一种非岩藻糖基化的人源抗 CD19 抗体，具有强大的 B 细胞耗竭活性，可用于治疗 B 细胞恶性肿瘤。
A nonfucosylated human antibody to CD19 with potent B-cell depletive activity for therapy of B-cell malignancies.
机构信息
Department of Cell Biology and Pharmacology, Medarex, 1324 Chesapeake Terrace, Sunnyvale, CA 94089, USA.
出版信息
Cancer Immunol Immunother. 2010 Feb;59(2):257-65. doi: 10.1007/s00262-009-0746-z.
Abstract
A human anti-CD19 antibody was expressed in fucosyltransferase-deficient CHO cells to generate nonfucosylated MDX-1342. Binding of MDX-1342 to human CD19-expressing cells was similar to its fucosylated parental antibody. However, MDX-1342 exhibited increased affinity for FcγRIIIa-Phe158 and FcγRIIIa-Val158 receptors as well as enhanced effector cell function, as demonstrated by increased potency and efficacy in antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis assays. MDX-1342 showed dose-dependent improvement in survival using a murine B-cell lymphoma model in which Ramos cells were administered systemically. In addition, low nanomolar binding to cynomolgus monkey CD19 and increased affinity for cynomolgus monkey FcγRIIIa was observed. In vivo administration of MDX-1342 in cynomolgus monkeys revealed potent B-cell depletion, suggesting its potential utility as a B-lymphocyte depletive therapy for malignancies and autoimmune indications.
摘要
一种人源抗 CD19 抗体在岩藻糖基转移酶缺陷型 CHO 细胞中表达，生成非岩藻糖基化的 MDX-1342。MDX-1342 与人 CD19 表达细胞的结合与其糖基化亲本抗体相似。然而，MDX-1342 对 FcγRIIIa-Phe158 和 FcγRIIIa-Val158 受体的亲和力增加，同时增强了效应细胞功能，这在抗体依赖性细胞毒性（ADCC）和吞噬作用测定中表现为效力和功效增加。在使用全身性给予 Ramos 细胞的小鼠 B 细胞淋巴瘤模型中，MDX-1342 显示出剂量依赖性的生存改善。此外，观察到对食蟹猴 CD19 的低纳摩尔结合和对食蟹猴 FcγRIIIa 的亲和力增加。在食蟹猴体内给予 MDX-1342 可导致强烈的 B 细胞耗竭，这表明其可能作为用于恶性肿瘤和自身免疫性疾病的 B 淋巴细胞耗竭疗法具有潜在的应用价值。
相似文献
1
A nonfucosylated human antibody to CD19 with potent B-cell depletive activity for therapy of B-cell malignancies.一种非岩藻糖基化的人源抗 CD19 抗体，具有强大的 B 细胞耗竭活性，可用于治疗 B 细胞恶性肿瘤。
Cancer Immunol Immunother. 2010 Feb;59(2):257-65. doi: 10.1007/s00262-009-0746-z.
2
In vitro and in vivo characterization of MDX-1401 for therapy of malignant lymphoma.用于恶性淋巴瘤治疗的MDX - 1401的体外和体内特性研究
Clin Cancer Res. 2009 May 15;15(10):3376-83. doi: 10.1158/1078-0432.CCR-08-3222. Epub 2009 Apr 28.
3
Nonfucosylated therapeutic IgG1 antibody can evade the inhibitory effect of serum immunoglobulin G on antibody-dependent cellular cytotoxicity through its high binding to FcgammaRIIIa.非岩藻糖基化治疗性IgG1抗体可通过与FcγRIIIa的高亲和力结合，规避血清免疫球蛋白G对抗体依赖性细胞毒性的抑制作用。
Clin Cancer Res. 2006 May 1;12(9):2879-87. doi: 10.1158/1078-0432.CCR-05-2619.
4
The impact of Fc engineering on an anti-CD19 antibody: increased Fcgamma receptor affinity enhances B-cell clearing in nonhuman primates.Fc工程对一种抗CD19抗体的影响：增强的Fcγ受体亲和力提高了非人灵长类动物中B细胞的清除率。
Blood. 2009 Apr 16;113(16):3735-43. doi: 10.1182/blood-2008-10-182048. Epub 2008 Dec 24.
5
A glycoengineered anti-CD19 antibody with potent antibody-dependent cellular cytotoxicity activity in vitro and lymphoma growth inhibition in vivo.一种糖基化工程化的抗 CD19 抗体，具有体外强大的抗体依赖性细胞细胞毒性活性和体内淋巴瘤生长抑制活性。
Br J Haematol. 2011 Nov;155(4):426-37. doi: 10.1111/j.1365-2141.2011.08857.x. Epub 2011 Sep 9.
6
A novel Fc-engineered monoclonal antibody to CD37 with enhanced ADCC and high proapoptotic activity for treatment of B-cell malignancies.一种新型 Fc 工程化的抗 CD37 单克隆抗体，具有增强的 ADCC 和高促凋亡活性，用于治疗 B 细胞恶性肿瘤。
Blood. 2011 Oct 13;118(15):4159-68. doi: 10.1182/blood-2011-04-351932. Epub 2011 Jul 27.
7
Chimeric, divalent and tetravalent anti-CD19 monoclonal antibodies with potent in vitro and in vivo antitumor activity against human B-cell lymphoma and pre-B acute lymphoblastic leukemia cell lines.嵌合的、二价和四价抗 CD19 单克隆抗体对人 B 细胞淋巴瘤和前 B 急性淋巴细胞白血病细胞系具有强大的体外和体内抗肿瘤活性。
Int J Cancer. 2011 Jul 15;129(2):497-506. doi: 10.1002/ijc.25695. Epub 2010 Nov 16.
8
A tetravalent bispecific TandAb (CD19/CD3), AFM11, efficiently recruits T cells for the potent lysis of CD19(+) tumor cells.一种四价双特异性串联抗体（CD19/CD3）AFM11能够有效募集T细胞，从而有力地裂解CD19(+)肿瘤细胞。
MAbs. 2015;7(3):584-604. doi: 10.1080/19420862.2015.1029216.
9
B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody.用一种去岩藻糖基化的抗 CD19 抗体进行体外和体内的 B 细胞耗竭。
J Pharmacol Exp Ther. 2010 Oct;335(1):213-22. doi: 10.1124/jpet.110.168062. Epub 2010 Jul 6.
10
Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity.通过工程改造新型 II 型抗 CD20 抗体，增强直接和免疫效应细胞介导的 B 细胞细胞毒性，提高 CD20 抗体治疗的疗效。
Blood. 2010 Jun 3;115(22):4393-402. doi: 10.1182/blood-2009-06-225979. Epub 2010 Mar 1.
引用本文的文献
1
iPSC-derived trimodal T cells engineered with CAR, TCR, and hnCD16 modalities can overcome antigen escape in heterogeneous tumors.经嵌合抗原受体（CAR）、T细胞受体（TCR）和人源化CD16（hnCD16）模式工程改造的诱导多能干细胞（iPSC）来源的三模态T细胞可克服异质性肿瘤中的抗原逃逸。
Cell Rep Med. 2025 Jul 15;6(7):102195. doi: 10.1016/j.xcrm.2025.102195. Epub 2025 Jun 19.
2
The Evolution of Anti-CD20 Treatment for Multiple Sclerosis: Optimization of Antibody Characteristics and Function.多发性硬化症抗CD20治疗的演变：抗体特性与功能的优化
CNS Drugs. 2025 Jun;39(6):545-564. doi: 10.1007/s40263-025-01182-8. Epub 2025 Apr 3.
3
Hypoxia-activated selectivity-improved anti-PKM2 antibody combined with prodrug TH-302 for potentiated targeting therapy in hepatocellular carcinoma.缺氧激活的选择性改善的抗 PKM2 抗体与前药 TH-302 联合用于增强肝细胞癌的靶向治疗。
Int J Biol Sci. 2024 Feb 11;20(5):1634-1651. doi: 10.7150/ijbs.92211. eCollection 2024.
4
Hypoxia-activated ADCC-enhanced humanized anti-CD147 antibody for liver cancer imaging and targeted therapy with improved selectivity.用于肝癌成像和靶向治疗的缺氧激活的ADCC增强型人源化抗CD147抗体，具有更高的选择性。
MedComm (2020). 2024 Mar 11;5(3):e512. doi: 10.1002/mco2.512. eCollection 2024 Mar.
5
Current state of NK cell-mediated immunotherapy in chronic lymphocytic leukemia.自然杀伤细胞介导的慢性淋巴细胞白血病免疫治疗的现状
Front Oncol. 2023 Jan 4;12:1077436. doi: 10.3389/fonc.2022.1077436. eCollection 2022.
6
Glycoconjugates: Synthesis, Functional Studies, and Therapeutic Developments.糖缀合物：合成、功能研究与治疗开发。
Chem Rev. 2022 Oct 26;122(20):15603-15671. doi: 10.1021/acs.chemrev.1c01032. Epub 2022 Sep 29.
7
NK Cells in Chronic Lymphocytic Leukemia and Their Therapeutic Implications.自然杀伤细胞在慢性淋巴细胞白血病中的作用及其治疗意义。
Int J Mol Sci. 2021 Jun 22;22(13):6665. doi: 10.3390/ijms22136665.
8
FUT8 Alpha-(1,6)-Fucosyltransferase in Cancer.癌症中的 FUT8 Alpha-(1,6)-Fucosyltransferase。
Int J Mol Sci. 2021 Jan 5;22(1):455. doi: 10.3390/ijms22010455.
9
Fc-Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies.具有增强Fc效应功能的Fc工程化抗体用于治疗B细胞恶性肿瘤
Cancers (Basel). 2020 Oct 19;12(10):3041. doi: 10.3390/cancers12103041.
10
Role of Non-Coding RNAs in the Development of Targeted Therapy and Immunotherapy Approaches for Chronic Lymphocytic Leukemia.非编码RNA在慢性淋巴细胞白血病靶向治疗和免疫治疗方法发展中的作用
J Clin Med. 2020 Feb 21;9(2):593. doi: 10.3390/jcm9020593.
本文引用的文献
1
Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials.利妥昔单抗维持治疗滤泡性淋巴瘤患者：随机试验的系统评价和荟萃分析
J Natl Cancer Inst. 2009 Feb 18;101(4):248-55. doi: 10.1093/jnci/djn478. Epub 2009 Feb 10.
2
HLA-DRhigh/CD27high plasmablasts indicate active disease in patients with systemic lupus erythematosus.HLA-DR 高表达/CD27 高表达浆母细胞提示系统性红斑狼疮患者处于疾病活动期。
Ann Rheum Dis. 2010 Jan;69(1):305-8. doi: 10.1136/ard.2008.096495.
3
The impact of Fc engineering on an anti-CD19 antibody: increased Fcgamma receptor affinity enhances B-cell clearing in nonhuman primates.Fc工程对一种抗CD19抗体的影响：增强的Fcγ受体亲和力提高了非人灵长类动物中B细胞的清除率。
Blood. 2009 Apr 16;113(16):3735-43. doi: 10.1182/blood-2008-10-182048. Epub 2008 Dec 24.
4
Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia.一种经Fc工程改造的抗CD19单克隆抗体对淋巴瘤和白血病具有强大的体外和体内活性。
Cancer Res. 2008 Oct 1;68(19):8049-57. doi: 10.1158/0008-5472.CAN-08-2268.
5
Tumor regression in cancer patients by very low doses of a T cell-engaging antibody.极低剂量的T细胞结合抗体使癌症患者肿瘤消退。
Science. 2008 Aug 15;321(5891):974-7. doi: 10.1126/science.1158545.
6
Fc gamma RIIIa expression is not increased on natural killer cells expressing the Fc gamma RIIIa-158V allotype.在表达FcγRIIIa - 158V同种异型的自然杀伤细胞上，FcγRIIIa的表达并未增加。
Cancer Res. 2008 Feb 15;68(4):976-80. doi: 10.1158/0008-5472.CAN-07-6523.
7
A decade of rituximab: improving survival outcomes in non-Hodgkin's lymphoma.利妥昔单抗十年：改善非霍奇金淋巴瘤的生存结局
Annu Rev Med. 2008;59:237-50. doi: 10.1146/annurev.med.59.060906.220345.
8
Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the Fc{gamma}RIIIa-158 V/V and V/F polymorphism.在表达FcγRIIIa - 158 V/V和V/F多态性的个体中，自然杀伤细胞CD16表达增加，与利妥昔单抗的结合及ADCC活性增强。
Blood. 2007 Oct 1;110(7):2561-4. doi: 10.1182/blood-2007-01-070656. Epub 2007 May 2.
9
Fcgamma receptor-dependent effector mechanisms regulate CD19 and CD20 antibody immunotherapies for B lymphocyte malignancies and autoimmunity.Fcγ受体依赖性效应机制调节针对B淋巴细胞恶性肿瘤和自身免疫性疾病的CD19和CD20抗体免疫疗法。
Springer Semin Immunopathol. 2006 Dec;28(4):351-64. doi: 10.1007/s00281-006-0057-9. Epub 2006 Nov 8.
10
CD19-/CD3-bispecific antibody of the BiTE class is far superior to tandem diabody with respect to redirected tumor cell lysis.双特异性T细胞衔接器（BiTE）类的CD19-/CD3-双特异性抗体在重定向肿瘤细胞裂解方面远优于串联双抗体。
Mol Immunol. 2007 Mar;44(8):1935-43. doi: 10.1016/j.molimm.2006.09.032. Epub 2006 Nov 2.
Zotero 插件