Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and lymphomas have poor patient outcomes; novel therapies are needed. CD22 is an attractive target for antibody–drug conjugates (ADCs), being highly expressed in R/R B-ALL with rapid internalization kinetics. ADCT-602 is a novel CD22-targeting ADC, consisting of humanized monoclonal antibody hLL2-C220, site-specifically conjugated to the pyrrolobenzodiazepine dimer–based payload tesirine. In preclinical studies, ADCT-602 demonstrated potent, specific cytotoxicity in CD22-positive lymphomas and leukemias. ADCT-602 was specifically bound, internalized, and trafficked to lysosomes in CD22-positive tumor cells; after cytotoxin release, DNA interstrand crosslink formation persisted for 48 h. In the presence of CD22-positive tumor cells, ADCT-602 caused bystander killing of CD22-negative tumor cells. A single ADCT-602 dose led to potent, dose-dependent, in vivo antitumor activity in subcutaneous and disseminated human lymphoma/leukemia models. Pharmacokinetic analyses (rat and cynomolgus monkey) showed excellent stability and tolerability of ADCT-602. Cynomolgus monkey B cells were efficiently depleted from circulation after 1 dose. Gene signature association analysis revealed IRAK1 as a potential marker for ADCT-602 resistance. Combining ADCT-602 + pacritinib was beneficial in ADCT-602-resistant cells. Chidamide increased CD22 expression on B-cell tumor surfaces, increasing ADCT-602 activity. These data support clinical testing of ADCT-602 in R/R B-ALL (NCT03698552) and CD22-positive hematological cancers.

中文翻译：

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ADCT-602，一种新型包含 PBD 二聚体的抗体药物偶联物，用于治疗 CD22 阳性血液恶性肿瘤

复发性或难治性 B 细胞急性淋巴细胞白血病 (R/R B-ALL) 和淋巴瘤的患者预后较差；需要新的疗法。 CD22 是抗体药物偶联物 (ADC) 的一个有吸引力的靶点，在 R/R B-ALL 中高度表达，具有快速的内化动力学。 ADCT-602是一种新型CD22靶向ADC，由人源化单克隆抗体hLL2-C220组成，该抗体与基于吡咯并苯二氮卓二聚体的有效负载tesirine进行位点特异性缀合。在临床前研究中，ADCT-602 在 CD22 阳性淋巴瘤和白血病中表现出有效、特异性的细胞毒性。 ADCT-602 特异性结合、内化并转运至 CD22 阳性肿瘤细胞中的溶酶体；细胞毒素释放后，DNA链间交联形成持续48小时。在存在 CD22 阳性肿瘤细胞的情况下，ADCT-602 会引起旁观者杀死 CD22 阴性肿瘤细胞。单剂量 ADCT-602 在皮下和播散性人类淋巴瘤/白血病模型中产生有效的、剂量依赖性的体内抗肿瘤活性。药代动力学分析（大鼠和食蟹猴）显示 ADCT-602 具有出色的稳定性和耐受性。 1 次给药后，食蟹猴 B 细胞从循环中被有效清除。基因特征关联分析表明，IRAK1 是 ADCT-602 耐药性的潜在标记。联合使用 ADCT-602 + pacritinib 对 ADCT-602 耐药细胞有益。西达本胺增加 B 细胞肿瘤表面的 CD22 表达，从而增加 ADCT-602 活性。这些数据支持 ADCT-602 在 R/R B-ALL (NCT03698552) 和 CD22 阳性血液癌症中的临床测试。