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  • Title: CD20-directed small modular immunopharmaceutical, TRU-015, depletes normal and malignant B cells.
    Author: Hayden-Ledbetter MS, Cerveny CG, Espling E, Brady WA, Grosmaire LS, Tan P, Bader R, Slater S, Nilsson CA, Barone DS, Simon A, Bradley C, Thompson PA, Wahl AF, Ledbetter JA.
    Journal: Clin Cancer Res; 2009 Apr 15; 15(8):2739-46. PubMed ID: 19351771.
    Abstract:
    PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSION: 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.
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