A Phase II, Single-arm and Open-labelled Clinical Study of Anti-PD-L1 Antibody KN035 Combined with Trastuzumab and Docetaxel in the Treatment of HER2-positive Advanced Breast Cancer

开始日期2019-07-05

申办/合作机构

中山大学孙逸仙纪念医院

100 项与 KD-005 相关的临床结果

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100 项与 KD-005 相关的转化医学

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100 项与 KD-005 相关的专利（医药）

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项与 KD-005 相关的文献（医药）

2024-06-12·Journal of the American Chemical Society

Genetically Encoded Epoxide Warhead for Precise and Versatile Covalent Targeting of Proteins

Article

作者: Wang, Xia ; Wang, Jie ; Zhang, Jinpeng ; Huang, Qingjun ; Ye, Jinsong

Genetically encoding a proximal reactive warhead into the protein binder/drug has emerged as an efficient strategy for covalently binding to protein targets, enabling broad applications. To expand the reactivity scope for targeting the diverse natural residues under physiological conditions, the development of a genetically encoded reactive warhead with excellent stability and broad reactivity is highly desired. Herein, we reported the genetic encoding of epoxide-containing tyrosine (EPOY) for developing covalent protein drugs. Our study demonstrates that EPOY, when incorporated into a nanobody (KN035), can cross-link with different side chains (mutations) at the same position of PD-L1 protein. Significantly, a single genetically encoded reactive warhead that is capable of covalent and site-specific targeting to 10 different nucleophilic residues was achieved for the first time. This would largely expand the scope of covalent warhead and inspire the development of covalent warheads for both small-molecule drugs and protein drugs. Furthermore, we incorporate the EPOY into a designed ankyrin repeat protein (Darpin^K13) to create the covalent binders of KRAS. This covalent KRAS binder holds the potential to achieve pan-covalent targeting of KRAS based on the structural similarity among all oncogenic KRAS mutants while avoiding off-target binding to NRAS/HRAS through a covalent interaction with KRAS-specific residues (H95 and E107). We envision that covalently targeting to H95 will be a promising strategy for the development of covalent pan-KRAS inhibitors in the future.

1986-01-01·Mutagenesis3区 · 医学

Absence of genotoxic effects in cells exposed to four ketonucleoside derivatives

3区 · 医学

Article

作者: Lasne, Cl. ; Antonakis, K. ; Alaoui-Jamali, M. A. ; Chouroulinkov, I.

The relationship between the structure and genotoxic potential of four new cytostatic compounds--the ketonucleosides KN-35, KN-43, KN-44 and KN-3--was investigated in short-term in vitro assays of hypoxanthine-guanine phosphoribosyl transferase locus mutation in V79 cells, induction of chromosomal aberrations and sister chromatid exchanges on human lymphocytes, induction of chromosomal aberrations and micronuclei in V79 cells, and transformation of Syrian hamster embryo cells. None of the ketonucleosides induced mutagenic effects in any of the assays. Their failure to exhibit significantly genotoxic activity may be ascribed to the probable absence of any reaction between these drugs and the cellular DNA, and indicates that they act by some other mechanism which probably differs from the one observed with alkylating or intercalating antitumoural agents. This suggests that the cytotoxic activity of ketonucleosides cannot be related to genotoxicity.

Microorganisms

Eco-Friendly Biomass Production and Identification of Active Compounds of Paenibacillus polymyxa EB.KN35 with Potent Anti-Fusarium oxysporum Effect

Article

作者: Nguyen, Dinh Sy ; Wang, San-Lang ; Nguyen, Anh Dzung ; Tran, Thi Ha Trang ; Ngo, Van Anh ; Nguyen, Van Bon ; Phan, Tu Quy

Fusarium oxysporum is a fungal plant pathogen for over 100 agricultural crop species. There are strategies for managing Fusarium wilt, including antagonistic bacteria that offer a promising and sustainable effect. In this work, among the various endophytic bacterial strains, Paenibacillus polymyxa EB.KN35 was selected as the best antifungal strain against F. oxysporum. For eco-friendly biomass production of this bacterium, some agricultural byproducts were tested for cultivation, and a soybean processing byproduct (SPBP) was found to be a suitable C/N source for P. polymyxa EB.KN35 fermentation. The utilization of a 14 L bioreactor system for P. polymyxa EB.KN35 fermentation achieved a high biomass productivity (3.46 × 1011 CFU/mL) in a short time (8 h). In bioactive compound analysis, EB.KN35 was found to be secreting several plant growth-promoting compounds such as GA3, IAA, kinetin, and zeatin (via HPLC) and eleven volatile compounds (via GC–MS). The docking study indicated that some volatile compounds (1, 2, 4, and 9) may play a significant role in inhibiting F. oxysporum. The study results highlight the potential for reusing a soybean processing byproduct as a C/N source for the bioproduction of P. polymyxa EB.KN35 with potential use as a biocontrol agent and biofertilizer.

项与 KD-005 相关的新闻（医药）

2023-07-12

·研发客

康宁杰瑞KN046晚期非小细胞肺癌研究结果在国际知名期刊EJC发表

2023年7月10日，中国苏州——康宁杰瑞生物制药（股票代码：9966.HK）宣布，PD-L1/CTLA-4双抗KN046单药治疗晚期非小细胞肺癌的Ⅱ期临床研究结果，在线发表于国际肿瘤领域知名期刊European Journal of Cancer（EJC，最新SCI影响因子8.4001）。上海市肺科医院周彩存教授为该文通讯作者。通讯作者：周彩存第一作者：熊安稳、李玮、李醒亚文章链接：https://www.ejcancer.com/article/S0959-8049(23)00275-7/fulltext 本研究是一项开放、多中心、多队列、单臂Ⅱ期临床研究（KN046-201），旨在评估KN046单药在非小细胞肺癌中的疗效、安全性和耐受性。队列A和队列B入组既往接受过一线含铂化疗治疗失败且未接受过免疫治疗的晚期非小细胞肺癌患者，入组的患者通过静脉滴注分别接受KN046 3 mg/kg(队列A)和5mg/kg(队列B) Q2W治疗。主要终点是BICR根据RECIST 1.1评估的客观缓解率(ORR)。研究共入组64例患者，3mg/kg组(队列A)和5mg/kg组(队列B)分别纳入30例和34例患者。截止2021年8月31日，3mg/kg组和5mg/kg组的中位随访时间分别为24.08个月和19.35个月。在3mg/kg和5mg/kg组中，BICR评估的客观缓解率（ORR）分别为13.3%和14.7%。中位无进展生存期(PFS)分别为3.68和3.68个月，总生存期(OS)分别为19.70和13.04个月。此外，在41例非鳞状非小细胞肺癌患者中客观缓解率（ORR）为17.1%，中位无进展生存期（mPFS）为3.68个月，中位总生存期（mOS）19.81个月；在20例鳞状非小细胞肺癌患者中，客观缓解率（ORR）为10.0%，中位无进展生存期（mPFS）为7.43个月，中位总生存期（mOS）为12.88个月。 64例患者全部纳入安全性分析，常见药物相关不良事件（TRAE）为贫血(28.1%)、高血糖(26.7%)和输液相关反应(26.7%)，3级及以上TRAEs发生率和TRAEs导致停药率分别为42.2%和14.1%。结论表明，KN046 3mg/kg和5mg/kg 治疗既往铂类化疗失败或不耐受的鳞状和非鳞状晚期非小细胞肺癌患者，具有良好的疗效和安全性。研究为KN046在非小细胞肺癌中的继续开发提供了更多决策依据。关于KN046 KN046是康宁杰瑞研发的PD-L1/CTLA-4双特异性抗体，具有自主知识产权。KN046创新设计包括：采用机制不同的CTLA-4与PD-L1单域抗体融合组成；可靶向富集于PD-L1高表达的肿瘤微环境及清除抑制肿瘤免疫的Treg细胞。 KN046在澳大利亚、美国和中国已开展覆盖非小细胞肺癌、胰腺癌、胸腺癌、肝癌、食管鳞癌、三阴乳腺癌等10余种肿瘤的近20项不同阶段临床试验，试验结果显示患者获得生存获益的优势。美国FDA基于在澳大利亚和中国取得的临床试验结果，批准KN046在美国直接进入Ⅱ期临床试验，并于2020年9月授予KN046用于治疗胸腺上皮肿瘤的孤儿药资格。目前KN046多项注册临床试验正在进行中，其中KN046联合化疗一线治疗非小细胞肺癌的Ⅲ期临床研究中期分析成功达到预设PFS终点。关于康宁杰瑞康宁杰瑞生物制药成立于2015年，公司以“让肿瘤成为可控、可治的疾病”为使命，专注于创新抗肿瘤大分子药物的研发、生产和商业化。2019年12月12日，康宁杰瑞生物制药在香港联交所主板上市，股票代码：9966.HK。公司汇聚了一支由归国顶尖科学家领衔的专业研发团队，拥有从创新药的早期研发、工艺开发、商业生产到临床研究的完整产业链，自主开发了蛋白质/抗体工程、抗体筛选和多功能抗体平台。公司已申报发明专利80项，授权26项。康宁杰瑞的产品管线由具备全球竞争力和差异化优势的单域抗体、双特异性抗体及抗体偶联物等抗肿瘤新药组成，其中2个品种入选国家“重大新药创制”专项，3个品种获美国FDA授予4项孤儿药资格。全球首个皮下注射PD-L1抑制剂恩沃利单抗注射液（研发代号：KN035，商品名：恩维达®）已获批上市，6个品种在中国、美国、澳大利亚开展30多项临床研究，其中3个品种8项研究在中美进入关键性临床研究阶段。 “康达病患，瑞济万家”，康宁杰瑞始终以临床价值和患者需求为导向，坚持国际化和差异化战略，聚焦创新、安全、可负担的抗肿瘤药开发，惠及中国和全球患者。内容来源于网络，如有侵权，请联系删除。

AACR会议临床结果

100 项与 KD-005 相关的药物交易

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