Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

Antibody-Drug Conjugates (ADCs): Navigating Four Pillars of Safety, Development, Supply Chain and Manufacturing Excellence

Antibody-drug conjugates (ADCs) are pioneering biologics that merge antibodies’ specificity with small molecules’ potency. With a handful of FDA-approved ADCs in the market and many under development, ADCs are poised to revolutionize therapeutics. This paper examines the complexities of ADC production, emphasizing the importance of process characterization and the pivotal role of supply chain characteristics, safety requirements, and Contract Manufacturing Organizations (CMOs) with proficiency. The swift transition of antibody-drug conjugate (ADC) programs from early to advanced clinical stages underscores the urgency for quick and efficient commercial launch preparation. This article delves into strategies to hasten commercial readiness, supply chain strategy, the significance of partnering with adept contract development and manufacturing organizations (CDMOs), and the challenges of ADC production.

The ABC of ADCs (Antibody-Drug Conjugates): A Comprehensive Review of Technical, Regulatory, and Clinical Challenges

Over the past several decades, there has been a significant surge in the development of Antibody-Drug Conjugates (ADCs). Designing an ideal ADC presents a multifaceted challenge, requiring the precise orchestration of various elements such as antigens, antibodies, linkers, and payloads. While ADCs aim to target tumor cells specifically, several antigens can also be found in regular tissues, potentially compromising the specificity of ADCs in therapeutic applications. The complexity extends to antibody selection, necessitating effective targeting of the desired antigen and ensuring compatibility with linkers for effective payload delivery. Additionally, the linker and payload combination are critical for the ADC’s therapeutic efficiency, balancing stability in circulation and timely payload release upon target binding. ADC doses must be safe for normal tissues while ensuring the released payloads are effective. The success of ADCs is attributed to their unmatched efficacy compared to traditional chemotherapy agents. The current research article aims to provide a technical review of Antibody-Drug Conjugates (ADCs) for cancer therapies. A brief discussion on the basics of ADCs, regulatory approach, overview, and technical complexities for quantification is presented. This review also summarizes recently approved ADCs and introduces the concepts of antibodies, linkers, and payloads. The article also outlines cancer-specific ADCs currently in late-stage clinical trials for cancer treatment.

Excellent effects and possible mechanisms of action of a new antibody–drug conjugate against EGFR-positive triple-negative breast cancer

Background:Triple-negative breast cancer(TNBC)is the most aggressive subtype and occurs in approximately 15%–20%of diagnosed breast cancers.TNBC is characterized by its highly metastatic and recurrent features,as well as a lack of specific targets and targeted therapeutics.Epidermal growth factor receptor(EGFR)is highly expressed in a variety of tumors,especially in TNBC.LR004-VC-MMAE is a new EGFR-targeting antibody–drug conjugate produced by our laboratory.This study aimed to evaluate its antitumor activities against EGFR-positive TNBC and further studied its possible mechanism of antitumor action.Methods:LR004-VC-MMAE was prepared by coupling a cytotoxic payload(MMAE)to an anti-EGFR antibody(LR004)via a linker,and the drug-to-antibody ratio(DAR)was analyzed by HIC-HPLC.The gene expression of EGFR in a series of breast cancer cell lines was assessed using a publicly available microarray dataset(GSE41313)and Western blotting.MDA-MB-468 and MDA-MB-231 cells were treated with LR004-VC-MMAE(0,0.0066,0.066,0.66,6.6 nmol/L),and the inhibitory effects of LR004-VC-MMAE on cell proliferation were examined by CCK-8 and colony formation.The migration and invasion capacity of MDA-MB-468 and MDA-MB-231 cells were tested at different LR004-VCMMAE concentrations(2.5 and 5 nmol/L)with wound healing and Transwell invasion assays.Flow cytometric analysis and tumorsphere-forming assays were used to detect the killing effects of LR004-VC-MMAE on cancer stem cells(MDA-MB-468 and MDA-MB-231 cells).The mouse xenograft models were also used to evaluate the antitumor efficacy of LR004-VC-MMAE in vivo.Briefly,BALB/c nude mice were subcutaneously inoculated with MDA-MB-468 or MDAMB-231 cells.Then they were randomly divided into 4 groups(n=6 per group)and treated with PBS,naked LR004(10 mg/kg),LR004-VC-MMAE(10 mg/kg),or doxorubicin,respectively.Tumor sizes and the body weights of mice were measured every 4 d.The effects of LR004-VC-MMAE on apoptosis and cell cycle distribution were analyzed by flow cytometry.Western blotting was used to detect the effects of LR004-VC-MMAE on EGFR,ERK,MEK phosphorylation and tumor stemness marker gene expression.Results:LR004-VC-MMAE with a DAR of 4.02 were obtained.The expression of EGFR was found to be significantly higher in TNBC cells compared with non-TNBC cells(P<0.01).LR004-VC-MMAE inhibited the proliferation of EGFRpositive TNBC cells,and the ICvalues of MDA-MB-468 and MDA-MB-231 cells treated with LR004-VC-MMAE for 72 h were(0.13±0.02)nmol/L and(0.66±0.06)nmol/L,respectively,which were significantly lower than that of cells treated with MMAE[(3.20±0.60)nmol/L,P<0.01,and(6.60±0.50)nmol/L,P<0.001].LR004-VC-MMAE effectively inhibited migration and invasion of MDA-MB-468 and MDA-MB-231 cells.Moreover,LR004-VC-MMAE also killed tumor stem cells in EGFR-positive TNBC cells and impaired their tumorsphere-forming ability.In TNBC xenograft models,LR004-VC-MMAE at 10 mg/kg significantly suppressed tumor growth and achieved complete tumor regression on day 36.Surprisingly,tumor recurrence was not observed until the end of the experiment on day 52.In a mechanistic study,we found that LR004-VC-MMAE significantly induced cell apoptosis and cell cycle arrest at G/M phase in MDAMB-468[(34±5)%vs.(12±2)%,P<0.001]and MDA-MB-231[(27±4)%vs.(18±3)%,P<0.01]cells.LR004-VC-MMAE also inhibited the activation of EGFR signaling and the expression of cancer stemness marker genes such as Oct4,Sox2,KLF4 and EpCAM.Conclusions:LR004-VC-MMAE showed effective antitumor activity by inhibiting the activation of EGFR signaling and the expression of cancer stemness marker genes.It might be a promising therapeutic candidate and provides a potential therapeutic avenue for the treatment of EGFR-positive TNBC.

Bispecific antibody drug conjugates:Making 1+1>2

Bispecific antibody‒drug conjugates(BsADCs)represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates(ADCs)and bispecific antibodies(BsAbs).Positioned as the next-generation ADC approach,BsADCs hold promise for ameliorating extant clinical challenges associated with ADCs,particularly pertaining to issues such as poor internalization,off-target toxicity,and drug resistance.Presently,ten BsADCs are undergoing clinical trials,and initial findings underscore the imperative for ongoing refinement.This review initially delves into specific design considerations for BsADCs,encompassing target selection,antibody formats,and the linker–payload complex.Subsequent sections delineate the extant progress and challenges encountered by BsADCs,illustrated through pertinent case studies.The amalgamation of BsAbs with ADCs offers a prospective solution to prevailing clinical limitations of ADCs.Nevertheless,the symbiotic interplay among BsAb,linker,and payload necessitates further optimizations and coordination beyond a simplistic“1+1”to effectively surmount the extant challenges facing the BsADC domain.

ADC联合PD-1抑制剂对比GC方案在膀胱癌新辅助治疗中的疗效及安全性研究

目的:分析真实世界中抗体偶联药物(antibody–drug conjugates,ADC)联合程序性死亡受体1(programmed cell death 1,PD-1)抑制剂在膀胱癌新辅助治疗中的疗效和安全性。方法:回顾性纳入2017年8月至2023年12月于重庆医科大学附属第一医院接受ADC联合PD-1抑制剂和吉西他滨/顺铂(Gemcitabine/Cisplatin,GC)方案新辅助治疗的29例膀胱癌患者,分为A组(维迪西妥单抗联合替雷利珠单抗)和B组(吉西他滨联合顺铂),对比分析2组患者的病理完全缓解率(pathological com-plete response,pCR)和病理降期率,同时评估用药期间患者所发生的不良事件(adverse events,AEs)。结果:A组共纳入17例患者,其中13例行膀胱根治切除术,4例选择保膀胱手术,B组共纳入12例患者,均行膀胱根治切除术。A组pCR为41.2%,B组的pCR为25.0%,P=0.449;A组的病理降期率为58.8%,B组的病理降期率为50.0%,P=0.716。A组中常见的AEs包括肝功能异常10例(58.8%),外周感觉神经功能减退8例(47.1%),贫血7例(41.2%)等,其中3~4级AEs共6例(35.3%)。B组中常见的AEs包括贫血9例(75%),中性粒细胞减少8例(66.7%),恶心8例(66.7%)等,其中3~4级AEs共3例(25.0%)。结论:在膀胱癌新辅助治疗中,ADC(维迪西妥单抗)联合PD-1抑制剂(替雷利珠单抗)较传统的GC方案具有更高的pCR和病理降期率,同时安全性可控,在人类表皮生长因子2阴性的患者中也有较好的疗效。

抗HER2乳腺癌ADC药物研究进展

乳腺癌发病率居女性恶性肿瘤首位,其是由于乳腺上皮细胞发生增殖失控,进而恶变。在乳腺癌治疗时,抗人表皮生长因子受体2(HER2)乳腺癌抗体药物耦联物(ADC)的应用逐渐受到重视,本文就对乳腺癌治疗中常用的抗HER2乳腺癌ADC药物(恩美曲妥珠单抗、德曲妥珠单抗、曲妥珠单抗多卡马嗪、维迪西妥单抗、MM-302、XMT-1522、ARX788、MEDI4276)的应用效果进行综述,以期为抗HER2乳腺癌ADC药物的合理应用提供参考。

HER3-targeted therapeutic antibodies and antibody-drug conjugates in non-small cell lung cancer refractory to EGFR-tyrosine kinase inhibitors

Human epidermal growth factor receptor 3(HER3)is a unique member of the human epidermal growth factor receptor(HER/EGFR)family,since it has negligible kinase activity.Therefore,HER3 must interact with a kinase-proficient receptor to form a heterodimer,leading to the activation of signaling cascades.Overexpression of HER3 is observed in various human cancers,including non-small cell lung cancer(NSCLC),and correlates with poor clinical outcomes in patients.Studies on the underlying mechanism demonstrate that HER3-initiated signaling promotes tumor metastasis and causes treatment failure in human cancers.Upregulation of HER3 is frequently observed in EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors(TKIs).Increased expression of HER3 triggers the so-called EGFR-independent mechanism via interactions with other receptors to activate“by-pass signaling pathways”,thereby resulting in resistance to EGFR-TKIs.To date,no HER3-targeted therapy has been approved for cancer treatment.In both preclinical and clinical studies,targeting HER3 with a blocking an-tibody(Ab)is the only strategy being examined.Recent evaluations of an anti-HER3 Ab-drug conjugate(ADC)show promising results in patients with EGFR-TKI-resistant NSCLC.Herein,we summarize our understanding of the unique biology of HER3 in NSCLC refractory to EGFR-TKIs,with a focus on its dimerization partners and subsequent activation of signaling pathways.We also discuss the latest development of the therapeutic Abs and ADCs targeting HER3 to abrogate EGFR-TKI resistance in NSCLC.

Strategies for Precise Engineering and Conjugation of Antibody Targeted-nanoparticles for Cancer Therapy

Improvements in the diagnosis and treatment of cancer are urgently needed for use in nanotechnology.Nanoparticles(NPs)can reduce the side effects of traditional chemotherapy by sustained release of loaded drugs and increase therapeutic efficiency.NPs can also enhance endothelial permeation retention by size effect and its accumulation in tumor cells through passive targeting.Furthermore,it is critical to treat cancer with a controlled targeted drug which can be specifically delivered into tumor cells and released there,resulting in a targeted therapy to eradicate tumor cells while sparing normal cells.To this end,antibody-mediated targeting therapy has been developed,but imperfections in antibodies(Abs)limit this therapy.Therefore,the combination of NPs and Abs has been highly valued in recent years,because conjugating special Abs on the surface of NPs can increase targeting efficiency,enabling selective delivery of anti-cancer drugs to tumor cells.In this mini-review,we would like to enumerate the strategies for the conjugation of Abs to the surface of the NPs as well as the precise engineering of targeted NPs.The application of targeting antibody fragments in this drug delivery system will also be discussed.

2022年度ADC在胰腺癌领域的研究新进展及展望

胰腺癌是发病率高且生存率低的一种恶性肿瘤,对于缺乏手术适应证及放化疗效果不好的患者,急需发展新型而高效的治疗手段。近年来,抗体药物偶联物(antibody-drug conjugate,ADC)因其高选择性和抗肿瘤活性等优点而逐渐成为研究热点,在胰腺癌的治疗中已取得一些成果,但是仍需面对诸多挑战。本文对2022年度ADC在胰腺癌领域的研究新进展进行综述。

Antibody-drug conjugates:Recent advances in payloads

Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field.An ideal ADC payload should possess sufficient toxicity,low immunogenicity,high stability,and modifiable functional groups.Common ADC payloads include tubulin inhibitors and DNA damaging agents,with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development.However,due to clinical limitations of traditional ADC payloads,such as inadequate efficacy and the development of acquired drug resistance,novel highly efficient payloads with diverse targets and reduced side effects are being developed.This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies,co-crystal structures,and designing strategies,and further discusses the future research directions of ADC payloads.This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy,low toxicity,adequate stability,and abilities to overcome drug resistance.

Treatment‐related adverse events of antibody‐drug conjugates in clinical trials:A systematic review and meta‐analysis

Background:The wide use of antibody‐drug conjugates(ADCs)is transforming the cancer‐treatment landscape.Understanding the treatment‐related adverse events(AEs)of ADCs is crucial for their clinical application.We conducted a meta‐analysis to analyze the profile and incidence of AEs related to ADC use in the treatment of solid tumors and hematological malignancies.Methods:We searched the PubMed,Embase,and Cochrane Library databases for articles published from January 2001 to October 2022.The overall profile and incidence of all‐grade and grade≥3 treatment‐related AEs were the primary outcomes of the analysis.Results:A total of 138 trials involving 15,473 patients were included in this study.The overall incidence of any‐grade treatment‐related AEs was 100.0%(95%confidence interval[CI]:99.9%–100.0%;I2=89%)and the incidence of grade≥3 treatment‐related AEs was 6.2%(95%CI:3.0%–12.4%;I2=99%).Conclusions:This study provides a comprehensive overview of AEs related to ADCs used for cancer treatment.ADC use resulted in a high incidence of any‐grade AEs but a low incidence of grade≥3 AEs.The AE profiles and incidence differed according to cancer type,ADC type,and ADC components.

Trastuzumab-Doxorubicin Conjugate Provides Enhanced Anti-Cancer Potency and Reduced Cardiotoxicity

Since trastuzumab monotherapy for treatment of breast cancer with HER2/ErbB2 over-expression has been shown to have limited efficacy, combined treatment of trastuzumab with chemotherapy is widely practiced in clinic. However, certain combination treatments of trastuzumab and chemotherapy (i.e. doxorubicin) are not recommended due to high risk of cardiotoxicity. Antibody-drug conjugates (ADCs) offer selective delivery of cytotoxic agents into targeted cancer cells, thereby allowing for reduced general cellular cytotoxicity caused by chemotherapeutic agents through antibody mediated specific recognition of tumor antigens. In this study, we constructed a trastuzumab-doxorubicin conjugate (T-Dox) using a thioether linkage and characterized both biophysical stability and anti-cancer potency of the T-Dox using a panel of HER2 expressing cancer cell lines. The T-Dox conjugate showed significantly improved anti-cancer potency in comparison with trastuzumab. The results demonstrated for the first time that there were significant differences in the uptake of T-Dox among high HER2 expression cancer cells and higher T-Dox uptake also showed stronger anti-cancer potency. Similar to trastuzumab, T-Dox selectively bound to HER2 overexpressing cancer cells and low HER2 expression cells had no detectable uptake of T-Dox. Consistent to the uptake data, human cardiomyocyte cells had no detectable HER2 expression and T-Dox showed minimal cytotoxic effects. On the contrary, a treatment with combination of trastuzumab and doxorubicin showed severe cytotoxicity to human cardiomyocytes (>90% cell death after 3 day exposure). This study demonstrated that trastuzumab conjugated with doxorubicin (T-Dox) can provide valuable alternative to the combination treatment with doxorubicin and trastuzumab for high HER2 expressing cancer patients.

ADC类药物治疗乳腺癌疗效与安全性的Meta分析

目的评价抗体药物偶联物(ADC)类药物治疗乳腺癌的疗效和安全性,为临床用药提供循证依据。方法计算机检索中国知网、万方数据库、维普网、PubMed、the Cochrane Library、Embase、Web of Science,收集恩美曲妥珠单抗、德曲妥珠单抗和戈沙妥珠单抗(试验组)对比化疗药物或其他抗肿瘤药物(对照组)的随机对照试验(RCT),检索时限为建库起至2023年4月。筛选文献,提取资料并评价文献质量后,采用RevMan 5.4.1软件进行Meta分析。结果共纳入8项RCT,共计5577例患者。Meta分析结果显示,试验组患者的无进展生存期(PFS)[HR=0.76,95%CI(0.69,0.83),P<0.00001]、总生存期(OS)[HR=0.87,95%CI(0.81,0.93),P<0.0001]、临床获益率(CBR)[OR=2.70,95%CI(1.15,6.33),P=0.02]均显著长于/高于对照组;两组患者的客观缓解率(ORR)比较,差异无统计学意义[OR=2.34,95%CI(0.59,9.33),P=0.23]。亚组分析结果显示,试验组人表皮生长因子受体-2(HER2)阳性、HER2阴性患者的PFS以及HER2阳性患者的OS均显著高于对照组(P<0.05)。试验组患者的贫血、天冬氨酸转氨酶升高发生率均显著高于对照组(P<0.05)。敏感性分析结果显示,以PFS、OS、ORR为指标时,所得结果较稳健;以CBR为指标时,所得结果缺乏稳健性。结论ADC类药物用于乳腺癌的疗效显著,但会增加贫血和天冬氨酸转氨酶升高的发生风险。

ADC药物配体结合生物分析常见技术问题探讨

目的:抗体药物偶联物(ADC)是一类新的生物治疗药物,通常由细胞毒性有效载荷通过连接子与抗体共价结合组成。ADC在体内经历不断的脱偶联和生物转化过程,导致形成复杂且结构不均一的混合物,除了脱偶联的游离抗体和游离载荷外,还存在不同程度与小分子药物偶联的ADC分子,因此,对生物分析方法的开发带来很大挑战。为了解ADC药物在非临床和临床研发阶段的药代和药效特征,以及免疫原性和安全性,对给药后体内存在的不同分子形式的实体比如药物偶联的抗体、裸抗和总抗体等需要使用不同的方法进行分析。本文总结了在ADC药物分析方法开发中遇到的较为常见的技术问题并提供相关的解决方案,以期为相关的分析方法开发提供参考,促进ADC药物安全有效地开发。

2024年欧洲肿瘤内科学会乳腺癌年会研究进展

2024年5月举行的欧洲肿瘤内科学会乳腺癌年会(European Society for Medical Oncology Breast Cance,ESMO BC)在德国柏林召开。本次年会展示了一系列针对乳腺癌治疗的最新进展,包括创新疗法和诊治策略。特别值得关注的是,细胞周期蛋白依赖性激酶4和6(cyclin-dependent kinases 4 and 6,CDK4/6)抑制剂联合内分泌治疗(endocrine therapy,ET)在早期乳腺癌新辅助治疗中的研究尚未达到主要终点,而探索性分析结果表明,该领域仍有待进一步研究。CDK4/6抑制剂联合ET继续作为高危患者辅助治疗的标准。同时,阿贝西利在携带BRCA1/2突变的患者亚组中显示出初步的一致性获益。瑞波西利虽然不良反应可控,但仍需进行密切监测。新型CDK4选择性抑制剂、AKT抑制剂、抗体药物偶联物(antibody-drug conjugates,ADC)以及免疫治疗为晚期乳腺癌患者提供了新的治疗选项。本次年会所展现的研究成果,不仅代表了乳腺癌治疗领域的进步,也为未来的研究方向和患者治疗策略提供了新的视野。本文就此次年会上重点的研究进展进行综述。

乳腺癌受体阳转阴的发生机理与治疗进展

乳腺癌因其高度异质性,给乳腺癌精准治疗带来挑战。雌激素受体(estrogen receptor, ER)、孕激素受体(progesterone receptor, PR)和人表皮生长因子受体-2(human epidermal growth factor receptor-2, HER2)状态是乳腺癌精准诊疗的重要依据。对于复发或转移性乳腺癌患者,既往治疗主要基于原发病灶受体状态。但研究发现部分患者复发/转移灶受体表达与原发病灶不同,推测可能与肿瘤异质性和治疗后的克隆选择效应相关。相较于受体表达“阴转阳”,受体“阳转阴”的发生率更高,且受体表达的缺失可能导致对原有疗法耐药且预后不良。重新评估乳腺癌复发/转移灶受体状态对调整治疗策略和判断预后具有显著临床意义,但能否基于受体变化情况指导临床决策,在临床研究或实践层面仍存在较大争议。随着靶向药物、免疫疗法及抗体偶联药物(antibody-drug conjugates, ADC)等新型抗肿瘤药物的应用,如何优化受体“阳转阴”乳腺癌患者的治疗方案以提高疗效成为未解决的临床需求。该文旨在深入探讨乳腺癌受体“阳转阴”的机理、预后影响以及治疗现状,为这类患者的治疗提供理论支持和实践指导。

癌症治疗中新型抗体偶联药物的研究进展

传统抗体偶联药物(antibody drug conjugates,ADC)通过将单克隆抗体与细胞毒性药物相结合,实现对癌细胞的精准打击,但在稳定性、靶向性、疗效及安全性等方面依然存在诸多不足。新型ADC,如双特异性、位点特异性、双有效载荷和前药型ADC,通过同时结合2个不同抗原或表位、选择更稳定的连接子、与抗体特定氨基酸位点偶联、携带不同药物有效载荷以及采用前药策略等优化方法,在保留传统ADC作用特点的基础上,显著提高药物的稳定性、靶向性、疗效和安全性,能更好地满足临床治疗的需求。新型ADC可能会在未来的癌症治疗中发挥重要的作用。探讨新型ADC在癌症治疗中的进展并分析其优势与挑战,可为开发抗癌策略提供理论支持,为药物研发提供方向。

抗体-药物偶联物毒性的发生机制与优化方法研究进展

自2000年抗体-药物偶联物(ADC)——针对CD33的Gemtuzumab ozogamicin(吉妥珠单抗)获批以来,到目前为止,获得FDA批准的药物已经有13种。该类药物虽然明显改善了多种类型晚期癌症患者的生存,但其明显的毒性却导致患者的治疗获益受损。ADC药物的不良反应具有复杂性,包括靶内和靶外毒性,其中载荷药物是决定因素,但抗体、连接剂均可能影响毒性程度。随着联合治疗成为抗肿瘤治疗的重要策略,在增加疗效的同时,治疗相关不良反应也相应增加。因此,本综述全面分析了当前ADC药物的毒性发生机制,并提出通过多方面优化策略来减小ADC药物毒性,如优化连接分子、升级抗体设计、改变给药策略等。

戈沙妥珠单抗的药物不良事件信号挖掘与分析

目的挖掘戈沙妥珠单抗的药物不良事件(ADE)信号,为其临床安全用药提供参考。方法收集美国FDA不良事件报告系统(FAERS)2020年4月1日至2024年4月30日上报的戈沙妥珠单抗ADE数据。采用报告比值比法、英国药品和保健品管理局综合标准法、贝叶斯置信度递进神经网络法进行数据挖掘。利用《国际医学用语词典》27.0版ADE术语集中的系统器官分类(SOC)、首选术语(PT)进行分类统计。结果共得到戈沙妥珠单抗ADE报告753份,包括46个ADE信号,涉及12个SOC、13个说明书中未记载的新的可疑的ADE信号。发生频次排名前5位的PT分别为疾病进展、死亡、腹泻、超说明书使用、产品给予时间表不当。信号强度排名前5位的PT分别为发热性骨髓再生障碍、中性粒细胞减少性结肠炎、疾病进展、肺脓毒症、一般身体状况异常。药品说明书未记录的新的可疑的ADE包括中性粒细胞减少性脓毒症、肝细胞溶解、脑膜炎、发育不全等。结论临床使用戈沙妥珠单抗时,应特别关注发热性中性粒细胞减少症、发热性骨髓再生障碍、体重波动、结肠炎等报告例数多且信号强度高的ADE;还应警惕中性粒细胞减少性脓毒症、肝细胞溶解、脑膜炎、发育不全等新的可疑的ADE,以保障患者用药安全。