作者: Ness, Sam ; Desmond, Howard ; Yahioglu, Gokhan ; Stamati, Ioanna ; Perez-Castro, Isabel ; Davies, Lowri ; Deonarain, Mahendra P. ; Ngiam, Malcolm ; Edwards, Bryan ; Diez-Posada, Soraya ; Xue, Quinn ; Pomowski, Anja ; Bouche, Laura ; Yap, Jeaniffer

AbstractAntibody Drug Conjugates (ADCs) have failed to deliver the successes seen in breast and urological tumours in Gastro-intestinal tumours such as stomach, colorectal and pancreatic due to 3 critical limitations: Low potency, ineffective solid-tumour penetration and poor tolerability. Approaches utilizing full-length Immunoglobulins dominate the industry, however, antibody fragments (e.g. single-chain Fvs-scFvs), which have many advantages including rapid tumour penetration, faster clearance, inexpensive manufacture, have been technologically challenging to apply in oncology. Our novel approach enables scFvs to have a high Drug:Antibody loading ratio (DAR) whilst retaining effective binding and other favourable biophysical properties, leading to a new product class tailored for solid tumours.Antikor has two FDC products in development for solid tumours, notably gastric: anti-HER2 FDC (ANT-043) and a second target (ANT-045, to be disclosed). ANT-043 has pM potencies in a range of HER2-expressing cell-lines, including trastuzumab-resistant models, excellent tumour ablation effects in breast, ovarian and gastric cancer xenograft models and superior tolerability compared to an ADC in rat toxicology studies at a dose of 1mg/kg/weekly. Quantitative payload tumour uptake and fluorescent immuno-histological studies demonstrate superior solid tumour penetration across the entire tumour and diffusion from blood vessels. In collaboration with our partners, Essex Biotechnology PLC, Antikor is taking ANT-043 into development. ANT-045, which emerged from Antikor’s proprietary FDC ‘discovery engine’, is progressing towards IND-filing and updated data will illustrate how ANT-045 could have a broader patient benefit in gastro-intestinal cancers. ANT-045 has excellent in vitro cell-kill potency (pM IC50s) and excellent stability and superior in vivo tumour cure efficacy, compared to a leading clinical stage benchmark ADC. This presentation will focus on Antikor’s FDC discovery platform (stable high-DAR scFv-display libraries, tailored linker-payloads and design features) that has the potential to generate first-in-class products for difficult to treat solid tumours for patient benefit and promising to succeed where ADCs have failed to make an impact.Citation Format: Mahendra P. Deonarain, Gokhan Yahioglu, Ioanna Stamati, Soraya Diez-Posada, Bryan Edwards, Anja Pomowski, Isabel Perez-Castro, Sam Ness, Laura Bouche, Jeaniffer Yap, Howard Desmond, Lowri Davies, Malcolm Ngiam, Quinn Xue. Gastric cancerantibody fragment drug-conjugates (FDCs): Applying a successful concept to solid tumours [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1530.

2022-06-15·Cancer Research

Abstract 1763: Gastric cancer antibody fragment drug-conjugates (FDCs): Succeeding in solid tumors where ADCs fail

作者: Edwards, Bryan ; Bouche, Laura ; Ngiam, Malcolm ; Stewart, Ashleigh ; Perez-Castro, Isabel ; Yahioglu, Gokhan ; Maciuszek, Monika ; Diez-Posada, Soraya ; Stamati, Ioanna ; Pomowski, Anja ; Xue, Quinn ; Deonarain, Mahendra P. ; Ness, Sam

AbstractAntibody Drug Conjugates (ADCs) are failing due to 3 critical limitations: Low potency, ineffective solid-tumor penetration and poor tolerability. The industry is full of approaches where full-length Immunoglobulins have been engineered to carry defined numbers of payloads with higher-loadings of less potent payloads appearing to be well-tolerated. However, antibody fragments (e.g. single-chain Fcs-scFvs), which have many advantages including rapid tumor penetration, faster clearance, inexpensive manufacture, have been technologically challenging to apply in oncology. Our novel approach enables scFvs to have a high Drug:Antibody loading ratio (DAR) whilst retaining effective binding and other favorable biophysical properties, leading to a new product class tailored for solid tumors. Antikor has two FDC products in development for solid tumors, notably gastric: anti-HER2 FDC (ANT-043) and a second target (ANT-045) which will be disclosed during this presentation. ANT-043 has pM potencies in a range of HER2-expressing cell-lines, including trastuzumab-resistant models, excellent tumor ablation effects in breast, ovarian and gastric cancer xenograft models and superior tolerability compared to an ADC in rat toxicology studies at a dose of 1mg/kg/weekly. Quantitative payload tumor uptake and fluorescent immuno-histological studies demonstrate superior solid tumor penetration across the entire tumor and diffusion from blood vessels. In collaboration with our partners, Essex Biotechnology, Antikor is taking ANT-043 into IND-enabling studies for clinical development. ANT-045, which emerged from Antikor’s proprietary FDC ‘discovery engine’, is progressing towards IND-filing and updated data will illustrate how ANT-045 could have a broader patient benefit in gastro-intestinal cancers. ANT-045 has excellent in vitro cell-kill potency (pM IC50s) and excellent stability and superior in vivo tumor cure efficacy, compared to a leading clinical stage benchmark ADC. This presentation will focus on Antikor’s FDC discovery platform (stable high-DAR scFv-display libraries, tailored linker-payloads and design features) that has the potential to generate first-in-class products for difficult to treat solid tumors for patient benefit and promising to succeed where ADCs have failed to deliver.Citation Format: Mahendra P. Deonarain, Gokhan Yahioglu, Ioanna Stamati, Bryan Edwards, Soraya Diez-Posada, Isabel Perez-Castro, Anja Pomowski, Laura Bouche, Ashleigh Stewart, Monika Maciuszek, Sam Ness, Malcolm Ngiam, Quinn Xue. Gastric cancer antibody fragment drug-conjugates (FDCs): Succeeding in solid tumors where ADCs fail [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1763.

2021-07-01·Cancer Research

Abstract 909: Antibody fragment drug-conjugates (FDCs)-application of ANT-043 and ANT-045 in solid tumors

作者: Edwards, Bryan ; Jurgenson, Triin ; Maciuszek, Monika ; Yahioglu, Gokhan ; Stamati, Ioanna ; Diez-Posada, Soraya ; Perez-Castro, Isabel ; Deonarain, Mahendra P. ; Ngiam, Malcolm ; Xue, Quinn ; Stewart, Ashleigh ; Ness, Sam ; Pomowski, Anja ; Bouche, Laura

AbstractDespite the recent resurgence, Antibody Drug Conjugates (ADCs) are failing to address challenging cancer indications due to 3 critical limitations: Low potency, ineffective solid-tumour penetration and poor tolerability. The industry is well-served by approaches where full-length Immunoglobulins are designed to carry defined numbers of payloads. However, antibody fragments (e.g. single-chain Fvs-scFvs), which have many advantages including rapid tumour penetration, faster clearance, inexpensive manufacture, have been technologically challenging to apply in oncology. Our novel approach enables scFvs to have a high Drug:Antibody loading ratio (DAR) whilst retaining effective binding and other favourable biophysical properties, leading to a new product class tailored for solid tumours. Antikor has two ‘first-in-class' FDC products in development for solid tumours: anti-HER2 FDC (ANT-043) a follow-up product against a second target (ANT-045) which will be disclosed during this presentation. ANT-043 has demonstrated excellent tumour ablation effects in breast, ovarian and gastric cancer xenograft models and superior tolerability compared to an ADC. Quantitative payload tumour uptake by mass spectrometry and fluorescent immuno-histological studies demonstrate superior solid tumour penetration across the entire tumour and diffusion from blood vessels and rapid kinetic uptake. In collaboration with our partners, Essex Biotechnology, ANT-043 is moving into IND-enabling studies for clinical development. Our new flagship product, ANT-045, which emerged from our proprietary FDC ‘discovery engine', is progressing well and new data will illustrate how ANT-045 could have a broader patient benefit in gastro-intestinal cancers. Like ANT-043, ANT-045 has potent in vitro cell-kill properties, excellent stability and drug-like features and illustrates how linker-payload design is critical for the tailoring properties of this emerging format of ADC. This presentation will focus on ANT-045's remarkable development and show that this FDC demonstrates superior efficacy and tolerability compared to an ADC when equated on an equi-mass, equi-molar and equi-payload basis. ANT-045 could be used to switch ‘immunologically-cold' tumour ‘hot' to benefit from checkpoint inhibitor therapy and data will be presented to support this concept.Citation Format: Mahendra P. Deonarain, Gokhan Yahioglu, Ioanna Stamati, Bryan Edwards, Soraya Diez-Posada, Anja Pomowski, Ashleigh Stewart, Isabel Perez-Castro, Laura Bouche, Triin Jurgenson, Monika Maciuszek, Sam Ness, Malcolm Ngiam, Quinn Xue. Antibody fragment drug-conjugates (FDCs)-application of ANT-043 and ANT-045 in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 909.

项与 Antikor Biopharma Ltd. 相关的新闻（医药）

2024-02-04

·同写意

偶联药物家族成员盘点，除了ADC还有哪些？

以“共创偶联药物产业未来”为主题，一场主论坛，九场主题论坛，火热报名中！最近，诺贝尔奖得主们正在陆续揭晓。这些杰出的科学家们对所在领域的影响十分深远。Paul Ehrlich在1908年因为他的偶氮染料获得了诺贝尔生理学或医学奖。但是，他的成就并不仅限于此。在1913年，Paul Ehrlich又提出了一个非常有前瞻性的概念，他称之为“魔术子弹”。这个理论主张将药物精准地送达病变细胞，而对正常细胞不造成任何伤害。这个独特的主张为现今抗体偶联药物（ADC）的崛起奠定了基础。ADC是一种非常有效的治疗方法，它能将药物直接送达到肿瘤细胞，从而最大限度地减少对周围组织的损害。Paul Ehrlich的“魔术子弹”理论开创了这种精准治疗的可能性，对医学产生了深远的影响。近些年来，随着偶联技术的发展，ADC迅速发展并已经取得了重大成果。现在，ADC药物已经是癌症治疗领域一个不可或缺的部分。但是，研发者们并不满足，他们希望将偶联技术的优势延申到更多药物研发中。如今，多种偶联技术不断涌现，行业内对偶联药物的研发热情还在延续。1ADCADC是一种将抗体和细胞毒素共价偶联的治疗手段。抗体是“导航”，可以特异性识别人体细胞表面的特殊标志物，将药物靶向递送到细胞内部，然后细胞毒素发挥作用，杀灭细胞以达到治疗目的。抗体部分与细胞毒素部分通过连接子结合成一个整体，而连接子的优劣则决定了ADC药物的安全性。足够理想的连接子应该可以保证ADC药物不会在到达“导航”的终点之前裂解，不会导致脱靶毒性。第一代ADC药物靶向性弱、药物递送量小，血药浓度低于有效浓度，疗效不佳；此外，这款药物使用的连接子也并不稳定，所以药物毒性较大。因此首款ADC药物——Mylotarg在2010年退市。DESTINY-Breast01研究显示，DS-8201在平均6线的治疗人群中客观缓解率（ORR）达到了60.9%，整体疾病控制率达到了97.3%，无进展生存期（PFS）达到了16.4个月。基于DS-8201的亮眼成绩，数据公布后不久，FDA批准DS-8201用于HER2阳性乳腺癌的后线治疗，此后，整个ADC赛道似乎都被其引爆。如今，全球已经有15款ADC药物获批上市，ADC药物作为一种新兴的生物技术产品，其市场前景广阔，但是其技术难度也不可小觑。未来几年,ADC的市场必然会更进一步。2PDC多肽偶联药物（PDC）由三个部分组成：归肽巢、连接子和具有细胞毒性的载荷。PDC与ADC的结构相似，唯一的区别是，PDC的“导航”部分是多肽。PDC使用的肽分为两种：细胞穿透肽（CPPs）和细胞靶向肽（CTPs）。这两者的区别在于CPPs可以跨细胞膜转运药物，而CTPs可以与细胞膜上的受体特异性结合。与ADC相比，PDC的分子量一般较低，对实体瘤抑制效果较好；合成更容易，并且多肽不容易引发免疫反应，安全性较好。但是多肽在体内容易被水解，所以需要增强多肽的稳定性以及细胞透过性。例如通过改变多肽链的一级结构以改变其氢键位置和电离结构；通过多肽链的环化来使其固定在刚性平面。PDC这种新疗法，有可能克服ADC的某些弊端，成为下一代靶向抗肿瘤药，但是目前PDC在临床应用方面仍然有许多问题需要解决。目前，全球有两款PDC药物上市，分别是诺华的Lutathera和Oncopeptides的Pepaxto。然而由于安全性问题，上市8个月后，Oncopeptides就主动将Pepaxto退市。3FDC抗体片段偶联药物（FDC）是一种用更小的抗体片段替代ADC抗体部分的疗法，因为其抗体片段分子量较小，靶向配体的尺寸可以减少50%～95%，所以FDC药物的肿瘤穿透性更好。也因此，相对于ADC而言，FDC更适合治疗实体瘤。此外，FDC药物半衰期通常比ADC药物短，毒副作用可以得到很好的控制，所以FDC药物的安全性较ADC更好。由于ADC药物技术壁垒高，许多涉足ADC的药企因为药效不佳或药物毒副作用大而失败。此后，Antikor Biopharma（Antikor）率先开发了FDC，致力于克服ADC的局限性。FDC这种“小型”ADC疗法，更加关注载荷而非抗体。FDC较短的半衰期使其拥有更宽的治疗窗口，但是可能需要更频繁的用药或更高的剂量才能维持有效血药浓度。Antikor表示，其建立的OptiLink技术，可系统性地分析、改进抗体片段和毒素之间的连接物。通过改变连接物的化学结构和长短，以及在偶联药物上添加PEG聚合物，可以精准调控FDC的毒素/抗体片段负载比例（DAR）、成药性、药效和安全性。4ISAC2020年12月，来自美国Bolt Biotherapeutics公司和斯坦福大学医学院的研究人员在Nature Cancer上发表了一篇文章，介绍了他们开发的免疫刺激抗体偶联药物（ISAC）。他们将抗体精确的靶向性和适应性免疫系统的杀伤性结合到一种药物（即ISAC）中，并在多种肿瘤模型中实现了肿瘤完全消退和持久的抗肿瘤免疫ISAC同样与ADC相似，不同的是，ISAC的载荷是先天免疫激动剂或调节剂。它具有将对免疫检查点敏感度低的冷肿瘤转化为敏感度较高的热肿瘤的能力。ISAC通过激活肿瘤内树突细胞发挥作用，刺激树突细胞表达的PPR受体来使人体产生免疫反应。不同于ADC直接携带细胞毒素直接靶向定位到肿瘤的“硬仗”，ISAC则是打入肿瘤内部，引起肿瘤的“内乱”。目前ISAC的First-in-class——Bolt Biotherapeutics（Bolt）的BDC-1001正在推进二期临床试验，开发用于治疗表达人表皮生长因子受体2（HER2）的癌症患者。以20mg/kg，每半个月给药一次作为RP2D，在可评估的HER2阳性肿瘤患者中，无论是单药治疗（2/7，29%）还是与纳武单抗联合治疗（2/7，29%），RP2D的缓解率为29%。5AOC抗体-寡核苷酸偶联物（AOC）是一类基于ADC药物设计的新型疗法，AOC是将抗体和寡核苷酸偶联而成的嵌合生物分子，这种偶联可以改善寡核苷酸的药物代谢动力学特性，扩大其应用范围。基于寡核苷酸在成像、检测治疗方面的功能，AOC已经被开发用于免疫测定方法，能够检测高特异性和高敏感度的广泛生物标志物。AOC一定程度上，可以解决当前上市的小核酸药物只能过脂质纳米颗粒（LNP）、N-乙酰半乳糖胺（GalNAc）递送系统靶向递送到肝脏的问题。此外，AOC疗法可以降低小核酸药物引起血小板减少的概率。2021年11月，Avidity Biosciences的AOC药物AOC 1001作为进入一期临床试验完成了首例受试者给药。这款产品用于治疗强直性肌营养不良1型（DM1）。这是全球首款进入临床的AOC药物，此后，AOC领域才开始热闹起来。6SMDC小分子偶联药物（SMDC），也是一种ADC衍生疗法。SMDC以小分子作为“导航”，与转运蛋白高选择性结合。在受体介导下，SMDC被细胞胞吞进入细胞内部，然后连接子被酶水解，细胞毒素释放，最终达到杀死肿瘤细胞的目的。小分子的靶向配体也决定了SMDC能更容易地渗透进肿瘤细胞内，不容易在细胞内聚集，即使药物脱靶，也会被迅速排出体外，减少药物对正常细胞的毒性。此外，因为SMDC的分子量小，其在实体瘤治疗方面有很好的表现。相比ADC，SMDC的生产技术更容易，理论上SMDC也不会产生免疫原性，安全性较好。但是，SMDC配体的选择是一个难点。SMDC的配体选择需要考虑到结合亲和力、靶标选择性和化合物大小等问题。SMDC的配体主要来自天然来源配体的衍生物。因此，SMDC的靶点并不丰富。目前SMDC的靶点集中在叶酸受体、前列腺特异性膜抗原和生长抑素受体等。SMDC的研发还在较早期阶段，还没有形成足够成熟的产业线。目前，大多数SMDC处在一期和二期临床试验阶段，还没有任何已上市的SMDC产品。曾经进展最快的一项SMDC研究，是默沙东与Endocyte合作研发的Vintafolide。然而在晚期铂类药物耐药卵巢癌的III期临床试验中，Vintafolide未能改善疾病无进展生存期，相对于常规化疗并没有更强的优越性，因此在2014年，这项研究被提前终止了。虽然SMDC的研发还为获得突破，但是默沙东、诺华、BMS等跨国药企也投身其中，相信随着SMDC研发的发展，会有更多药企参与其中。SMDC的前景一片光明。7RDC放射性核素偶联药物（RDC）是一种新兴的偶联药物，其与其他偶联药物的最大区别是是RDC的载荷是放射性核素而非细胞毒性物质。使用不同放射性核素的RDC，有显像或治疗等功能，一些RDC甚至可以兼具两种功能。放射性核素是一种不稳定的原子核，能够自发的放出射线（如α、β射线等），可以通过衰变形成稳定的核素。放射性核素是一种高效的细胞毒性物质，其通过电离辐射的方式破坏细胞，而这种破坏是不可逆的。因此，单独使用核药治疗，或多或少都会存在一些毒副作用，会对治疗点位周围的健康细胞造成损害。而RDC这种治疗方式则可以很大程度的降低核素对健康组织的损害。不同于核药，RDC药物治疗不需要将放射性核素释放出来，甚至不需要接触肿瘤细胞，只需要通过内照射杀死肿瘤细胞，因此RDC药物治疗具有旁观者效应、远端效应。基于RDC的这个特性，RDC在扩散性肿瘤中有很大的发展前景。目前RDC药物最常使用的核素是177Lu，它产生β射线，半衰期约为一周，适合小体积瘤和转移灶的清除。最近几年新兴起的核素225Ac也在步入临床，225Ac产生α射线半衰期约为10天。相比β射线，α射线的穿透性较弱，但是对细胞的杀伤性更强，因此这两种方向的核素，可以依其不同特性发展不同的适应症，以达到更好的治疗效果。RDC在国外的进展较快，诺华是其中的佼佼者。目前诺华已经有四款RDC药物上市。2018年，诺华的首款RDC药物Lutathera获得FDA批准上市，用于治疗罕见病SSTR阳性的胃肠胰神经内分泌肿瘤患者。2022年3月，诺华的的RDC药物Pluvicto获得FDA批准上市，用于治疗PSMA阳性转移去势抵抗性前列腺癌（mCRPC）患者。8VDC病毒样药物偶联物（VDC）是一种将病毒衣壳设计为非感染性蛋白纳米颗粒（病毒样颗粒，VLP），作为高效递送载体的一种偶联药物形式。其活性物质是一种可被红外光线激活的强效细胞毒性物质。这种物质被激活后，可以产生高水平的单线态氧，选择性破坏肿瘤细胞，造成肿瘤细胞的急性坏死，此外，免疫原性细胞的死亡可以引起机体的免疫反应进行抗肿瘤应答。这样双重机制的治疗手段可以用于原发性病变的早期治疗。并且能够产生长期的抗肿瘤免疫应答以防止癌细胞的远端转移。Aura Biosciences（Aura）是当前VDC领域的先行者。而AU-011优势Aura管线中领先的候选VDC疗法。2021年11月，Aura公布了首个VDC疗法AU-011在不确定病变（ILs）和脉络膜黑色素瘤（CM）中的的临床试验数据。AU-011的1b/2期试验（NCT03052127）评估了AU-011使用IVT给药治疗ILs和CM的安全性和有效性。12个月的试验结果显示，14名接受药物治疗的患者中肿瘤控制率为64%（9/14），此外，患者的视力留存率为71%。总体而言，AU-011具有良好的安全性和耐受性，它可能可以为CM的一线治疗提供靶向视力保护治疗。— 小结 — 尽管许多偶联药物技术目前仍面临挑战，有许多想法尚未能得到充分验证，但偶联药物领域已经已经有了很多喜人的进展。如今整个行业对偶联药物的发展高度关注，相关的研发工作也日益活跃。展望未来，我们期待偶联新药能不断涌现，为抗击肿瘤提供强有力的帮助。未来可期，那是一片蔚蓝辽阔的天空！参考文献：（上下滑动查看更多）1.https://mp.weixin.qq.com/s/8nsCg4vo5I_G5q4G3aARww2.【干货】抗体偶联药物（ADC）浅析 - 知乎 (zhihu.com)3.https://zhuanlan.zhihu.com/p/6367549274.https://mp.weixin.qq.com/s/JQBmsXc06mia-nWZUGabzQ5.https://mp.weixin.qq.com/s/3hpL1iR8V1-gDgXoC8g9yg6.https://mp.weixin.qq.com/s/O-YkNF8Lz8d_RjQjHuQPtA7.推陈出新 | 抗体-寡核苷酸偶联物（AOCs）技术服务来袭！- 知乎 (zhihu.com)8.https://www.medicilon.com.cn/hang-ye-zi-xun/aocdevelopment.shtml9.https://www.sciencedirect.com/science/article/abs/pii/S1740674918300428?via%3Dihub10.https://investors.boltbio.com/news-releases/news-release-details/bolt-biotherapeutics-highlights-comprehensive-clinical-data11.https://mp.weixin.qq.com/s/nBIm1It6p_uV4wXCRZGk0g12.https://mp.weixin.qq.com/s/wLDgZ-d3ZcutF5EViVn2ow13.https://mp.weixin.qq.com/s/95l3PjqCy9KwF3_a2-SaRg14.https://mp.weixin.qq.com/s/LPSqz8dk9-Ly1_1pWi5xEg15.https://xueqiu.com/5603603160/20450742616.https://mp.weixin.qq.com/s/ZNELPmo7YdzemkMVbpVpMw17.其他公开资料更多优质内容，欢迎关注↓↓↓

抗体药物偶联物多肽偶联药物

100 项与 Antikor Biopharma Ltd. 相关的药物交易

登录后查看更多信息

100 项与 Antikor Biopharma Ltd. 相关的转化医学

登录后查看更多信息