Ocaratuzumab, an Fc- engineered antibody demonstrates enhanced antibody- dependent cell- mediated cytotoxicity in chronic lymphocytic leukemia
Ocaratuzumab, an Fc- engineered antibody demonstrates enhanced antibody- dependent cell- mediated cytotoxicity in chronic lymphocytic leukemia
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Fc 工程抗体 Ocaratuzumab 在慢性淋巴细胞白血病中显示出更强的抗体依赖性细胞介导的细胞毒性
DOI：
10.4161/mabs.28282
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发表时间：
2014-05-01
期刊：
影响因子：
5.3
通讯作者：
Byrd, John C.
中科院分区：
文献类型：
--
作者：
Cheney, Carolyn M.;Stephens, Deborah M.;Byrd, John C.
慢性淋巴细胞白血病（CLL）在发达国家和发展中国家都很常见，这些国家显然需要廉价和方便的治疗。Ocaratuzumab是一种新型Fc工程化人源化IgG 1抗CD 20单克隆抗体（mAb），设计用于在极低浓度下有效的抗体依赖性细胞介导的细胞毒性（ADCC），可促进皮下（与静脉内）给药。在此，我们报告了ocaratuzumab对CLL细胞的效力。在CLL细胞上进行了ocaratuzumab的直接细胞毒性（DC）、补体依赖性细胞毒性（CDC）、抗体依赖性细胞吞噬（ADCP）和ADCC的体外评估。Ocaratuzumab诱导DC、CDC和ADCP与利妥昔单抗或奥法木单抗（抗CD 20 mAb）相似。然而，ocaratuzumab在NK细胞介导的ADCC中显示出优于这些抗体的优势。在同种异体ADCC中，[E：T（效应子：靶）比= 25：1，12：1，6：1]，与利妥昔单抗或奥法木单抗相比，ocaratuzumab（10 μ g/mL）可使ADCC改善3倍（所有测试的E：T比均为P < 0.001）。值得注意的是，在低浓度（0.1-10 ug/ml; P < 0.03;同种异体试验）下观察到ocaratuzumab诱导的ADCC的优越性。在扩展的同种异体ADCC E：T滴定中，ocaratuzumab（0.1 μ g/mL）的细胞毒性比利妥昔单抗高19.4%（E：T = 0.38：1; P = 0.0066），比奥法木单抗高21.5%（E：T = 1.5：1; P = 0.0015）。在自体ADCC中，ocaratuzumab（10 μ g/mL）在所有E：T比下（E：Ts = 25：1、12：1、6：1;所有P < 0.001）的细胞毒性均比利妥昔单抗或奥法木单抗增加1.5倍。Obinutuzumab是一种糖基化的抗CD 20 mAb，与ocaratuzumab相比，其ADCC活性没有改善。ocaratuzumab的ADCC增强表明它可能在低浓度下有效。如果得到临床研究的支持，这一特征可能允许低剂量皮下给药，从而扩大发展中国家化学免疫治疗的潜力。
Chronic lymphocytic leukemia (CLL) is common in both developed and developing nations where the need for inexpensive and convenient administration of therapy is apparent. Ocaratuzumab is a novel Fc-engineered humanized IgG1 anti-CD20 monoclonal antibody (mAb) designed for effective antibody-dependent cell-mediated cytotoxicity (ADCC) at very low concentrations that may facilitate sub-cutaneous (vs. intravenous) dosing. Here, we report ocaratuzumab's potency against CLL cells.In vitro assessment of ocaratuzumab's direct cytotoxicity (DC), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and ADCC was performed on CLL cells.Ocaratuzumab induced DC, CDC, and ADCP similarly to rituximab or ofatumumab (anti-CD20 mAbs). However, ocaratuzumab showed an advantage in NK cell-mediated ADCC over these antibodies. In allogeneic ADCC, [E:T (effector:target) ratios = 25:1, 12:1, 6:1], ocaratuzumab (10 mu g/mL) improved ADCC by similar to 3-fold compared with rituximab or ofatumumab (P < 0.001 all tested E:T ratios). Notably, the superiority of ocaratuzumab-induced ADCC was observed at low concentrations (0.1-10 ug/ml; P < 0.03; allogeneic assays). In extended allogeneic ADCC E:T titration, ocaratuzumab (0.1 mu g/mL) demonstrated 19.4% more cytotoxicity than rituximab (E:T = 0.38:1; P = 0.0066) and 21.5% more cytotoxicity than ofatumumab (E:T = 1.5:1; P = 0.0015). In autologous ADCC, ocaratuzumab (10 mu g/mL) demonstrated similar to 1.5-fold increase in cytotoxicity compared with rituximab or ofatumumab at all E:T ratios tested (E:Ts = 25:1,12:1,6:1; all P < 0.001). Obinutuzumab, a glyco-engineered anti-CD20 mAb, showed no improvement in ADCC activity compared with ocaratuzumab.The enhanced ADCC of ocaratuzumab suggests that it may be effective at low concentrations. If supported by clinical investigation, this feature could potentially allow for subcutaneous dosing at low doses that could expand the potential of administering chemoimmunotherapy in developing countries.