Clinical experience with CD64-directed immunotherapy. An overview
Clinical experience with CD64-directed immunotherapy. An overview
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DOI：
10.1007/s002620050435
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发表时间：
1997-11-01
影响因子：
5.8
通讯作者：
Curnow, RT
中科院分区：
文献类型：
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作者：
Curnow, RT
I型Ig G受体(FcγRI或CD64受体)存在于关键的细胞毒效应细胞上，在体外可启动对肿瘤细胞的破坏，并被认为在特发性血小板减少性紫癜(ITP)中对抗体包被的细胞(如血小板)的破坏起作用。本文总结了CD64双特异性抗体MDX-447[人源化Fab抗CD64 x人源化Fab抗(表皮生长因子受体，EGFR)]和MDX-H210(人源化Fab抗DC64 x Fab抗HER2/neu)，以及抗CD64单抗MDX-33(H22)体内调节单核细胞CD64的临床经验。在一项正在进行的逐步剂量递增的I/II期开放试验中(1-15 mg/m(2))，治疗难治性EGFR阳性癌症(肾细胞癌、头颈部、膀胱癌、卵巢癌、前列腺癌和皮肤癌)的患者每周接受静脉注射MDX-447，并加或不加粒细胞集落刺激因子(G-CSF)。MDX-447已被发现在所有剂量下都具有免疫活性，与循环中的单核细胞和中性粒细胞结合(在给予G-CSF时)，导致单核细胞减少并刺激循环中血浆细胞因子的增加。MDX-447耐受性良好，主要毒性是发热、寒战、血压不稳定和疼痛/肌痛。在36例可评价疗效的患者中，9例病情稳定，病程3-6个月。最佳剂量和最大耐受剂量(MTD)尚未确定；剂量递增继续更好地定义这种双特异性抗体的剂量、毒性和潜在的治疗作用。目前正在进行三项MDX-H210第二阶段试验，均使用15 mg/m(2)的静脉剂量与粒细胞/巨噬细胞(GM-CSF)一起给予。这些试验包括对肾癌患者、前列腺癌患者和结直肠癌患者的治疗各一项试验，这些患者都未能通过标准治疗。在撰写本文时，已有11名患者在这些II期试验中接受治疗。已有4名患者表现出抗肿瘤作用。有反应的患者包括2名肾癌患者和2名前列腺癌患者。一名肾癌患者的肝转移灶大小减少了54%，另一名患者的肺转移灶大小减少了49%，同时清除了其他无法测量的肺部病变。对于两名前列腺癌患者，其中一名患者的血清前列腺特异性抗原(PSA；118-11 ng/ml)下降了90%，这种下降持续了几个月；另一名前列腺癌患者在治疗的第一个月内，血清PSA下降了70%(872 ng/ml至208 ng/ml)。两名患者的症状也都有所改善。在已完成的I期和正在进行的I/II期临床试验中，难治性HER2/neu阳性癌症(乳腺癌、卵巢癌、结直肠癌、前列腺癌)的患者接受了MDX-H210的治疗，MDX-H210已经单独以及与G-CSF、GM-CSF和干扰素伽马(干扰素伽马)一起服用。这些试验是开放的、渐进的剂量递增(0.35-135 mg/m(2))研究，在这些研究中，单次，更经常地，每周多次给药。MDX-H210耐受性良好，不良反应主要是轻到中度的流感样症状。MTD尚未定义。MDX-H210具有免疫活性，与循环单核细胞结合，导致单核细胞减少，并刺激血浆细胞因子水平上升。此外，一些患者在接受MDX-210治疗后有积极的抗肿瘤免疫的证据。MDX-H210给药的抗肿瘤效应已经显现；其中包括1个部分、2个轻微和1个混合肿瘤反应；发生了15个方案定义的稳定疾病反应。在完成的第一阶段试验中，MDX-33作为单次静脉给药给17名正常受试者，以评估其作为免疫调节剂治疗特发性血小板减少性紫癜和其他免疫疾病的潜力。剂量分别为1.5、3.0、5.0和7.5 mg/m(2)。对MDX-33的反应进行评估的变量包括循环单核细胞和中性粒细胞计数、单核细胞CD64介导的吞噬功能、单核细胞CD64调节、MDX-33药代动力学和各种安全参数。MDX-33在5.0 mg/m(2)或更低的剂量下耐受性良好，主要毒性反应为寒战、低热、头痛和肌肉疼痛。MDX-33与80-99%的循环单核细胞持续结合至少6天；单核细胞CD64表达下调，也持续6天以上。所有剂量的MDX-33均显著抑制单核细胞CD64介导的吞噬功能。在3.0 mg/m(2)和5.0 mg/m(2)剂量下，吞噬作用至少在6天内被完全抑制，在给药后20天恢复到基线水平。这些结果清楚地表明，单抗MDX-33可以在最小的临床毒性下完成对单核细胞CD64的免疫调节，并进一步表明MDX-33在治疗ITP和其他自身免疫性疾病方面的潜力。总之，CD64指导的bsAB MDX-447和MDX-H210的已完成和正在进行的临床试验的结果显示，在对所有可用的治疗方法都无效的肿瘤中，具有良好的耐受性，并具有良好的抗肿瘤效果。CD64导向的单抗MDX-33的试验结果也很有希望，它显示了在临床环境中调节单核细胞CD64的能力。目前正在进行研究，以阐明这些方法和使用CD64指导的免疫疗法的其他方法的全部潜力。
The class I IgG receptor (Fc gamma RI or CD64 receptor), which is present on key cytotoxic effector cells, has been shown to initiate the destruction of tumor cells in vitro and has been hypothesized to play a role in the destruction of antibody-coated cells such as platelets in idiopathic thrombocytopenia purpura (ITP). This overview summarizes the clinical experience with CD64-directed immunotherapy in cancer patients with the bispecific antibodies MDX-447 [humanized Fab anti-CD64 x humanized Fab anti-(epidermal growth factor receptor, EGFR)] and MDX-H210 (humanized Fab anti-DC64 x Fab anti-HER2/neu), and with the anti-CD64 monoclonal antibody (mAB) MDX-33 (H22) in the modulation of monocyte CD64 in vivo. In an ongoing phase I/II open-label trial with progressive dose escalation (1-15 mg/m(2)), patients with treatment refractory EGFR-positive cancers (renal cell carcinoma (RCC), head and neck, bladder, ovarian, prostate cancer and skin cancer) are treated weekly with intravenous MDX-447, with and without granulocyte-colony-stimulating factor (G-CSF). MDX-447 has been found to be immunologically active at all doses, binding to circulating monocytes and neutrophils (when given with G-CSF), causing monocytopenia and stimulating increases in circulating plasma cytokines. MDX-447 is well tolerated, the primary toxicities being fever, chills, blood pressure lability, and pain/myalgias. Of 36 patients evaluable for response, 9 have experienced stable disease of 3-6 month's duration. The optimal dose and the maximal tolerated dose (MTD) have yet to be defined; dose escalation continues to define better the dose, toxicity, and the potential therapeutic role of this bispecific antibody. Three MDX-H210 phase II trials are currently in progress, all using the intravenous dose of 15 mg/m(2) given with granulocyte/macrophage (GM-CSF). These consist of one trial each in the treatment of RCC patients, patients with prostrate cancer, and colorectal cancer patients, all of whom have failed standard therapy.At the time of writing, 11 patients have been treated in these phase II trials. Four patients have demonstrated antitumor effects. Patients demonstrating responses include 2 with RCC and 2 with prostate cancer. One RCC patient has had a 54% reduction in size of a hepatic metastatic lesion and the other has had a 49% decrease in the size of a lung metastasis with simultaneous clearing of other non-measurable lung lesions. Regarding the two patients with prostate cancer, one has had a 90% reduction in serum prostate-specific antigen (PSA; 118-11 ng/ml), which has persisted for several months; the other patient with prostate has had a 70% reduction of serum PSA (872 ng/ml to 208 ng/ml) within the first month of treatment. Both patients have also demonstrated symptomatic improvement. In a completed phase I and in ongoing phase I/II clinical trials, patients with treatment-refractory HER2/neu positive cancers (breast, ovarian, colorectal, prostate) have been treated with MDX-H210, which has been given alone and in conjunction with G-CSF, GM-CSF, and interferon gamma (IFN gamma). These trials have been open-label, progressive dose-escalation (0.35-135 mg/m(2)) studies in which single, and more often, multiple weekly doses have been administered. MDX-H210 has been well tolerated, with untoward effects being primarily mild-to-moderate flu-like symptoms. The MTD has not yet been defined. MDX-H210 is immunologically active, binding to circulating monocytes, causing monocytopenia, as well as stimulating increases in plasma cytokine levels. Furthermore, some patients have evidence of active antitumor immunity following treatment with MDX-210. Antitumor effects have been seen in response to MDX-H210 administration; these include 1 partial, 2 minor, and 1 mixed tumor response; 15 protocol-defined stable disease responses have occurred. In a completed phase I trial, MDX-33 was administered as a single intravenous dose to 17 normal subjects in order to assess its potential as an immunomodulator for the treatment of idiopathic thrombocytopenia purpura and other immune disorders. Doses of 1.5, 3.0, 5.0, and 7.5 mg/m(2) were administered. The variables evaluated in response to MDX-33 were circulating monocyte and neutrophil counts, monocyte CD64-mediated phagocytosis, monocyte CD64 modulation, MDX-33 pharmocokinetics, and various safety parameters.MDX-33 is well tolerated at doses of 5.0 mg/m(2) or less, the primary toxicities being chills, low-grade fever, headache, and muscle aches. Persistent binding of MDX-33 to 80-99% of circulating monocytes is seen for at least 6 days; down-modulation of monocyte CD64 occurs and also lasts more than 6 days. Monocyte CD64-mediated phagocytosis is significantly inhibited at all doses of MDX-33. At the 3.0 mg/m(2) and 5.0-mg/m(2) dose, phagocytosis is fully inhibited for at least 6 days, returning to baseline levels by 20 days after dosing. These results clearly demonstrate that immunomodulation of monocyte CD64 by the mAB MDX-33 can be accomplished with minimal clinical toxicity, and further indicate the potential of MDX-33 in the treatment of ITP and other auto-immune disorders. In conclusion, the results from completed and ongoing clinical trials with the CD64-directed bsAB MDX-447 and MDX-H210 demonstrate excellent tolerability in association with promising antitumor effects in tumors that have become refractory to all available therapies. Also promising are the results from the trial of the CD64-directed mAB, MDX-33, which show the ability to modulate monocyte CD64 in the clinical setting. Studies are currently being conducted to elucidate the full potential of these and other approaches using CD64-directed immunotherapy.