Probody Therapeutics: An Emerging Class of Therapies Designed to Enhance On-Target Effects with Reduced Off-Tumor Toxicity for Use in Immuno-Oncology.
Probody Therapeutics: An Emerging Class of Therapies Designed to Enhance On-Target Effects with Reduced Off-Tumor Toxicity for Use in Immuno-Oncology.
复制标题
概率疗法：一种新兴类型的疗法，旨在增强靶向效应，并降低肿瘤毒性，用于免疫肿瘤学。
DOI：
10.1158/1078-0432.ccr-19-1457
复制
发表时间：
2020-03-01
期刊：
影响因子：
--
通讯作者：
Naing A
中科院分区：
文献类型：
--
作者：
Autio KA;Boni V;Humphrey RW;Naing A
基于抗体的免疫疗法（如免疫检查点抑制剂（ICI））的深度和持久的抗肿瘤作用已经彻底改变了肿瘤学，并改变了许多癌症的治疗前景。几种抗程序性死亡受体1和抗程序性死亡受体配体1抗体已被批准用于晚期实体瘤，包括黑素瘤、非小细胞肺癌（NSCLC）、膀胱癌和其他癌症。ICI在许多肿瘤类型中正在开发中，初步结果令人信服。然而，ICI与重度免疫相关不良事件（irAE）相关，包括皮疹、腹泻、结肠炎、垂体炎、肝毒性和甲状腺功能减退症，在某些情况下导致高发病率，可能危及生命，并限制治疗持续时间。当程序性细胞死亡-1和程序性细胞死亡配体-1抑制剂与抗CTLA-4和/或其他多种药物方案联合使用时，重度irAE的发生率进一步增加。Probody™治疗剂是一类新的重组、蛋白水解活化的抗体前药，处于早期开发阶段，旨在利用肿瘤蛋白酶活性失调的标志，在肿瘤微环境（TME）而不是外周组织中递送其治疗效果。TME靶向，而不是全身靶向，可能会减少远离肿瘤的组织中的irAE。Probody治疗技术已应用于多种抗体形式，包括免疫疗法、Probody药物缀合物和T细胞重定向双特异性Probody治疗剂。在临床前模型中，与非Probody亲本抗体相比，Probody治疗剂在动物中始终保持抗癌活性并具有改善的安全性。在临床环境中，Probody疗法可以扩大或创造抗癌疗法的治疗窗口。
The deep and durable antitumor effects of antibody-based immunotherapies such as immune checkpoint inhibitors (ICIs) have revolutionized oncology and transformed the therapeutic landscape for many cancers. Several anti–programmed death receptor 1 and anti–programmed death receptor ligand 1 antibodies have been approved for use in advanced solid tumors, including melanoma, non–small cell lung cancer (NSCLC), bladder cancer, and other cancers. ICIs are under development across many tumor types and preliminary results are compelling. However, ICIs have been associated with severe immune-related adverse events (irAEs), including rash, diarrhea, colitis, hypophysitis, hepatotoxicity, and hypothyroidism, which in some cases lead to high morbidity, are potentially life-threatening, and limit the duration of treatment. The incidence of severe irAEs increases further when programmed cell death-1 and programmed cell death ligand-1 inhibitors are combined with anti-CTLA-4 and/or other multi-drug regimens. Probody™ therapeutics, a new class of recombinant, proteolytically activated antibody prodrugs are in early development and are designed to exploit the hallmark of dysregulation of tumor protease activity to deliver their therapeutic effects within the tumor microenvironment (TME) rather than peripheral tissue. TME targeting, rather than systemic targeting, may reduce irAEs in tissues distant from the tumor. Probody therapeutic technology has been applied to multiple antibody formats, including immunotherapies, Probody drug conjugates, and T-cell–redirecting bispecific Probody therapeutics. In preclinical models, Probody therapeutics have consistently maintained anti-cancer activity with improved safety in animals compared with the non-Probody parent antibody. In the clinical setting, Probody therapeutics may expand or create therapeutic windows for anti-cancer therapies.