Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
Front Immunol. 2020 Jun 26;11:1261. doi: 10.3389/fimmu.2020.01261. eCollection 2020.
Immunotoxins are cytolytic fusion proteins developed for cancer therapy, composed of an antibody fragment that binds to a cancer cell and a protein toxin fragment that kills the cell. exotoxin A (PE) is a potent toxin that is used for the killing moiety in many immunotoxins. Moxetumomab Pasudotox (Lumoxiti) contains an anti-CD22 Fv and a 38 kDa portion of PE. Lumoxiti was discovered in the Laboratory of Molecular Biology at the U.S. National Cancer Institute and co-developed with Medimmune/AstraZeneca to treat hairy cell leukemia. In 2018 Lumoxiti was approved by the US Food and Drug Administration for the treatment of drug-resistant Hairy Cell Leukemia. Due to the bacterial origin of the killing moiety, immunotoxins containing PE are highly immunogenic in patients with normal immune systems, but less immunogenic in patients with hematologic malignancies, whose immune systems are often compromised. LMB-100 is a de-immunized variant of the toxin with a humanized antibody that targets mesothelin and a PE toxin that was rationally designed for diminished reactivity with antibodies and B cell receptors. It is now being evaluated in clinical trials for the treatment of mesothelioma and pancreatic cancer and is showing somewhat diminished immunogenicity compared to its un modified parental counterpart. Here we review the immunogenicity of the original and de-immunized PE immunotoxins in mice and patients, the development of anti-drug antibodies (ADAs), their impact on drug availability and their effect on clinical efficacy. Efforts to mitigate the immunogenicity of immunotoxins and its impact on immunogenicity will be described including rational design to identify, remove, or suppress B cell or T cell epitopes, and combination of immunotoxins with immune modulating drugs.
免疫毒素是为癌症治疗开发的细胞毒性融合蛋白，由与癌细胞结合的抗体片段和杀死细胞的蛋白毒素片段组成。外毒素 A (PE) 是一种有效的毒素，在许多免疫毒素中用作杀伤部分。Moxetumomab Pasudotox (Lumoxiti) 包含抗 CD22 Fv 和 38 kDa 部分的 PE。Lumoxiti 是在美国国立癌症研究所的分子生物学实验室发现的，与 Medimmune/AstraZeneca 合作开发用于治疗毛细胞白血病。2018 年，Lumoxiti 获得美国食品和药物管理局批准用于治疗耐药性毛细胞白血病。由于杀伤部分的细菌起源，在免疫系统正常的患者中，含有 PE 的免疫毒素具有高度免疫原性，但在免疫功能常常受损的血液系统恶性肿瘤患者中免疫原性较低。LMB-100 是一种去免疫化的毒素变体，具有针对间皮素的人源化抗体和经过合理设计以降低与抗体和 B 细胞受体反应性的 PE 毒素。目前正在临床试验中评估其用于治疗间皮瘤和胰腺癌的效果，并显示出与未修饰亲本相比，其免疫原性略有降低。在这里，我们回顾了原始和去免疫化的 PE 免疫毒素在小鼠和患者中的免疫原性、抗药物抗体 (ADA) 的产生、它们对药物可用性的影响及其对临床疗效的影响。将描述减轻免疫毒素的免疫原性及其对免疫原性的影响的努力，包括通过识别、去除或抑制 B 细胞或 T 细胞表位进行合理设计，以及将免疫毒素与免疫调节药物联合使用。
