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. Pseudomonas 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而开发的溶细胞融合蛋白，由与癌细胞结合的抗体片段和杀死细胞的蛋白质毒素片段组成。假单胞菌属外毒素 A (PE) 是一种强效毒素，可用于许多免疫毒素中的杀伤部分。Moxetumomab Pasudotox (Lumoxiti) 含有一种抗 CD22 Fv 和一个 38 kDa 的 PE 部分。Lumoxiti 是在美国国家癌症研究所分子生物学实验室发现的，并与 Medimmune/AstraZeneca 共同开发用于治疗毛细胞白血病。2018年Lumoxiti获美国食品药品监督管理局批准用于治疗耐药毛细胞白血病。由于杀伤部分的细菌来源，含有 PE 的免疫毒素在免疫系统正常的患者中具有高免疫原性，但在免疫系统经常受损的血液系统恶性肿瘤患者中免疫原性较低。LMB-100 是该毒素的一种去免疫变体，具有一种靶向间皮素的人源化抗体和一种 PE 毒素，该毒素经过合理设计以降低与抗体和 B 细胞受体的反应性。现在正在对治疗间皮瘤和胰腺癌的临床试验进行评估，与未经修饰的亲本对应物相比，它的免疫原性有所降低。在这里，我们回顾了原始和去免疫的 PE 免疫毒素在小鼠和患者中的免疫原性、抗药物抗体 (ADA) 的发展、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，包括识别、去除或抑制 B 细胞或 T 细胞表位的合理设计，