Division of Hematology-Oncology, Mayo Clinic, Phoenix, AZ, USA.
Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Medical Center, Duarte, CA, USA.
Blood Cancer J. 2019 Feb 4;9(2):17. doi: 10.1038/s41408-019-0178-8.
FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3-2.4 mg/kg every 3 weeks or 0.8-1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients. Exposure of total antibody and antibody-conjugate-MMAE analytes was linear across the doses tested. There were 37 (95%) adverse events (AEs), 8 (21%) serious AEs, and 15 (39%) AEs ≥ grade 3. Anemia (n = 10, 26%) was the most common AE considered related to DFRF4539A. Two cases of grade 3 acute renal failure were attributed to DFRF4539A. There were no deaths; the MTD was not reached. DFRF4539A demonstrated limited activity in patients at the doses tested with 2 (5%) partial response, 1 (3%) minimal response, 18 (46%) stable disease, and 16 (41%) progressive disease. FcRH5 was confirmed to be expressed and occupied by antibody post-treatment and thus remains a valid myeloma target. Nevertheless, this MMAE-based antibody-drug-conjugate targeting FcRH5 was unsuccessful for myeloma.
FcRH5 是一种细胞表面标志物，与其他血液系统恶性肿瘤和正常组织相比，在恶性浆细胞中更为丰富。DFRF4539A 是一种抗 FcRH5 抗体药物偶联物，与单甲基奥瑞他汀 E（MMAE）偶联，MMAE 是一种有效的抗有丝分裂剂。这项 I 期研究评估了复发/难治性多发性骨髓瘤患者中 DFRF4539A 的安全性、耐受性、最大耐受剂量（MTD）、抗肿瘤活性和药代动力学。DFRF4539A 以 0.3-2.4mg/kg 的剂量每 3 周或 0.8-1.1mg/kg 的剂量每周静脉输注一次，共给 39 例患者使用。总抗体和抗体偶联物-MMAE 分析物的暴露在测试剂量范围内呈线性。有 37 例（95%）不良事件（AE），8 例（21%）严重 AE，15 例（39%）AE≥3 级。贫血（n=10，26%）是最常见的与 DFRF4539A 相关的 AE。有 2 例 3 级急性肾衰竭归因于 DFRF4539A。无死亡病例，未达到 MTD。在测试剂量下，DFRF4539A 在患者中显示出有限的活性，有 2 例（5%）部分缓解，1 例（3%）微小缓解，18 例（46%）稳定疾病，16 例（41%）疾病进展。FcRH5 在治疗后被证实表达并被抗体占据，因此仍然是一个有效的骨髓瘤靶标。然而，这种针对 FcRH5 的基于 MMAE 的抗体药物偶联物在骨髓瘤中没有成功。
