Valone F H, Kaufman P A, Guyre P M, Lewis L D, Memoli V, Deo Y, Graziano R, Fisher J L, Meyer L, Mrozek-Orlowski M
Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
J Clin Oncol. 1995 Sep;13(9):2281-92. doi: 10.1200/JCO.1995.13.9.2281.
MDX-210 is a bispecific antibody that binds simultaneously to type I Fc receptors for immunoglobulin G (IgG) (Fc gamma RI) and to the HER-2/neu oncogene protein product. MDX-210 effectively directs Fc gamma RI-positive effector cells such as monocytes and macrophages to phagocytose or kill tumor cells that overexpress HER-2/neu. The goals of this phase Ia/Ib trial were to determine the maximum-tolerated dose (MTD) and/or the optimal biologic dose (OBD) of MDX-210.
Patients with advanced breast or ovarian cancer that overexpressed HER-2/neu were eligible for treatment. Cohorts of three patients received a single intravenous (IV) infusion of MDX-210 at increasing dose levels from 0.35 to 10.0 mg/m2.
Treatment was well tolerated, with most patients experiencing transient grade 1 to 2 fevers, malaise, and hypotension only. Two patients experienced transient grade 3 hypotension at 10.0 mg/m2. Transient monocytopenia and lymphopenia developed at 1 to 2 hours, but no other hematologic changes were observed. Doses of MDX-210 > or = 3.5 mg/m2 saturated > or = 80% of monocyte Fc gamma RI and produced peak plasma concentrations > or = 1 microgram/mL, which is greater than the concentration for optimal monocyte/macrophage activation in vitro. Elevated plasma levels of the monocyte products tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and neopterin were observed with maximal levels at doses > or = 7.0 mg/m2. Localization of MDX-210 in tumor tissue was demonstrated in two patients. One partial and one mixed tumor response were observed among 10 assessable patients.
MDX-210 is immunologically active at well-tolerated doses. The MTD and OBD is 7 to 10 mg/m2.
MDX - 210是一种双特异性抗体，可同时结合免疫球蛋白G（IgG）的I型Fc受体（FcγRI）和HER - 2/neu癌基因蛋白产物。MDX - 210能有效地引导FcγRI阳性效应细胞（如单核细胞和巨噬细胞）吞噬或杀死过度表达HER - 2/neu的肿瘤细胞。该I期a/I期b试验的目的是确定MDX - 210的最大耐受剂量（MTD）和/或最佳生物学剂量（OBD）。
HER - 2/neu过度表达的晚期乳腺癌或卵巢癌患者符合治疗条件。每组三名患者接受单次静脉输注MDX - 210，剂量水平从0.35 mg/m²递增至10.0 mg/m²。
治疗耐受性良好，大多数患者仅出现短暂的1至2级发热、不适和低血压。两名患者在剂量为10.0 mg/m²时出现短暂的3级低血压。在1至2小时出现短暂的单核细胞减少和淋巴细胞减少，但未观察到其他血液学变化。MDX - 210剂量≥3.5 mg/m²可使≥80%的单核细胞FcγRI饱和，并产生≥1微克/毫升的血浆峰值浓度，这高于体外单核细胞/巨噬细胞最佳激活浓度。在剂量≥7.0 mg/m²时观察到血浆中单核细胞产物肿瘤坏死因子α（TNFα）、白细胞介素 - 6（IL - 6）、粒细胞集落刺激因子（G - CSF）和蝶呤水平升高，且在该剂量时达到最高水平。在两名患者中证实了MDX - 210在肿瘤组织中的定位。在10名可评估患者中观察到1例部分缓解和1例混合肿瘤反应。
MDX - 210在耐受性良好的剂量下具有免疫活性。最大耐受剂量和最佳生物学剂量为7至10 mg/m²。
