Hematologically derived tumors make up ∼10% of all newly diagnosed cancer cases in the United States. Of these, the non-Hodgkin lymphoma (NHL) designation describes a diverse group of cancers that collectively rank among the top 10 most commonly diagnosed cancers worldwide. Although long-term survival trends are improving, there remains a significant unmet clinical need for treatments to help patients with relapsed or refractory disease, one cause of which is drug efflux through upregulation of xenobiotic pumps, such as MDR1. CD22 is a clinically validated target for the treatment of NHL, but no anti-CD22 agents have yet been approved for this indication. Recent approval of an anti-CD22 antibody–drug conjugate (ADC) for the treatment of relapsed/refractory ALL supports the rationale for targeting this protein. An opportunity exists for a next-generation anti-CD22 antibody–drug conjugate (ADC) to address unmet medical needs in the relapsed/refractory NHL population. We describe a site-specifically conjugated antibody–drug conjugate, made using aldehyde tag technology, targeted against CD22 and bearing a noncleavable maytansine payload that is resistant to MDR1-mediated efflux. The construct was efficacious against CD22+ NHL xenografts and could be repeatedly dosed in cynomolgus monkeys at 60 mg/kg with no observed significantly adverse effects. Exposure to total ADC at these doses (as assessed by AUC0-inf) indicated that the exposure needed to achieve efficacy was below tolerable limits. Together, the data suggest that this drug has the potential to be used effectively in patients with CD22+ tumors that have developed MDR1-related resistance to prior therapies. Mol Cancer Ther; 17(1); 161–8. ©2017 AACR.

中文翻译：

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CAT-02-106 是一种位点特异性偶联的抗 CD22抗体，带有抗 MDR1 的美登素有效载荷，在临床前模型中具有出色的功效和安全性

血液学来源的肿瘤约占美国所有新诊断癌症病例的 10%。其中，非霍奇金淋巴瘤 (NHL) 名称描述了多种癌症，这些癌症共同跻身全球前 10 名最常诊断的癌症之列。尽管长期生存趋势正在改善，但仍存在显着未满足的临床需求，即治疗复发或难治性疾病的患者，其原因之一是通过外源泵（如 MDR1）的上调导致药物流出。CD22 是经过临床验证的治疗 NHL 的靶点，但尚未批准任何抗 CD22 药物用于该适应症。最近批准用于治疗复发/难治性 ALL 的抗 CD22 抗体-药物偶联物 (ADC) 支持靶向该蛋白质的基本原理。下一代抗 CD22 抗体-药物偶联物 (ADC) 有机会解决复发/难治性 NHL 人群未满足的医疗需求。我们描述了一种位点特异性偶联的抗体-药物偶联物，该偶联物使用醛标签技术制成，靶向 CD22 并带有对 MDR1 介导的外排具有抗性的不可切割的美登素有效载荷。该构建体对 CD22+ NHL 异种移植物有效，并且可以在食蟹猴中以 60 mg/kg 的剂量重复给药，没有观察到显着的副作用。暴露于这些剂量的总 ADC（通过 AUC0-inf 评估）表明达到疗效所需的暴露低于耐受限度。一起，数据表明，该药物有可能有效用于已对先前疗法产生 MDR1 相关耐药性的 CD22+ 肿瘤患者。摩尔癌症治疗; 17(1); 161-8。©2017 AACR。