎患者研究主要目的：评估SM17在成年中重度特应性皮炎患者中多次给药的安全性与耐受性。次要目的：评估SM17在成年中重度特应性皮炎患者中多次给药的PK特征。评估SM17在成年中重度特应性皮炎患者中的免疫原性。评估SM17治疗成年中重度特应性皮炎患者的初步有效性。探索性目的：探索SM17在成年中重度特应性皮炎患者中多次给药后的药效学（PD）特征。探索SM17多次给药后的PK/PD相关性。探索PD标志物与特应性皮炎有效性评估指标之间的相关性。

[Translation]

Part I: Phase Ia healthy subject study Primary objective: To evaluate the safety and tolerability of SM17 after single and multiple administrations in healthy Chinese adult subjects. Secondary objective: To evaluate the pharmacokinetic (PK) characteristics of SM17 after single and multiple administrations in healthy Chinese subjects. To evaluate the immunogenicity of SM17 in healthy Chinese subjects. Part II: Phase Ib study in adult patients with moderate to severe atopic dermatitis Primary objective: To evaluate the safety and tolerability of SM17 after multiple administrations in adult patients with moderate to severe atopic dermatitis. Secondary objective: To evaluate the PK characteristics of SM17 after multiple administrations in adult patients with moderate to severe atopic dermatitis. To evaluate the immunogenicity of SM17 in adult patients with moderate to severe atopic dermatitis. To evaluate the preliminary efficacy of SM17 in the treatment of adult patients with moderate to severe atopic dermatitis. Exploratory objective: To explore the pharmacodynamic (PD) characteristics of SM17 after multiple administrations in adult patients with moderate to severe atopic dermatitis. To explore the PK/PD correlation of SM17 after multiple administrations. To explore the correlation between PD markers and effectiveness evaluation indicators for atopic dermatitis.

Start Date21 Nov 2023

Sponsor / Collaborator

Sinolink Pharma (Suzhou) Limited

NCT05332834

/ CompletedPhase 1

A Phase 1, First-in-Human, Double-Blind, Placebo-Controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SM17 When Administered Intravenously as a Single Ascending Dose in Healthy Subjects (Part A) and as Multiple Ascending Doses in Healthy Subjects (Part B)

This trial is a phase 1, first-in-human, randomized, double-blind, placebo-controlled dose escalation trial following single and multiple doses intravenous administration of SM17.
It aims to evaluate the safety, tolerability, pharmacokinetic characteristics, pharmacodynamic effect and immunogenicity of single and multiple doses of SM17 injection in healthy subjects.

Start Date14 Jun 2022

Sponsor / Collaborator

Sinomab Bioscience Ltd.

100 Clinical Results associated with IL17RB

100 Translational Medicine associated with IL17RB

0 Patents (Medical) associated with IL17RB

440

Literatures (Medical) associated with IL17RB

01 Dec 2024·Molecular Cell

STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment

Article

Author: Gonzalo-Hansen, Camila ; Pines, Alex ; Bernecky, Carrie ; Demmers, Jeroen A A ; Zhou, Di ; Sixma, Titia K ; Marteijn, Jurgen A ; Slade, Dea ; Blom, Cindy M A ; Ramadhin, Anisha R ; Vermeulen, Wim ; Raams, Anja ; van Sluis, Marjolein ; Dekkers, Dick ; Bezstarosti, Karel ; Salmazo, Anita ; Lee, Shun-Hsiao ; Janssens, Roel C

Transcription-coupled nucleotide excision repair (TC-NER) efficiently eliminates DNA damage that impedes gene transcription by RNA polymerase II (RNA Pol II). TC-NER is initiated by the recognition of lesion-stalled RNA Pol II by CSB, which recruits the CRL4^CSA ubiquitin ligase and UVSSA. RNA Pol II ubiquitylation at RPB1-K1268 by CRL4^CSA serves as a critical TC-NER checkpoint, governing RNA Pol II stability and initiating DNA damage excision by TFIIH recruitment. However, the precise regulatory mechanisms of CRL4^CSA activity and TFIIH recruitment remain elusive. Here, we reveal human serine/threonine-protein kinase 19 (STK19) as a TC-NER factor, which is essential for correct DNA damage removal and subsequent transcription restart. Cryogenic electron microscopy (cryo-EM) studies demonstrate that STK19 is an integral part of the RNA Pol II-TC-NER complex, bridging CSA, UVSSA, RNA Pol II, and downstream DNA. STK19 stimulates TC-NER complex stability and CRL4^CSA activity, resulting in efficient RNA Pol II ubiquitylation and correct UVSSA and TFIIH binding. These findings underscore the crucial role of STK19 as a core TC-NER component.

01 Dec 2024·Cancer Gene Therapy

SEMA7A-mediated juxtacrine stimulation of IGFBP-3 upregulates IL-17RB at pancreatic cancer invasive front

Article

Author: Hu, Chun-Mei ; Hsu, Min-Fen ; Chien, Hung Jen ; Ko, Yi-Ling ; Chang, Yu-Ting ; Tien, Sui-Chih ; Chang, Chin-Chun ; Tien, Yun-Wen ; Chen, Yi-Ing ; Chang, Ming-Chu ; Jeng, Yung-Ming ; Peng, Hsuan-Yu

Tumor invasion is the hallmark of tumor malignancy. The invasive infiltration pattern of tumor cells located at the leading edge is highly correlated with metastasis and unfavorable patient outcomes. However, the regulatory mechanisms governing tumor malignancy at the invasive margin remain unclear. The IL-17B/IL-17RB pathway is known to promote pancreatic cancer invasion and metastasis, yet the specific mechanisms underlying IL-17RB upregulation during invasion are poorly understood. In this study, we unveiled a multistep process for IL-17RB upregulation at the invasive margin, which occurs through direct communication between tumor cells and fibroblasts. Tumor ATP1A1 facilitates plasma membrane expression of SEMA7A, which binds to and induces IGFBP-3 secretion from fibroblasts. The resulting gradient of IGFBP-3 influences the direction and enhances IL-17RB expression to regulate SNAI2 in invasion. These findings highlight the importance of local tumor-fibroblast interactions in promoting cancer cell invasiveness, potentially leading to the development of new therapeutic strategies targeting this communication.

01 Dec 2024·Cancer Medicine

Mutational Landscape of Bone Marrow CD19 and CD138 Cells in Waldenström Macroglobulinemia (WM) and IgM Monoclonal Gammopathy of Undetermined Significance (IgM MGUS)

Article

Author: Stefanucci, Marta Rachele ; Beghini, Alessandro ; Di Camillo, Barbara ; Trojani, Alessandra ; Frustaci, Annamaria ; Bossi, Luca Emanuele ; Palumbo, Cassandra ; Greco, Antonino ; Cairoli, Roberto

ABSTRACTBackgroundDespite recurrent and activating mutations, including MYD88, CXCR4, ARID1A, KMT2D, and CD79B were identified, the genetic basis for Waldenström's Macroglobulinemia (WM) and the risk of progression of IgM MGUS to WM remain to be fully elucidated.MethodsWe investigated the mutation status of WM (n = 8), sWM (n = 7), and IgM MGUS (n = 5) patients, by performing high‐throughput targeted AmpliSeq NGS on 117 target genes. Specifically, we analyzed the CD19+ cells from 15 WM/sWM patients and five IgM MGUS patients. We also analyzed the CD138+ cells from four WM/sWM patients and two IgM MGUS patients.ResultsWe detected the classic mutation MYD88L265P in 93% of WM/sWM and in 60% of IgM MGUS patients. The CXCR4S338Ter mutation was identified in 26% of WM/sWM patients, whereas it was undetectable in IgM MGUS subjects. Interestingly, we identified new mutated genes, including WNK2 somatic mutations affecting 46% of WM/sWM patients, for which a recurrent allelic variant (V1635Ter) was observed in this cohort. Moreover, sequencing evaluation revealed recurrently frameshift or missense mutations involving NFKB2 (L473Afs) in 60% of IgM MGUS and 20% of WM/sWM, PTPN13 (P1546Tfs) in 20% of IgM MGUS and 7% of WM/sWM, CARD11 (S622del) in 20% of IgM MGUS and 20% of WM/sWM, KMT2C (I823T) in all IgM MGUS and 93% of WM/sWM, and ATM in 20% of IgM MGUS and 47% of WM/sWM patients.ConclusionIn conclusion, we uncovered new insights into the mutational landscape of WM, depicting a more complex involvement of the NF‐kB pathway, and providing evidence of the recurrence of some variants (MYD88, IL17RB, NFKB2, ATM, CARD11, PTPN13, and WNK2) also in IgM MGUS.

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