Patients with relapsed/refractory B-cell malignancies such as non-Hodgkin lymphoma (B-NHL) or acute lymphoblastic leukemia have a poor prognosis. Despite measurable clinical activity with new targeted therapies, many patients do not achieve a complete or durable response suggesting an opportunity to improve upon existing therapies. Here we describe SGN-CD19B, a pyrrolobenzodiazepine (PBD)-based anti-CD19 antibody drug conjugate (ADC) being investigated for treatment of B-cell malignancies, which has improved potency compared with other ADCs. CD19-expressing tumor cells rapidly internalize SGN-CD19B, and the released PBD drug induces DNA damage, resulting in G2/M cell cycle arrest and cell death. SGN-CD19B demonstrated activity against a broad panel of malignant B-cell lines and induced durable regressions in mice bearing xenografts derived from these B-cell malignancies. A single dose of SGN-CD19B induced durable regressions at 300 μg/kg (3 μg/kg drug equivalents); combination with rituximab decreased the curative dose to 100 μg/kg (1 μg/kg drug equivalents). These doses are significantly lower than the level of drug required with other ADC payloads. In cynomolgus monkeys, SGN-CD19B effectively depleted CD20+ B lymphocytes in peripheral blood and lymphoid tissues confirming that SGN-CD19B is pharmacodynamically active at well-tolerated doses. In summary, preclinical studies show SGN-CD19B is a highly active ADC, which releases a DNA cross-linking agent rather than a microtubule inhibitor. The distinct mechanism of action, broad potency, and potential to combine with rituximab suggest that SGN-CD19B may offer unique clinical opportunities in B-cell malignancies. A phase 1 clinical trial is in progress to investigate the therapeutic potential of SGN-CD19B in relapsed/refractory B-NHL. This trial was registered at www.clinicaltrials.gov as #NCT02702141.

中文翻译：

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SGN-CD19B（一种基于 PBD 的抗 CD19 药物缀合物）治疗 B 细胞恶性肿瘤的治疗潜力


患有复发/难治性 B 细胞恶性肿瘤（例如非霍奇金淋巴瘤 (B-NHL) 或急性淋巴细胞白血病）的患者预后较差。尽管新的靶向疗法具有可测量的临床活性，但许多患者并未达到完全或持久的反应，这表明有机会改进现有疗法。在这里，我们描述了 SGN-CD19B，这是一种基于吡咯并苯二氮卓 (PBD) 的抗 CD19 抗体药物偶联物 (ADC)，正在研究用于治疗 B 细胞恶性肿瘤，与其他 ADC 相比，其效力有所提高。表达CD19的肿瘤细胞迅速内化SGN-CD19B，释放的PBD药物诱导DNA损伤，导致G2/M细胞周期停滞和细胞死亡。 SGN-CD19B 表现出针对多种恶性 B 细胞系的活性，并在携带源自这些 B 细胞恶性肿瘤的异种移植物的小鼠中诱导持久消退。单剂量的 SGN-CD19B 在 300 μg/kg（3 μg/kg 药物当量）下诱导持久消退；与利妥昔单抗联合用药将治疗剂量降低至 100 μg/kg（1 μg/kg 药物当量）。这些剂量明显低于其他 ADC 有效负载所需的药物水平。在食蟹猴中，SGN-CD19B 有效耗尽外周血和淋巴组织中的 CD20+ B 淋巴细胞，证实 SGN-CD19B 在耐受良好的剂量下具有药效活性。总之，临床前研究表明SGN-CD19B是一种高活性ADC，它释放DNA交联剂而不是微管抑制剂。独特的作用机制、广泛的效力以及与利妥昔单抗联合的潜力表明，SGN-CD19B 可能为 B 细胞恶性肿瘤提供独特的临床机会。 一项 1 期临床试验正在进行中，以研究 SGN-CD19B 在复发/难治性 B-NHL 中的治疗潜力。该试验在 www.clinicaltrials.gov 上注册为#NCT02702141。