抗体耦联药物SGN-CD19B可用于治疗B细胞肿瘤

Title：
Therapeutic potential of SGN-CD19B, a PBD-based anti-CD19 drug conjugate, for treatment of B-cell malignancies

DOI：
10.1182/blood-2017-04-779389

Abstract：
Patients with relapsed/refractory B-cell malignancies such as non-Hodgkin lymphoma (B-NHL) or acute lymphoblastic leukemia (B-ALL) 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 to 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 mcg/kg (3 mcg/kg drug equivalents); combination with rituximab decreased the curative dose to 100 mcg/kg (1 mcg/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-crosslinking 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 [NCT02702141].

All Authors：
Maureen C Ryan,Maria Corinna Palanca-Wessels,Brian Schimpf,Kristine A Gordon,Heather Kostner,Brad Meyer,Changpu Yu,Heather Van Epps,Dennis Benjamin

First Authors：
Maureen C Ryan

Correspondence：
Dennis Benjamin

摘要：

      SGN-CD19B是基于吡咯并苯并二氮杂（PBD）的CD19抗体-药物偶联物（ADC），表达CD19的肿瘤细胞能够迅速内化SGN-CD19B并释放PBD引起DNA损伤，导致G2-M细胞周期停止和细胞死亡；在B细胞恶性肿瘤的异种移植物小鼠中，单剂300mcg/kg SGN-CD19B能引起持久的肿瘤消退，剂量明显低于其他ADC药物；SGN-CD19B能有效清除食蟹猴外周血和淋巴组织中的CD20+B淋巴细胞；GN-CD19B治疗复发/难治性B-非霍奇金淋巴瘤的I期临床试验正在进行。