Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the proto-oncogene HER-2/neu.
Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the proto-oncogene HER-2/neu.
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DOI：
10.1200/jco.1995.13.9.2281
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发表时间：
1995-09
期刊：
影响因子：
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通讯作者：
F. Valone;P. Kaufman;P. Guyre;L. Lewis;V. Memoli;Y. Deo;R. Graziano;J. Fisher;L. Meyer;M. Mrozek-Orlowski
中科院分区：
文献类型：
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作者：
F. Valone;P. Kaufman;P. Guyre;L. Lewis;V. Memoli;Y. Deo;R. Graziano;J. Fisher;L. Meyer;M. Mrozek-Orlowski
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（Fc γ RI）和HER-2/neu癌基因蛋白产物。MDX-210有效地指导Fc γ RI阳性效应细胞如单核细胞和巨噬细胞吞噬或杀死过表达HER-2/neu的肿瘤细胞。本Ia/Ib期试验的目的是确定MDX-210的最大耐受剂量（MTD）和/或最佳生物剂量（OBD）。患者和方法HER-2/neu过表达的晚期乳腺癌或卵巢癌患者有资格接受治疗。3例患者的队列接受了剂量水平从0.35 mg/m2增加至10.0 mg/m2的MDX-210单次静脉（IV）输注。结果治疗耐受性良好，大多数患者仅出现一过性1 - 2级发热、不适和低血压。2例患者在10.0 mg/m2剂量下发生一过性3级低血压。在1 - 2小时发生一过性单核细胞减少症和淋巴细胞减少症，但未观察到其他血液学变化。>或= 3.5 mg/m2的MDX-210剂量饱和>或= 80%的单核细胞Fc γ RI，并产生>或= 1微克/mL的峰值血浆浓度，其大于体外最佳单核细胞/巨噬细胞活化的浓度。观察到单核细胞产物肿瘤坏死因子α（TNF α）、白细胞介素-6（IL-6）、粒细胞集落刺激因子（G-CSF）和新蝶呤的血浆水平升高，剂量≥ 7.0 mg/m2时达到最大水平。在两名患者中证实了MDX-210在肿瘤组织中的定位。在10例可评估患者中观察到1例部分和1例混合肿瘤缓解。结论在耐受剂量下，MDX-210具有免疫活性。MTD和OBD为7 - 10 mg/m2。
PURPOSE 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 AND METHODS 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. RESULTS 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. CONCLUSION MDX-210 is immunologically active at well-tolerated doses. The MTD and OBD is 7 to 10 mg/m2.