Cheney Carolyn M, Stephens Deborah M, Mo Xiaokui, Rafiq Sarwish, Butchar Jonathan, Flynn Joseph M, Jones Jeffrey A, Maddocks Kami, O'Reilly Adrienne, Ramachandran Abhijit, Tridandapani Susheela, Muthusamy Natarajan, Byrd John C
Division of Hematology; Department of Internal Medicine; The Ohio State University; Columbus, OH USA.
Center for Biostatistics; The Ohio State University; Columbus, OH USA.
MAbs. 2014 May-Jun;6(3):749-55. doi: 10.4161/mabs.28282. Epub 2014 Mar 4.
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 µg/mL) improved ADCC by ~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 µg/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 µg/mL) demonstrated ~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.
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，在这些国家，对廉价且方便给药的治疗方法的需求很明显。奥卡拉珠单抗是一种新型的经Fc工程改造的人源化IgG1抗CD20单克隆抗体（mAb），设计用于在非常低的浓度下实现有效的抗体依赖性细胞介导的细胞毒性（ADCC），这可能有助于皮下（相对于静脉内）给药。在此，我们报告了奥卡拉珠单抗对CLL细胞的效力。对CLL细胞进行了奥卡拉珠单抗的直接细胞毒性（DC）、补体依赖性细胞毒性（CDC）、抗体依赖性细胞吞噬作用（ADCP）和ADCC的体外评估。奥卡拉珠单抗诱导DC、CDC和ADCP的效果与利妥昔单抗或奥法木单抗（抗CD20 mAb）相似。然而，奥卡拉珠单抗在NK细胞介导的ADCC方面比这些抗体具有优势。在同种异体ADCC中，[效应细胞：靶细胞（E:T）比例 = 25:1、12:1、6:1]，与利妥昔单抗或奥法木单抗相比，奥卡拉珠单抗（10 µg/mL）使ADCC提高了约3倍（所有测试的E:T比例下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）下观察到奥卡拉珠单抗诱导的ADCC具有优越性。在扩展的同种异体ADCC E:T滴定中，奥卡拉珠单抗（0.1 µg/mL）显示出比利妥昔单抗更高19.4%的细胞毒性（E:T = 0.38:1；P = 0.0066），比奥法木单抗更高21.5%的细胞毒性（E:T = 1.5:1；P = 0.0015）。在自体ADCC中，在所有测试的E:T比例（E:T = 25:1、12:1、6:1；所有P<0.001）下，与利妥昔单抗或奥法木单抗相比，奥卡拉珠单抗（10 µg/mL）显示出细胞毒性增加了约1.5倍。奥妥珠单抗，一种糖基工程改造的抗CD20 mAb，与奥卡拉珠单抗相比，在ADCC活性方面没有改善。奥卡拉珠单抗增强的ADCC表明它可能在低浓度下有效。如果得到临床研究的支持，这一特性可能允许低剂量皮下给药，这可能会扩大在发展中国家进行化学免疫治疗的潜力。
