A humanized monovalent CD3 antibody which can activate homologous complement

Abstract

The rat monoclonal antibody (mAb) YTH12.5, specific for the CD3 antigen complex on human T cells has been modified in order to improve its efficacy in human therapy. With the aim of rendering it less immunogenic, it has been humanized using the method of framework grafting. During this process sequence analysis of the YTH12.5 V_L gene indicated that it was of the λ subclass, however, it was markedly dissimilar from previously published rat and mouse V_λ gene sequences and may represent a new V_λ gene family. The humanization of this light chain represents the first successful reshaping of a λ light chain V region. To improve the effector function of the antibody we have created a monovalent form (1 Fab, 1 Fc) using a novel method involving the introduction of an N‐terminally truncated human IgG₁ heavy chain gene into cells producing the humanized CD3 mAb. Comparison of the mono‐ and bivalent humanized mAb in a complement‐mediated cell lysis assay revealed that the monovalent antibody mediated lysis of human T cell blasts whereas the bivalent form did not. The availability of a humanized, complement‐fixing CD3 mAb may improve opportunities for human therapy, in the management of organ rejection, autoimmunity and the treatment of T cell lymphoma.