Abstract
A murine anti-human B-cell monoclonal antibody, Lym-1, has shown considerable promise for the treatment of human malignant lymphomas and has been utilized as a new radioimmunotherapy for refractory lymphoma. In order to enhance its clinical potential, a genetically engineered chimeric Lym-1 (chLym-1) with murine variable reyions and human γl and κ constant reyions was constructed and expressed. The goal of this study was to yenerate a Lym-1 reayent with decreased immunoyenicity and improved effector functions. Murine Lym-1 variable region cDNAs were isolated from the murine Lym-1 hybridoma cell line, fused to γl and κ constant region cDNAs, and expressed in an insect cell expression system with the baculovirus transfer vector pAcUW31. The chLym-1 antibody expressed in this system was correctly processed and assembled into the expected immunoglobulin monomer. Chimeric Lym-1 bound to both target antigen-bearing Raji cells and a Lym-1 anti-idiotype antibody and had a similar binding affinity as murine Lym-1. The chimeric and murine versions of Lym-1 were assayedfor their ability to mediate antibody-dependent cellular cytotoxicity (ADCC) and to induce complement-mediated cytotoxicity (CMC) against Raji targets. Chimeric Lym-1 mediated a two-fold hiyher level of ADCC than murine Lym-1 and slightly lower levels of CMC than murine Lym-1. In addition, in Raji lymphoma-bearing nude mice, chLym-1 localized to the tumor with approximately equal uptake at 24 and 72 hours. Chimeric Lym-1, however, cleared from the blood of non tumor-bearing mice approximately 5 times faster than murine Lym-1 (20h vs. 5 days), as expected for a xenogeneic protein. The improved in vitro and in vivo activities of this genetically enyineered monoclonal antibody render it a new potential immunotherapeutic reagent for the treatment of human malignant lymphomas.
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