Gemtuzumab Ozogamicin

On July 10, BeiGene and DualityBio have announced an agreement for BeiGene to acquire an exclusive option for a global clinical and commercial license to an investigational ADC therapy for patients with select solid tumors. DualityBio will continue preclinical research activities and support Investigational New Drug filing while BeiGene will hold global clinical, manufacturing, and commercial rights upon exercising its option. Under the terms of the agreement, DualityBio will receive an upfront payment and will be eligible for additional payments based on certain development, regulatory, and commercial milestones, totaling up to $1.3 billion, in addition to tiered royalties. The partnership aims to accelerate the development of this asset and bring more breakthrough ADC medicines to patients worldwide. This is the latest move by the biotech industry to jump on the ADC bandwagon. Antibody drug conjugates (ADCs) are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike conventional chemotherapy, which can damage healthy cells, ADCs are intended to target and kill tumor cells while sparing healthy cells. In the Synapse database, there are already 1,163 drugs that fall into this category, with a variety of targets. The concept of ADCs originated from Paul Ehrlich's work in 1900. He envisioned drugs that act like a “magic bullet” by selectively delivering toxic agents to microbes or tumor cells. The first successful ADC clinical trial occurred in 1983, using an anti-carcinoembryonic antigen antibody conjugated to vindesine. In the 1990s, the first generation of ADCs used murine antibodies as a backbone. However, the linkers were unstable in human circulation and ADCs had a short half-life. In 2000, the FDA approved the first ADC: gemtuzumab ozogamicin (trade name Mylotarg), targeting CD33-positive acute myeloid leukemia. It used calicheamicin as the cytotoxic payload linked by a hydrazone linker. However, it was withdrawn in 2010 due to severe hepatotoxicity and lack of benefit. It was reintroduced in 2017 at a lower dose and different schedule. Since then, several ADCs have been approved for various cancers like Hodgkin lymphoma, breast cancer, urothelial cancer, and multiple myeloma. These ADCs employ different antibodies, linkers and payloads to achieve better efficacy and safety. Examples include brentuximab vedotin (Adcetris), trastuzumab emtansine (Kadcyla), inotuzumab ozogamicin (Besponsa), and belantamab mafodotin (Blenrep). In the rapidly evolving field of cancer research, the development of ADCs comes with its unique set of challenges. To start, the selection of the target antigen is crucial. This antigen should ideally be highly expressed on tumor cells and minimally expressed on normal cells to alleviate toxicity risk. This antigen should also enable internalization upon antibody binding to directly facilitate payload delivery, and be stable enough not to be affected by the tumor microenvironment or therapy measures. Next, antibody engineering is paramount. It requires high specificity and affinity for the target antigen, along with favorable pharmacokinetics and biodistribution. These antibodies should also demonstrate minimal adverse effects like immunogenicity, cytokine release, or compliment activation. Besides, provisions for an optimal linker and payload attachment might require a suitable conjugation site and drug-to-antibody ratio (DAR). Linker design also poses hurdles. It necessitates a balance between stability in the bloodstream and cleavability in the tumor cell to allow active payload release. Consideration towards the linker's length, flexibility, toxicity, and immunogenicity is critical for ADC's conformations and functions. Payload selection is another concern. These payloads should be potent and efficacious against tumor cells with minimal off-target toxicity, resistance, and optimal solubility for such conjugation and delivery. Manufacturing poses an additional challenge. ADCs production is a complex, costly process that demands tight control over aspects like conjugation reaction, purification, formulation, and storage. The quality is influenced by factors like aggregation, degradation, heterogeneity, impurities, and stability. Lastly, the clinical development of ADCs is demanding due to dose selection, patient selection, biomarker identification, safety monitoring, and efficacy evaluation. Regulatory hurdles, such as the need for novel endpoints, surrogate markers, combination strategies, and post-marketing studies, also pose significant barriers. Despite these formidable obstacles, the potential benefits of ADCs are immense, making their development a vital element in contemporary cancer research and treatment. Emerging directions for ADC development are eagerly being explored. One key area of focus revolves around exploiting new target antigens, such as cell surface receptors, enzymes, transporters, or glycoproteins, offering novel opportunities for selective targeting of tumor cells and their microenvironments. Efforts are also being made to increase the drug-to-antibody ratio (DAR), expected to enhance ADCs' potency by delivering more payload molecules per antibody. This may be achieved by using site-specific conjugation methods, multivalent antibodies, or even polymer-based carriers. Increasing antibody penetration into solid tumors, through the use of smaller antibody fragments, bispecific antibodies, or engineered antibodies, is another intriguing perspective, which could contribute to better distribution of ADCs within tumor tissues. Search for strategies to combat resistance mechanisms conferred to ADCs, such as reduced antigen expression levels or payload resistance, is also underway. The use of combination therapies, alternative payloads, or novel linkers may be decisive in this field. Enhancing the efficiency of ADC uptake and processing by tumor cells is a promising avenue where pH-sensitive linkers, enzyme-responsive linkers, or self-immolative linkers may lead to better payload activation within tumor cells. Contending with off-target payload exposure is a crucial issue, and methods such as masked payloads, prodrug payloads, or targeted delivery systems are being considered to reduce the systemic toxicity and adverse effects associated with ADCs. Finally, the employment of non-cytotoxic payloads - like immunomodulators, gene silencers, or radioligands - opens up an exciting area of exploration that may introduce new modes of action for ADCs. Despite the complexity and multiplicity of challenges, the future of ADCs appears promising, wielding substantial potential for improving cancer treatment outcomes. The content above comes from the network. if any infringement, please contact us to modify.

首款获批的抗体偶联药物（ADC）吉妥珠单抗奥唑米星，曾为癌症治疗带来新希望。但由于患者出现严重副作用甚至死亡病例，该药物随后被加上黑框警告并撤市。不过，这并未阻止生物制药公司在该领域加快研究，以期开发出更安全的替代药物。在研发耐受性良好的癌症疗法的竞赛中，BiVictriX 公司在开发急性髓系白血病（AML）靶向治疗药物方面处于领先地位。 急性髓系白血病是一种血癌，据估计，仅在美国，今年就有超过 2 万人受其影响。它约占所有癌症的 1%，起源于未成熟的白细胞。由于这些白细胞未完全发育成熟，不具备保护身体免受感染的特性。随着这些细胞不受控制地增多，红细胞和血小板的数量会下降，从而引发白血病的一些症状，如疲劳、感染风险增加、皮肤易瘀伤和关节疼痛。和其他癌症一样，急性髓系白血病的确切病因尚不完全清楚，但辐射暴露增加、被诊断出患有某些血液疾病以及之前接受过癌症治疗，都会增加患急性髓系白血病的风险。 目前，化疗、干细胞移植以及放射治疗被视为标准治疗方案，但抗体偶联药物如今正重新兴起。抗体偶联药物由单克隆抗体、连接子和抗癌药物组成，单克隆抗体能与癌细胞中的癌蛋白结合，连接子则在抗体与癌细胞结合后输送抗癌药物。因此，与传统化疗不同，这类药物往往能避开健康细胞，是一种更具针对性的癌症治疗方法。目前，已有 14 种抗体偶联药物上市，其中不少是在过去几年获批的。 BiVictriX 公司位于英国柴郡，其针对急性髓系白血病的主打项目是 BVX001，这是一种双特异性抗体偶联药物，靶向 CD7 和 CD33 两种抗原的组合。这些抗原存在于白血病细胞上，近四分之一的急性髓系白血病患者体内都有。 1.BiVictriX 如何解决抗体偶联药物的缺陷？BiVictriX 首席执行官蒂芙尼・索恩表示：“我们设计这款药物，是为了保留抗体偶联药物的所有强效优势，同时提高对癌细胞的选择性。急性髓系白血病最大的问题之一是严重的毒性，尤其是对骨髓的毒性，会导致中性粒细胞减少和中性粒细胞减少性败血症，这实际上是致命的。事实上，它是急性髓系白血病患者的主要死因之一。我们的主打治疗药物 BVX001，对靶向癌细胞非常有效，但在目前的测试中，似乎不会对骨髓产生任何毒性。” 化疗常见的副作用是骨髓毒性，当骨髓产生的免疫细胞减少时就会出现。这可能导致中性粒细胞减少，即对抗感染的中性粒细胞数量下降，使身体更容易受到感染；还可能引发中性粒细胞减少性败血症，这是中性粒细胞减少的并发症，可能致命。 索恩表示，在临床前研究中，BiVictriX 取得了令人期待的结果，如果这些结果在临床试验中得以重现，那将具有革命性意义。在带有人类急性髓系白血病细胞系的小鼠模型帮助下，小鼠背部长出实体瘤。然后给它们注射候选药物 BVX001，在第一种模型中，肿瘤缩小了 93%。在第二种模型中，肿瘤生长程度更大，但在 28 天结束时，观察到肿瘤大小减少了 97%。 索恩说：“一开始，我们选择这个极具挑战性的细胞系，确实让研究难度增加了不少。但我们是有意为之，就是为了充分展示这款药物的优势。” 她还补充说，这些结果 “在统计学上具有高度显著性”。 2.靶向治疗的前景除了临床前试验，该药物在今年早些时候还进行了安全性研究。BVX001 在人源化小鼠模型上进行测试，这种模型复制了人类免疫系统。该研究将 BVX001 与吉妥珠单抗奥唑米星（商品名 Mylotarg）进行对比，吉妥珠单抗奥唑米星在 2010 年撤市，由于急性髓系白血病研究缺乏重大突破，2017 年它以较低剂量重新获批。研究显示，BVX001 不会导致骨髓毒性或中性粒细胞减少，证明其安全性良好。 索恩说：“据我们所知，没有其他人在研究这个特定概念。我们设计的抗体偶联药物能够真正区分癌细胞和健康细胞。基本上，这种药物只与癌细胞结合，并在癌细胞内释放有效载荷。” 这样可以确保有效载荷不会在血浆或可能表达相似抗原的健康细胞中释放。索恩表示，这款药物专为 60 岁及以上不适合强化治疗的患者设计，对于那些需要一种没有市场上许多其他药物副作用的疗法的患者来说，它可能是一种有效且能治愈疾病的选择。 索恩说：“如果临床前数据能在临床中得到验证，我认为这将是一款非常重要的药物，特别是对于那些无法承受其他强化治疗的患者。目前急性髓系白血病市场上的大多数药物都是小分子药物，它们针对导致疾病的特定分子机制。而作为一家研发抗体偶联药物的公司，我们主要针对癌细胞，将一种非常有效的化疗药物输送到癌细胞内部，从内部将其杀死。” 此外，由于该药物靶向白血病细胞表面的两种抗原，这些抗原就像细胞的特定标签，只有当这些抗原存在时，药物才会被细胞内化，从而使健康细胞免受损害。 这项技术的灵感源于索恩在英国国家医疗服务体系（NHS）接受临床免疫学家培训期间。索恩说：“我想正是那段经历让我有了独特的见解…… 如果你观察癌细胞表面的模式，会发现它们实际上有这些‘条形码’，这使你能够在样本中区分癌细胞和健康细胞。”2017 年，索恩在获得初始投资后创立了 BiVictriX，以进一步推进其药物研发管线。 3.该平台能治疗多种癌症吗？由于 BVX001 的作用机制可用于治疗其他类型的癌症，该公司的 Bi-Cygni ADC 平台在开发另外两种候选药物 BVX002 和 BVX003 时也发挥了关键作用，这两种药物用于治疗卵巢癌、膀胱癌和实体瘤。目前，这两种候选药物都处于研发阶段，很快将进入临床前试验。 为了展示 BVX001 对急性髓系白血病的临床疗效，BiVictriX 希望最终能通过合作推进抗体偶联药物的开发。本月，该公司通过有条件募资筹集了 200 万英镑（约 258 万美元），距离将其抗体偶联药物技术推向市场又近了一步。 “我真的非常相信这项技术，主要是因为它长期以来一直用于诊断目的。在英国、欧洲和美国，这项技术已经用于诊断某些类型的癌症长达 20 多年。我只是很惊讶，居然没有人从治疗角度尝试利用它来减少临床副作用。希望我们的临床前数据能在临床中得到良好验证，我们能够生产出没有目前常见严重副作用的药物。” 参考来源：This biotech is defying leukemia with promising targeted therapies 内容来源于网络，如有侵权，请联系删除。