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Clin Cancer Res ; 15(8): 2739-46, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19351771

RESUMO

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.


Assuntos
Antígenos CD20/imunologia , Linfócitos B/efeitos dos fármacos , Depleção Linfocítica , Linfoma de Células B/terapia , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Linfócitos B/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Nus , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes/farmacologia , Rituximab , Transplante Heterólogo/imunologia
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