Hayden-Ledbetter Martha S, Cerveny Chuck G, Espling Erik, Brady William A, Grosmaire Laura S, Tan Philip, Bader Robert, Slater Sonya, Nilsson Christy A, Barone Dauphine S, Simon Alexander, Bradley Cheryl, Thompson Peter A, Wahl Alan F, Ledbetter Jeffrey A
Trubion Pharmaceuticals, Inc., Seattle, Washington 98121, USA.
Clin Cancer Res. 2009 Apr 15;15(8):2739-46. doi: 10.1158/1078-0432.CCR-08-1694. Epub 2009 Apr 7.
CD20-directed therapy with rituximab is effective in many patients with malignant lymphoma or follicular lymphoma. However, relapse frequently occurs within 1 year, and patients become increasingly refractory to retreatment. Our purpose was to produce a compact, single-chain CD20-targeting immunotherapeutic that could offer therapeutic advantages in the treatment of B-cell lymphoma.
Rituximab is a chimeric antibody containing two heavy chains and two light chains. Here, we describe the properties of TRU-015, a small modular immunopharmaceutical specific for CD20, encoded by a single-chain construct containing a single-chain Fv specific for CD20 linked to human IgG1 hinge, CH2, and CH3 domains but devoid of CH1 and CL domains.
TRU-015 mediates potent direct signaling and antibody-dependent cellular cytotoxicity but has reduced size and complement-mediated cytotoxicity activity compared with rituximab. TRU-015 is a compact dimer of 104 kDa that comigrates with albumin in size exclusion chromatography and retains a long half-life in vivo. TRU-015 induced growth arrest in multiple B lymphoma cell lines in vitro and showed effective antitumor activity against large, established subcutaneous Ramos or Daudi xenograft tumors in nude mice. TRU-015 also showed rapid, dose-dependent, and durable depletion of peripheral blood B cells following single-dose administration to nonhuman primates.
These results indicate that TRU-015 may improve CD20-directed therapy by effectively depleting embedded malignant B cells and nonmalignant pathogenic B cells and do so with reduced complement activation.
利妥昔单抗介导的CD20靶向治疗对许多恶性淋巴瘤或滤泡性淋巴瘤患者有效。然而，复发常发生在1年内，且患者对再次治疗的耐药性越来越高。我们的目的是制备一种紧凑的单链CD20靶向免疫治疗药物，它在B细胞淋巴瘤治疗中可能具有治疗优势。
利妥昔单抗是一种含有两条重链和两条轻链的嵌合抗体。在此，我们描述了TRU-015的特性，它是一种针对CD20的小型模块化免疫药物，由一个单链构建体编码，该构建体包含一个针对CD20的单链Fv，与人类IgG1铰链区、CH2和CH3结构域相连，但不含CH1和CL结构域。
与利妥昔单抗相比，TRU-015介导强大的直接信号传导和抗体依赖性细胞毒性，但尺寸减小且补体介导的细胞毒性活性降低。TRU-015是一种104 kDa的紧凑二聚体，在尺寸排阻色谱中与白蛋白共迁移，在体内具有较长的半衰期。TRU-015在体外诱导多种B淋巴瘤细胞系生长停滞，并对裸鼠体内已形成的大型皮下Ramos或Daudi异种移植肿瘤显示出有效的抗肿瘤活性。对非人灵长类动物单剂量给药后，TRU-015还显示出外周血B细胞的快速、剂量依赖性和持久耗竭。
这些结果表明，TRU-015可能通过有效清除嵌入的恶性B细胞和非恶性致病B细胞来改善CD20靶向治疗，并且补体激活减少。
