CD20-directed small modular immunopharmaceutical, TRU-015, depletes normal and malignant B cells

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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 Blympho- ma 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 Bcells following single-dose administration to nonhuman primates. Conclusion: These results indicate that TRU-015 may improve CD20-directed therapy by effectively depleting embedded malignant Bcells and nonmalignant pathogenic B cells and do so with reduced complement activation. © 2009 American Association for Cancer Research.

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Hayden-Ledbetter, M. S., Cerveny, C. G., Espling, E., Brady, W. A., Grosmaire, L. S., Tan, P., … Ledbetter, J. A. (2009). CD20-directed small modular immunopharmaceutical, TRU-015, depletes normal and malignant B cells. Clinical Cancer Research, 15(8), 2739–2746. https://doi.org/10.1158/1078-0432.CCR-08-1694

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