The Novel use of Labetuzumab as Adjuvant Immunotherapy in Patients with Primary Colon Adenocarcinoma with Intact PELPK Binding Motif in their CEACAM5 gene in a Phase II clinical trial regarding the Development of Metachronous Liver Metastases (i.e., those at ‘high-risk’ of metachronous CRCLMs)

开始日期2024-02-05

申办/合作机构

St. George Hospital

100 项与拉贝珠单抗相关的临床结果

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100 项与拉贝珠单抗相关的转化医学

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100 项与拉贝珠单抗相关的专利（医药）

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项与拉贝珠单抗相关的文献（医药）

2023-10-10·Journal of advanced research

A first-in-class dimethyl 2-acetamido terephthalate inhibitor targeting Conyza canadensis SHMT1 with a novel herbicidal mode-of-action.

Article

作者: Wu, Di ; Ma, Changsheng ; Luo, Dingfeng ; Bai, Haodong ; Han, Jincai ; Li, Zuren ; Bai, Lianyang ; Liu, Na ; Bai, Zhendong

INTRODUCTION:

Herbicide application is a highly efficiency method of weed control that boots agricultural output and assures food security. The development of novel herbicides focuses on improved bioactivity and new modes of action. The amino acid biosynthesis was validated as a promising novel mode of action for herbicidal compounds. However, the amino acid biosynthesis enzyme remains largely unexplored for herbicidal targets.

OBJECTIVES:

Serine hydroxymethyl transferase (SHMT) is an essentialenzyme in the photorespiratory cycle. The study aims to explore Conyza canadensis SHMT1 (CcSHMT1) as a promising target for herbicide discovery.

METHODS:

Structure determination of CcSHMT1 was resolved by X-ray crystallography. Virtual screening docking experiments were performed with Glide version 5.5. Novel derivatives of dimethyl 2-acetamido terephthalate were further designed, synthesized, and bioassay. The druggability of the inhibitor was evidenced by ultrastructural changes in mitochondria, in vivo and vitro enzyme activity assays, and genetics analysis.

RESULTS:

CcSHMT1 has a typical PLP-dependent enzyme 3D structure. The dimethyl 2-acetamido terephthalate-containing compounds had herbicidal activity. Dimethyl 2-(2-(4-(2-(4-bromo-2-chlorophenoxy) acetyl)piperazin-1-yl)acetamido) terephthalate (Compound 9ay, EC₅₀ = 193.8 g a.i./ ha) exhibited the highest herbicidal activity on tested weed among the synthesized compounds. Compound 9ay had no obvious adverse effect on the growth of maize and honeybees. Compound 9ay was verified to target CcSHMT1 as an herbicide candidate.

CONCLUSION:

A first-in-class CcSHMT1 inhibitor that could be developed as a potent herbicide with a new mode of action and provide an avenue for discovering novel inhibitors of pyridoxal-5-phosphate-dependent enzymes.

2021-02-01·Clinical cancer research : an official journal of the American Association for Cancer Research1区 · 医学

Regulation of CEACAM5 and Therapeutic Efficacy of an Anti-CEACAM5–SN38 Antibody–drug Conjugate in Neuroendocrine Prostate Cancer

1区 · 医学

Article

作者: De Sarkar, Navonil ; Cardillo, Thomas M. ; Haffner, Michael C. ; Nelson, Peter S. ; Ang, Lisa ; True, Lawrence D. ; Hopkins, James E. ; Lee, John K. ; Zhang, Ailin ; Morrissey, Colm ; Schweizer, Michael T. ; da Costa, Rui M. Gil ; DeLucia, Diana C. ; Corey, Eva ; Labrecque, Mark P. ; Coleman, Ilsa

Abstract:

Purpose::

Neuroendocrine prostate cancer (NEPC) is an aggressive form of castration-resistant prostate cancer (CRPC) for which effective therapies are lacking. We previously identified carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as a promising NEPC cell surface antigen. Here we investigated the scope of CEACAM5 expression in end-stage prostate cancer, the basis for CEACAM5 enrichment in NEPC, and the therapeutic potential of the CEACAM5 antibody–drug conjugate labetuzumab govitecan in prostate cancer.

Experimental Design::

The expression of CEACAM5 and other clinically relevant antigens was characterized by multiplex immunofluorescence of a tissue microarray comprising metastatic tumors from 34 lethal metastatic CRPC (mCRPC) cases. A genetically defined neuroendocrine transdifferentiation assay of prostate cancer was developed to evaluate mechanisms of CEACAM5 regulation in NEPC. The specificity and efficacy of labetuzumab govitecan was determined in CEACAM5+ prostate cancer cell lines and patient-derived xenografts models.

Results::

CEACAM5 expression was enriched in NEPC compared with other mCRPC subtypes and minimally overlapped with prostate-specific membrane antigen, prostate stem cell antigen, and trophoblast cell surface antigen 2 expression. We focused on a correlation between the expression of the pioneer transcription factor ASCL1 and CEACAM5 to determine that ASCL1 can drive neuroendocrine reprogramming of prostate cancer which is associated with increased chromatin accessibility of the CEACAM5 core promoter and CEACAM5 expression. Labetuzumab govitecan induced DNA damage in CEACAM5+ prostate cancer cell lines and marked antitumor responses in CEACAM5+ CRPC xenograft models including chemotherapy-resistant NEPC.

Conclusions::

Our findings provide insights into the scope and regulation of CEACAM5 expression in prostate cancer and strong support for clinical studies of labetuzumab govitecan for NEPC.

2020-04-17·Cell cycle (Georgetown, Tex.)3区 · 生物学

Stat5a promotes brown adipocyte differentiation and thermogenic program through binding and transactivating the Kdm6a promoter

3区 · 生物学

Article

作者: Ji, Yuqiang ; Zhang, Beining ; Xiao, Yanfeng ; Chu, Haiping ; Liu, Weihua ; Yin, Chunyan

Previous studies reported that Stat5 promotes adipogenesis and white adipocyte differentiation. However, the role of Stat5 in brown adipocyte development is poorly understood. We found Stat5a was higher expressed in brown adipocytes than in white adipocytes, and its level was increased during the process of brown adipocyte differentiation. In addition, Stat5a expression was affected by cold stress and high-fat diet-feeding, suggesting a potential role in thermogenesis. Knockdown of Stat5a induced downregulation of brown fat specific genes (UCP1, PGC-1α, Acox-1 and Cidea), while overexpression of Stat5a did the opposite effect. What is more, bioinformatics analysis, ChIP assay and Luciferase activity assay all verified that Stat5a directly bind and transactivate Kdm6a promoter (Lysine-specific demethylase 6A). Further, we found that Stat5a overexpression promoted the expression of Kdm6a and inhibited the trimethylation of H3K27. While inhibiting of Kdm6a reversed the promoting effect of Stat5a overexpression on the expression of brown fat specific genes. Therefore, we conclude that Stat5a participated in brown adipocyte differentiation and thermogenic program through binding and transactivating the Kdm6a promoter.Abbreviations: Stat5: Signal transducers and activators of transcription 5; BAT: brown adipose tissue; WAT; white adipose tissue; eWAT: epididymal white adipose tissue; sWAT: subcutaneous white adipose tissue; SVFs: stromal vascular fractions; UCP1: Uncoupling protein 1; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Acox-1: Peroxisomal acyl-coenzyme A oxidase 1; Cidea: Cell death activator CIDE-A; ChIP: Chromatin Immunoprecipitation; HFD: High fat diet; FBS: Fetal bovine serum; siStat5a: Stat5a siRNA; siKdm6: Kdm6a siRNA; pcDNA-Stat5a: over expression of Stat5a pcDNA3.1 vector; IgG: mouse immunoglobulin G; Kdm6a: Lysine-specific demethylase 6A; H3K27me3: trimethylated H3K27.

项与拉贝珠单抗相关的新闻（医药）

2022-11-13

·生物制品圈

非内化ADC可开发靶点全球研究进展

截至2022年7月，全球总计14款ADC药物（其中FDA批准了12款）获批用于血液系统恶性肿瘤和实体瘤，此外，尚有100多款ADC候选药物处于临床试验的不同阶段。ADC通常需要内化到癌细胞中，以释放其payload，需要具有高表达高内化靶点才能发挥优异的疗效，事实上，目前FDA批准的所有12种ADC都是内化ADC，其中大多数（10/12）含有可裂解的连接体。有7款（7/12）ADC针对非实体肿瘤类型，即血液癌症，包括白血病、淋巴瘤和骨髓瘤。尽管抗乳腺、宫颈和膀胱等实体瘤的ADC已经成功，也需要非内化ADC来扩大癌症靶点范围，尤其是治疗具有致密肿瘤基质的癌症。非内化ADC使得payload可以在内化不良的抗原或其他肿瘤抗原结合时从可裂解linker中释放出来。这不仅可避免ADC药物开发对高表达抗原的依赖，潜在的低效内化导致的疗效不佳，并且可以将癌症靶点的范围大大扩展到细胞外肿瘤基质。这篇综述综述了非内化ADC的最新进展，包括最新的癌症相关细胞表面和细胞外蛋白、癌症基质靶向以及能够释放细胞外有效载荷的连接化学。靶向膜蛋白靶抗原的特征对ADC的成功至关重要，优秀靶抗原应在癌细胞上高度表达，而在健康细胞上不表达，以确保治疗的特异性并避免靶外毒性。抗体-抗原结合相互作用的性质决定了ADC是否发生内化（以及速度）。内化ADC，抗体必须可以诱导快速受体内化、内体运输和溶酶体加工。相反，对于非内化ADC，由于抗原抗体结合后不需要高效内化也能产生较好的疗效。随着人们对非内化ADC的兴趣越来越大，越来越多的不被内化的抗原被发现。B细胞抗原CD20、CD21和CD72Polson等人研究了CD20、CD21和CD72等非内化ADC靶点。在该工作中，使用二硫键、Val-Cit二肽、不可裂解的linker合成了多种ADC（图。研究发现，可裂解的二硫键ADC在体内即使内化非常差的抗原靶点CD20、CD21和CD72也能产生疗效。据推测，二硫键接头可以在细胞外裂解，并通过非内化机制起作用。此外，在这项工作中，包含Val-Cit连接子的抗CD21 ADC的MMAE有效载荷被MMAF替代，MMAF是一种含有带电羧酸末端的类似物（图4C），这阻碍了其发挥旁观者效应。这一变化使得以MMAF为payload的非内化ADC无活性，表明释放的有效载荷在细胞膜上的扩散对活性至关重要，该实验表明Val-Cit连接子可在细胞外释放的作用机制。显然，这一数据与经典观点相矛盾（二硫键和Val-Cit可裂解接头需要内化以释放有效载荷），因此二硫键、VC linker可在TME胞外裂解，释放payload，从而发挥药效。DiJoseph等人的研究证明CD20是有效非内化靶点。通过酸不稳定（腙键）或酸稳定（酰胺）接头将卡利霉素与抗CD20抗体利妥昔单抗偶联。酸可裂解ADC对小鼠B细胞淋巴瘤能有效抑制，而酸稳定ADC（药效与未偶联的利妥昔单抗类似）效果明显不如酸可裂解的ADC，这表明酸介导的连接体裂解的重要性，并意味ADC内化效率较低（否则内化后两种ADC在胞内二硫键均会断裂释放卡利霉素，两者药效可能不会有显著差异）。通过与内化抗原CD22的类似ADC的比较来验证。在这种情况下，酸不稳定ADC与不可裂解ADC的药效相似。因此，由于肿瘤细胞的相对酸性（pH 5.5–7.0）细胞外环境，酸性不稳定的ADC预计可在胞外裂解。PD-L1PD-L1抗体有效率受肿瘤异质性及致密肿瘤基质的不良渗透的限制。因此，开发非内化PD-L1 ADC具有吸引力，因为细胞外有效载荷释放可以克服这些问题。然而，对PD-L1的性质及其内在作用知之甚少。例如，Hung等人构建了几种特异性识别PD-L1糖基化位点的PD-L1抗体。在评估的10种抗体中，只有识别N192和N200糖基化位点的抗体被内化。这表明抗体-抗原结合相互作用的性质是决定其作用机制和是否诱导内化的关键。对于任何ADC的设计，都应仔细考虑这一点。利用FDA批准的avelumab单抗的ADC以前被证明能内化, Boerman等人通过对抗人PD-L1抗体的放射性标记研究表明只能缓慢内化，其在PD-L1 阳性的MDAMB-231孵育24h后仅有25%被内化。，Xiao et al等人发现，avelumab-Val-Cit-MMAE ADC在体外对PD-L1阳性细胞系无效，其IC50与avelumab相似。这是因为ADC缺乏内化（这可能是溶酶体二肽裂解所必需的）。流式细胞术分析显示，孵育2h后，在MC-38、SK-MES和MDA-MB-231细胞系中仅有约20%的avelumab内化，但在MDA-MB231细胞系中约有40% atezolizumab内化。鉴于avelumab缀合物的有限内化，avelumab可能更适合于开发抗PD-L1非内化ADC。尽管在先前的研究中，观察到可裂解的Val-Cit连接子在细胞外裂解，但在本研究中，可能是因为在细胞外Val-Cit连接子裂解水平不够，因此仍需要内化。胞外蛋白酶或其他连裂解接触因素因细胞系、肿瘤类型以及临床前小鼠模型和人而异。CEACAM5癌胚抗原细胞粘附分子5（CEACAM5）是许多种类型癌症的生物标志物，通常不会显著内化。靶向该抗原已在临床前肿瘤模型中得到成功验证，利用pH敏感的碳酸盐或酯连接体与中间体在细胞外酸性肿瘤微环境中ADC释放SN-38。22–24Goldenberg等人研究了抗CEACAM5 labetuzumab ADC，ADC含有酸不稳定的碳酸盐或酯、另外也具有蛋白酶可裂解的苯丙氨酸赖氨酸（Phe-Lys）（图6）。酸不稳定接头具有中等稳定性，在人血清中的半衰期为10-65小时。令人欣慰的是，尽管CEACAM5内化不良，但24个ADC在靶CEACAM4阳性淋巴瘤肿瘤模型种具有良好的效果，其中携带双可裂解连接子CL2的ADC的体内表现最佳。作者提出了SN-38从ADC细胞外缓慢释放的非内化机制，游离药物的局部积累。SN-38与Auristatin或maytansinoid有效载荷相比，具有中等的细胞毒性，碳酸盐/酯键的相对不稳定性被认为适合与SN38一起使用，这允许药物较易释放而不会产生明显的靶向毒性。高度内化抗原Trop-2，用高度稳定的连接取代CL2A连接显著降低效率，表明从CL2A接头逐渐释放SN-38有助于效率。26NKANa+/K+-ATP酶（NKA）的非内化ADC。NKA是一种质膜离子泵，对所有细胞的功能至关重要：抑制NKA可导致细胞死亡。与经典的ADC方法不同，没有开发针对NKA的抗体（正常细胞也表达该蛋白），而是利用了与NKA之间的关联性的其他癌症相关蛋白。Dysadherin是一种细胞膜糖蛋白，在许多转移性癌症中过度表达，并与NKA相互作用。将NKA的抑制剂与抗Dysadherin抗体结合，使抗体与dysadherin结合，从而使抑制剂与NKA非常接近。抑制剂与NKA的结合随后通过诱导细胞肿胀和随后的膜破裂导致细胞死亡。这种策略特别有趣，因为其无需可裂解linker，抑制剂在细胞外起作用。已知与NKA相互作用的靶蛋白包括CD20、CD38、CD147和CD56。令人兴奋的是，ADC剂量低350倍就能达到与游离药物相似的抗肿瘤效果，这验证了靶向方法的优越性。靶向肿瘤微环境依赖靶向膜抗原有几个缺点：很少有癌症均匀地过表达抗原肿瘤可以通过抗原表达的改变获得抗性细胞外基质中的靶蛋白Gal-3-BP半乳糖凝集素-3-结合蛋白（Gal-3-BP）是大多数癌症中大量持续分泌的，这使其成为靶向癌症微环境的ADC的一个有吸引力的靶点。Iacobelli等人开发了一种对Gal-3-BP的凝集素结合域具有特异性的人源化抗体。通过直接与C端半胱氨酸和含硫醇的DM1、DM3或DM4形成二硫键，以“无接头”方式实现药物的偶联。LRG1富含亮氨酸的α-2-糖蛋白1（LRG1）是一种在许多肿瘤的微环境中丰富的分泌型糖蛋白。LRG1的高表达与不良预后相关，因为它会导致血管功能障碍并阻碍治疗药物通过血流输送.Chudasama等人证实，LRG1在分泌后保持在细胞外，因此可构建非内化ADC，包括通过蛋白酶裂解的Val-Cit接头与magacizumab、MMAE偶联。在体外，由于细胞培养中细胞外组织蛋白酶浓度有限，其最初对LRG1阳性的B16F0细胞无效。尽管无效，但证实了LRG1 ADC的非内化特性。用小剂量顺铂联合治疗（5 mM）后将使组织蛋白酶从濒死细胞中有效释放，以激活其ADC。这种组合方法ADC的IC50为15 pM，表明通过联合使用额外的化疗药物启动连锁反应，随着细胞死亡的增加，ADC的药物释放得到改善。MMP9基质金属蛋白酶（MMPs）是一个蛋白酶家族，在癌症进展中具有多种作用，在乳腺癌中经常上调。尽管抑制MMP是一种有吸引力的抗癌策略，但由于该家族催化域中的序列相似性，已证明很难用小分子选择性靶向家族中的一种MMP，靶向MMP抑制剂通常选择性较低，因剂量限制毒性或临床效率不足而终止。为了改进这些小分子MMP抑制剂，Merritt等人通过将泛MMP抑制剂与高度特异性的MMP9靶向抗体结合，开发了细胞外ADC。靶向基质或肿瘤血管系统许多实体瘤表现出致密的细胞间基质：结缔组织和血管网络，阻碍大分子深入肿瘤。这是ADC治疗实体瘤的障碍。靶向基质屏障后面的肿瘤细胞的一种新兴策略是靶向基质本身。基质中ADC的积累可以使细胞外有效载荷在肿瘤微环境中释放，然后可以扩散到附近的肿瘤细胞中。由于小分子的扩散大于抗体，活性药物对实体肿瘤的渗透性有望提高。这被称为“肿瘤基质靶向治疗”（CAST）。此外，由于靶抗原表达的异质性，对几种实体肿瘤ADC（结肠、肺、胰腺）的治疗受到限制。肿瘤细胞外基质的成分包括Collagen、Fibrin、tenascin-C和Fibronectin，这些是治疗实体瘤有吸引力的靶点。CollagenCollagen是肿瘤细胞外基质中基质的主要成分。Matsumura及其同事的针对肿瘤微环境设计了一种靶向Collagen-4的ADC，以使SN-38能够在肿瘤微环境中持续释放。SN-38通过酯酶可裂解的酯键与Collagen-4的单抗偶联， DAR为7-8。FibrinFibrin是一种实体肿瘤基质含量较高的纤维蛋白，Matsumura等人开发靶向Fibrin的ADC。与针对Collagen-4的工作类似，他们利用酯键结合SN-38。在这种情况下，分支接头在每个半胱氨酸偶联三个SN-38，得到DAR24的ADC。Fibronectin快速血管生成是大多数浸润肿瘤的特征，但不是健康组织的特征，因此选择性靶向肿瘤血管是可能的。此外，与靶向异质表达的抗原相比，靶向癌症血管系统使肿瘤治疗分布更广泛。Fibronectin是一种与血管生成相关的糖蛋白，是肿瘤血管内皮下细胞外基质的组成部分。由于选择性剪接，存在不同形式的纤维连接蛋白，即EDA和EDB。这些物质在实体肿瘤中大量存在，积聚在新形成的血管周围，健康组织中很少，这使其成为针对新形成的肿瘤血管中的诱人靶点。L19抗体已被确定为纤维连接蛋白EDB结构域的高亲和力抗体，且不内化。F8抗体为了靶向纤维连接蛋白的EDA结构域高亲和力抗体。Tenascin-CTenascin-C是一种存在于实体瘤基质中的丰富蛋白，但不存在于健康组织中。Tenascin-C的A1结构域可以被F16抗体靶向。Val-Cit-MMAE合成了非内化抗tenascin-C ADC。令人印象深刻的是，ADC在两种不同的小鼠异种移植模型疗效达到100%。虽然这表明在肿瘤部位成功释放有效载荷，但IgG ADC在小鼠血浆中不稳定，在瓜氨酸部位观察到裂解，可能是由于小鼠血浆中的羧基酯酶1c（Ces1c），已知其可酶切该部分。因此，尚不清楚有效载荷的释放和由此产生的ADC功效是否是连接子在小鼠血浆不稳定性的结果，还是细胞外肿瘤组织蛋白酶切割的结果。通过外源触发在细胞外释放虽然大多数ADC依赖于内源性触发物来释放有效载荷，例如肿瘤相关酶或不同的pH，但已经开发了一种替代方法，通过该方法，小分子触发物被外源性地引入使ADC发生裂解。外源触发可裂解的非内化ADC，允许有足够的时间使ADC与靶抗原结合，并有足够时间从血液中清除任何未结合的非靶向ADC。随后，施用外源性释放触发器，仅激活作用部位的ADC。与传统的ADC不同，这种方法不依赖于天然生物激活机制的切割，因此，外源激活具有可预测的药物释放速率。Click-to-release肿瘤相关糖蛋白72（TAG72）在多种实体肿瘤的癌细胞表面过表达。Rossin等人证明了其作为非内化ADC靶点的适用性，他们利用生物正交反电子需求Diels-Alder（IEDDA）反应生成非内化抗TAG-72 ADC。Exogenous palladiumBernardes等人开发了一种含双功能硫醚炔丙基氨基甲酸酯接头，允许外源钯激活裂解释放有效载荷。HER2纳米体ADC通过半胱氨酸与连接到阿霉素的硫醚炔丙基氨基甲酸酯接头的生物连接构建。Exogenous platinum非内化抗tenascin C ADC的通过铂外源激活释放有效载荷，Oliveira等人描述了一种基于抗tenascin-C的F16抗体的非内化ADC，利用铂外源激活释放有效载荷。结论目前越来越多的注意力转向了具有细胞外有效载荷释放机制的非内化ADC的开发，目的是改善与经典内化ADCs相关缺陷。非内化ADC是一个令人兴奋的新兴领域，可能有助于克服内化ADCs一些障碍，并有望在未来实现更广泛实体瘤治疗。参考文献：Non-internalising antibody–drug conjugates.DOI: 10.1039/d2cs00446a‍‍

抗体药物偶联物

2021-07-15

·BiG生物创新社

新靶点ADC药物的临床进展

抗体偶联药物(Antibody–DrugConjugates，ADC)被提出已经有四十多年的时间了，众多科学家不断的优化抗体、小分子毒性药物、连接子、临床检测、临床试验方案，近两年迎来了丰收，FDA批准了多款ADC药物。国内荣昌生物维迪西妥单抗也获得批复。 RegulatoryToxicology and Pharmacology 122 (2021) 104890 获批和在研的ADC药物，以经典靶点为主，如HER2，BCMA等。但是近年也有新的靶点不断涌现。 1 叶酸受体α 叶酸受体α(Folate receptor alpha,FRα)，高表达于实体瘤，比如间皮瘤（72-100%），三阴性乳腺癌（35-68%），卵巢癌（76-89%），非小细胞肺癌（14-74%），参与肿瘤的浸润、转移、进展，成为肿瘤治疗有吸引力的靶点。 FRα表达（Nat Rev Clin Oncol . 2020 Jun;17(6):349-359.） MORAb-202 卫材收购Morphotek获得了FRα单抗Farletuzumab，但是2016年发表的3期治疗铂抵抗卵巢癌患者临床数据，没有达到主要设计终点PFS。之后，卫材开发了ADC药物MORAb-202（farletuzumab和eribulin偶联），临床前数据良好，正在开展两项临床研究（NCT04300556，NCT03386942），6月17日，BMS首付款6.5亿美金和卫材达成合作开发协议。 IMGN853 Mirvetuximab soravtansine（IMGN853）由ImmunoGen研发，细胞毒性药物DM4与人源化的抗FRα单克隆抗体，通过可切割linker连接。2015年，美国FDA授予卵巢癌患者治疗的孤儿药物资格。2018年6月，FDA授予该ADC药物快速通道。 3期临床FORWARD I研究(NCT02631876)未达到主要终点，但是显示出有效性。和FDA协商后，ImmunoGen启动了两项新3期临床研究，SORAYA研究(NCT04296890)；MIRASOL 研究(NCT04209855)，主要针对铂抵抗，高表达FRα的卵巢癌患者，预计2021年底或者2022年获得结果。 2 组织因子组织因子（Tissue factor，TF)是一种跨膜糖蛋白，由内皮下细胞和成纤维细胞表达，在止血调节中发挥重要作用。肿瘤微环境的多种因素如缺氧、TGF-β等均会上调肿瘤细胞TF表达，而TF可以促进肿瘤的生长、血管生成、转移和血栓形成。 TF的转录调控（BLOOD, 26 JANUARY 2012） Tisotumab vedotin Tisotumab vedotin是组织因子抗体（HuMax-TF)和MMAE偶联药物，由Seagen和Genmab联合开发，，子宫颈癌已经进入三期（NCT04697628）,实体瘤2期（NCT03485209），卵巢癌2期。 Tisotumab vedotin临床进度（Genmab官网） InnovaTV 201是第一次人类临床试验研究了高表达TF，并对微管抑制剂敏感的肿瘤，包括卵巢患者、宫颈患者、食管患者，膀胱，子宫内膜癌，前列腺癌，头和颈部鳞癌(HNSCC)和NSCLC。常见的副作用鼻出血（69%）、疲劳（56%）、恶心（52%），脱发（44%）、结膜炎（43%）、食欲下降（36%）、便秘（35%）、腹泻（30%）、呕吐（29%）、周围神经病变（22%）、干眼病（22%）和腹痛（20%）。ORR为15.6%，在子宫颈癌活性高。2期InnovaTV204研究复发性转移性子宫颈癌（r/mcc），ORR为24%，DCR为72%，中位DOR为8.3个月，中位PFS 4.3月，中位OS 12.1月。基于InnovaTV204的研究结果，2021年4月9日Seagen和Genmab宣布，FDA接受了Tisotumab vedotin BLA优先评审申请，加速上市审批。 3 LIV1 LIV-1属于锌转运体ZIP超家族，是一个跨膜蛋白。他们在组织的表达是异质性的，反映了他们的不同功能。其中，LIV1(ZIP6)蛋白主要表达在激素控制组织中，其表达对雌激素水平敏感。它首先在乳腺癌细胞系被鉴定为一种雌激素诱导基因，随后发现与HR阳性乳腺癌的相关。除了乳腺癌，还在胰腺、前列腺、黑色素瘤、宫颈癌和子宫癌中检测到。 SGN-LIV1A Ladiratuzumab vedotin （(SGN‑LIV1A）由Seagen开发，LIVA抗体和MMAE偶联。 SGN-LIV1A临床进度（Seagen官网）乳腺癌1期临床（NCT01969643）已经开展，计划入组508个病人。早期结果观察了69个转移性乳腺癌，治疗总体表现良好，其毒性特征与其他基于MMAE的ADCs相似。疲劳（59%）、恶心（51%）、周围神经病变（44%）、脱发（36%）、食欲下降（33%）、便秘（30%）、腹痛（25%）、腹泻（25%）和中性粒细胞减少症（25%）。中性粒细胞减少（25%）和贫血（15%）为≥3级。在HR+/HER2−(DCR59%)和TNBC(DCR64%)亚组中均观察到初步的抗肿瘤活性。值得注意的是，631例肿瘤样本LIV1表达率为91%，75%的病例为中高表达。 SGN‑LIV1A还可以诱导免疫原性细胞死亡(immunogenic cell death ，ICD)，可以增加免疫治疗的效果。1项和Pembrolizumab联用的1/2期临床（NCT03310957）正在进行中，治疗晚期乳腺癌或者转移性三阴性乳腺癌。此外，针对多种实体瘤的2期临床（NCT04032704）也在招募患者。 4 CEACAM 癌胚抗原相关细胞粘附分子(carcinoembryonicantigen-related cell adhesion molecules ，CECACAMs)是一个12个免疫球蛋白相关蛋白家族，在生理上在许多上皮组织的细胞膜上表达，它们作为不同过程的调节剂，如细胞粘附、分化、增殖和生存。 CEACAMs和癌症之间有密切关系，发现CEA(CEACAM5)是肿瘤生物标记物，此外参与癌症进展和转移的信号调节作用。针对CEACAM1、CEACACAM5或CEACAM6的研究药物已经开始在开发。特别是，CEACAM5在几种肿瘤中高度表达，包括CRC、肺和胃肿瘤，成为ADC药物开发的主要靶点。 SAR408701 由Sanofi研发，CEACACAM5抗体和DM4偶联。第一个人体临床研究，31名患者接受了8个剂量水平(从5-150mg/m2)的治疗，包括CRC（18）、GC（7）、GEJ（3)、食道(1）、BC（1）和胰腺癌(PC)（1）。用IHC对CEACAM5的表达进行了回顾性评估。最常见的不良事件（≥20%）为疲劳/无力（32%）、恶心和食欲下降（26%）、腹泻、便秘和角膜病（23%）。5例患者发生了剂量限制毒性(DLTs)，最大耐受剂量(MTD)在100mg/m2Q2W。SAR408701随后在三个扩展队列中，招募了CRC、肺癌(小细胞肺癌和非鳞状NSCLC)和GC患者。最有希望的数据来自非鳞状NSCLC队列，其中高抗肿瘤活性尤其是高表达CEACAM5的患者（≥50%；ORR20.3%，SD42.2%），而中度表达者的反应降低（1-49%；ORR7.1%）。因此，SAR408701的后续开发主要集中在CEACAM5阳性非鳞状NSCLC患者，三个正在进行临床研究：单药治疗（CARMEN-LC03）、联用ramucirumab单抗（CARMEN-LC04）或联合PD-1（CARMEN-LC05） IMMU‑130 Labetuzumab govitecan（IMMU‑130），由GileadSciences研发。Labetuzumab（CEACACAM5抗体）偶联SN-38。由于前期临床结果不理想，现在已经没有临床研究在进行。 — 小结 — ADC药物这两年获得飞速发展，国内也有众多企业加入研发行列。除了HER2等经典的靶点之外，叶酸受体、组织因子、LIV-1、CEACAM等新靶点也取得了积极进展，叶酸受体和组织因子均有药物进入三期临床，Tisotumab vedotin已经递交了BLA，相信这两年在ADC领域还会有新的药物上市。除了上述靶点，HER3、Mesothelin、c‑Met等靶点的ADC，也开始进入1/2期临床。主要参考文献1.Vergote, I. et al. Arandomized, double- blind, placebo- controlled, phase III study to assessefficacy and safety of weekly farletuzumab in combination with carboplatin andtaxane in patients with ovarian cancer in first platinum- sensitive relapse. J.Clin. Oncol. 34, 2271–2278 (2016).2.Mariana Scaranti et al，Exploiting the folate receptor α in oncology，Nat Rev Clin Oncol . 2020 Jun;17(6):349-359.3.Taylor KM, Morgan HE, Smart K,Zahari NM, Pumford S, Ellis IO, Robertson JFR, Nicholson RI. The emerging roleof the LIV-1 subfamily of zinc transporters in breast cancer. Mol Med.2007;13:396–406.4. Modi S, Pusztai L, Forero A,et al. Abstract PD3–14: phase 1 study of the antibody-drug conjugate SGN-LIV1Ain patients with heavily pretreated triple-negative metastatic breast cancer.Cancer Res. 2018;78:PD3-14-PD3-14.5.Gazzah A, Stjepanovic N, RyuMH, et al. First-in-human phase I trial of the anti-CEACAM5 antibody-drugconjugate SAR408701 in patients with advanced solid tumors (NCT02187848). Eur JCancer. 2016;69:S14–5.6.Gazzah A, Ricordel C, Cousin S,et al. Efcacy and safety of the antibodydrug conjugate (ADC) SAR408701 inpatients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC)expressing carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5).J Clin Oncol. 2020;38:9505–9505. 免责声明 “药渡”公众号所转载文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片，文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。

抗体药物偶联物抗体免疫疗法合作优先审批

2021-02-10

·BioSpace

Carcinoembryonic Antigen Testing Market: Rise in global cancer patient population is expected to drive the market

Carcinoembryonic antigen (CEA) test used to help to diagnose and management of colon and rectal cancers preferably. CEA is a glycoprotein normally found in embryonic endodermal epithelium. The best use of CEA is as a tumour marker, especially for gastrointestinal tract related cancers. Tumor markers are the biomarker or molecule produced by body in response to cancer and found in the body fluids and body tissue. A rising CEA level is significance of reoccurrence of the cancer. Increased knowledge about specific cancer biomarker is providing great market opportunity to treat cancer patients through improvement in the detection. The technological advancements in the field of biotechnology have enabled the identification of potential cancer biomarkers and some of these biomarkers have been commercialized. Moreover, with this paradigm shift in the drug discovery and development process, several pharmaceutical companies are shifting their focus towards the development of novel targeted tests like CEA test. According to American Cancer Society, Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women. According to a study conducted by National Cancer Institute, in 2014, there were an estimated 1,317,247 people living with colon and rectum cancer in the United States. Read Report Overview - Global CEA test market is anticipated to witness lucrative growth during the forecast period attributed to rise in global cancer patient population, development of novel biomarkers, presence of favourable government initiatives regarding cancer awareness and control by the organizations such as National Cancer Institute, Cancer Prevention and Control Research Network (CPCRN). Moreover, growing demand for cancer diagnostic and testing, increased accuracy of diagnostic procedures and rigours research and development initiatives taken by government further fuel the market growth. The market is also witnessing restraints in its path such as high cost of procedure and stringent regulatory approval criteria. Request Brochure of Report - The market of global carcinoembryonic antigen testing can be segmented on the basis of application, distribution channel and geography. Based on application, global carcinoembryonic antigen testing market is segmented into colorectal cancer, thyroid cancer, pancreatic cancer, ovarian cancer, breast cancer and others. Among these segments, colorectal cancer is anticipated to be one of the largest revenue generating segment during the projected period. Increasing prevalence of colorectal cancer and use of CEA test at each stage of colorectal cancer are the significant factors contributing to rising adoption of CEA test for colorectal cancer indication. Moreover, breast cancer is anticipated be the fastest growing application segment in the global carcinoembryonic antigen testing market. According to World Health Organization’s survey, breast cancer is the second most common cancer in the world and, by far, the most frequent cancer among women with an estimated 1.67 million new cancer cases diagnosed in 2012 which is equal to 25% of all cancers. Request for Analysis of COVID-19 Impact on Carcinoembryonic Antigen Testing Market- Geographically, global carcinoembryonic antigen testing market is classified into five regional markets, includes North America, Europe, Asia-Pacific, Latin America, Middle East and Africa. North America is one of the leading regions in CEA testing market in terms of revenues and acceptance of products among diagnostic labs and technicians. Increasing incidence and prevalence of various types of Cancers among middle aged and elder population are prominent drivers to the growth of market in North America. Increasing investments of the largest market players in this region towards biomarker discovery followed by development of novel companion diagnostics tests. Furthermore, increasing collaboration between the major market players has effectively contributed in uplifting CEA testing market in North America, especially in the United States. Asia pacific being home to more than a billion people of the world represents a large pool of patients suffering from life threatening diseases such as cardiovascular and cancer offering lucrative opportunity to the player operating in the market. Request for Custom Research - Various key players contributing to the global carcinoembryonic antigen testing market comprises Abbott Laboratories, F. Hoffmann- La Roche Ltd, Quest Diagnostics Incorporated, Genway Biotech Inc., Amgen Inc., and others. Pre Book Carcinoembryonic Antigen Testing Market Report - About Us Transparency Market Research is a next-generation market intelligence provider, offering fact-based solutions to business leaders, consultants, and strategy professionals. Our reports are single-point solutions for businesses to grow, evolve, and mature. Our real-time data collection methods along with ability to track more than one million high growth niche products are aligned with your aims. The detailed and proprietary statistical models used by our analysts offer insights for making right decision in the shortest span of time. For organizations that require specific but comprehensive information we offer customized solutions through ad hoc reports. These requests are delivered with the perfect combination of right sense of fact-oriented problem solving methodologies and leveraging existing data repositories. TMR believes that unison of solutions for clients-specific problems with right methodology of research is the key to help enterprises reach right decision. Contact Mr. Rohit Bhisey Transparency Market Research State Tower, 90 State Street, Suite 700, Albany NY - 12207 United States USA - Canada Toll Free: 866-552-3453 Email: sales@transparencymarketresearch.com Website:

100 项与拉贝珠单抗相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D08936	-	-	DB05097

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
胰腺癌	临床2期	美国	Immunomedics, Inc.	2000-01-01
胰腺癌	临床2期	德国	Immunomedics, Inc.	2000-01-01
胰腺癌	临床2期	匈牙利	Immunomedics, Inc.	2000-01-01
胰腺癌	临床2期	荷兰	Immunomedics, Inc.	2000-01-01
乳腺癌	临床2期	-	Immunomedics, Inc.	-
结直肠癌	临床2期	-	Immunomedics, Inc.	-
卵巢癌	临床2期	-	Immunomedics, Inc.	-
小细胞肺癌	临床2期	-	Immunomedics, Inc.	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ASCO2008	临床2期	结直肠癌肝转移	32	Repeated anti-CEA-radioimmunotherapy (RAIT) with 131iodine-labetuzumab	構構繭顧淵構網窪鏇構(蓋鑰膚襯衊獵膚憲願製) = 壓製艱艱網製鹽鏇醖廠鹹膚餘齋壓選齋網獵獵 (繭艱鑰觸窪繭獵範觸範 ) 更多	-	2008-05-20
				Single dose RAIT after salvage resection of colorectal liver metastases (CRC-LM)	顧夢糧遞鏇鏇鏇願艱糧(遞顧襯襯膚鹽觸糧蓋鹹) = 膚鑰鑰積積窪淵繭製糧繭醖簾壓蓋鑰壓範襯鹹 (齋鑰廠窪廠觸顧構窪選 )
ASCO2007	临床2期	结直肠癌肝转移	26	131I-labetuzumab	膚膚鑰膚製鏇製襯膚蓋(夢遞齋襯繭齋襯廠繭願) = 鏇蓋網憲遞憲鹽願構醖餘選網網襯鹽糧淵積網 (壓齋蓋鏇鬱鏇製繭簾膚 )	-	2007-06-20
ASCO2006	临床2期	结直肠癌肝转移	13	131I-Labetuzumab	廠願襯壓淵範鹹襯糧壓(夢築鏇膚積廠築糧壓襯) = 餘齋壓襯鹽壓夢獵衊簾製憲憲蓋壓淵膚鏇範鑰 (廠鏇蓋蓋觸積簾構壓願 ) 更多	-	2006-06-20
ASCO2005	N/A	结直肠癌肝转移	23	131I-labetuzumab	齋遞構簾餘夢夢齋繭選(鏇願鹹醖蓋遞簾襯顧廠) = the major side effect was a transient myelosuppression, resulting mostly in a grade ≤ 3 neutropenia and/or thrombocytopenia 簾醖衊艱廠鬱襯憲齋壓 (獵構壓鬱願繭夢鑰範積 )	积极	2005-06-01
				131I-labetuzumab (Control group)