Obinutuzumab (GA101) compared to rituximab significantly enhances cell death and antibody-dependent cytotoxicity and improves overall survival against CD20+ rituximab-sensitive/-resistant Burkitt lymphoma (BL) and precursor B-acute lymphoblastic leukaemia (pre-B-ALL): potential targeted therapy in patients with poor risk CD20+ BL and pre-B-ALL
Obinutuzumab (GA101) compared to rituximab significantly enhances cell death and antibody-dependent cytotoxicity and improves overall survival against CD20+ rituximab-sensitive/-resistant Burkitt lymphoma (BL) and precursor B-acute lymphoblastic leukaemia (pre-B-ALL): potential targeted therapy in patients with poor risk CD20+ BL and pre-B-ALL
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DOI：
10.1111/bjh.13764
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发表时间：
2015-12-01
影响因子：
6.5
通讯作者：
Cairo, Mitchell S.
中科院分区：
文献类型：
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作者：
Awasthi, Aradhana;Ayello, Janet;Cairo, Mitchell S.
Obinutuzumab是一种新型糖工程化的II型CD 20单克隆抗体。大约100%的伯基特淋巴瘤（BL）儿童和青少年和40%的前体B细胞急性淋巴细胞白血病（pre-B-ALL）儿童和青少年表达CD 20。我们在体外和人BL或Pre-B-ALL异种移植小鼠中评估了obinutuzumab与利妥昔单抗对利妥昔单抗耐药（Raji 4 RH）和敏感（Raji）BL和pre-B-ALL（U698-M）细胞的抗肿瘤活性。我们证明，与利妥昔单抗相比，obinutuzumab显著增强了针对Raji的细胞死亡35.6 +/- 3.1%对25.1 +/-2.0%，（P = 0.001）、Raji4RH 19.7 +/- 2.2% vs. 7.9 +/- 1.5%（P = 0-001）和U-698-M 47.3 +/- 4.9% vs. 23.2 +/- 0.5%（P = 0.001）。Obinutuzumab与利妥昔单抗相比，还诱导了K562-IL 15 -41 BBL扩增的NK细胞针对Raji的抗体依赖性细胞毒性（ADCC）的显著增加，73.8 +/- 8.1%对56.81 +/- 4.6%。（P = 0-001）、Raji-4RH 40.0 +/- 1.6% vs. 0-5 +/- 1.1%（P = 0.001）和U-698-M 70.0 +/- 1.6% vs. 45.5 +/- 0.1%（P = 0.001）。与接受30 mg/kg利妥昔单抗的那些相比，接受30 mg/kg奥努珠单抗的肿瘤异种移植小鼠的总体存活率分别在131; Ran（P = 0.05）、Raji 4 RH（P = 0.02）和U698-M（P = 0.03）中显著增加。这些临床前数据表明obinutuzumab在诱导细胞死亡、ADCC和针对利妥昔单抗敏感/耐药BL和pre-B-ALL异种移植小鼠方面显著上级利妥昔单抗。总而言之，这些临床前结果提供了证据，表明有必要在复发性/难治性CD 20（+）BL和/或前B-ALL患者中进一步研究obinutumab。
Obinutuzumab is a novel glycoengineered Type-II CD20 monoclonal antibody. CD20 is expressed in approximately 100% of children and adolescents with Burkitt lymphoma (BL) and 40% with precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL). We evaluated the anti-tumour activity of obinutuzumab versus rituximab against rituximab-resistant (Raji 4RH) and -sensitive (Raji) BL and pre-B-ALL (U698-M) cells in vitro and in human BL or Pre-B-ALL xenografted mice. We demonstrated that obinutuzumab compared to rituximab significantly enhanced cell death against Raji 35.6 +/- 3.1% vs. 25.1 +/- 2.0%, (P = 0.001), Raji4RH 19.7 +/- 2.2% vs. 7.9 +/- 1.5% (P = 0-001) and U-698-M 47.3 +/- 4.9% vs. 23.2 +/- 0.5% (P = 0.001), respectively. Obinutuzumab versus rituximab also induced a significant increase in antibody-dependent cellular cytotoxicity (ADCC) with K562-IL15-41 BBL expanded NK cells against Raji 73.8 +/- 8.1% vs. 56.81 +/- 4.6% (P = 0-001), Raji-4RH 40.0 +/- 1.6% vs. 0-5 +/- 1.1% (P = 0.001) and U-698-M 70.0 +/- 1.6% vs. 45.5 +/- 0.1% (P = 0.001), respectively. Overall survival in tumour xenografted mice receiving 30 mg/kg of obinutuzumab was significantly increased when compared to those receiving 30 mg/kg of rituximab in 13I,; Ran (P = 0.05), Raji4RH (P = 0.02) and U698-M (P = 0.03), respectively. These preclinical data suggest obinutuzumab is significantly superior to rituximab in inducing cell death, ADCC and against rituximab-sensitive/-resistant BL and pre-B-ALL xenografted mice. Taken together, these preclinical results provide evidence to suggest that future investigation of obinutuzumab is warranted in patients with relapsed/refractory CD20(+) BL and/or pre-B-ALL.