Anti-CD3 x anti-B-cell antigen bispecific monoclonal antibodies (bsAbs) can redirect T-cell-mediated lysis toward malignant B cells. Clinical trials with CD3-based bsAbs have shown @entity137 in @entity1 which is likely related to nonspecific T-cell activation and targeting. Our current studies were designed to explore the mechanisms responsible for the observed in vivo @entity137 by evaluating the immunologic effects of 2 different bsAb preparations in vitro. 1D10 was used as the @entity5 specific arm of the bsAbs. This antibody reacts with a variant of HLA-DR found on a majority of pre-B- and B-cell @entity5 , and normal B cells in some individuals. Anti-CD3 served as the T-cell specific arm. A 1D10 x anti-CD3 bispecific IgG (bsIgG) produced using the hybrid-hybridoma method was compared to a 1D10 x anti-CD3 bispecific F(ab')2 [bsF(ab')2] produced using the @entity368 zipper technique. In @entity137 assays, both bsIgG and bsF(ab')2 induced lysis by pre-activated T cells of 1D10 (+) malignant B cells. bsIgG at high concentrations also induced lysis of 1D10 (-) @entity5 cells, while bsF(ab')2 did not. Proliferation of T cells induced by bsIgG and bsF(ab')2 was also evaluated. Both forms of bsAbs induced T-cell proliferation in the presence of antigen (+) Raji cells, while only bsIgG did so in the presence of antigen (-) malignant B cells. bsF(ab')2 induced T-cell activation in the absence of any @entity5 cells when testing was performed on samples where the 1D10 target antigen was present on normal peripheral blood B cells. We conclude that non-specific T-cell activation from bsAbs can occur in an antigen-independent manner due to the Fc/Fc receptor (FcR) interaction, or in an antigen-dependent manner when antigen is expressed on normal or @entity5 cells. Both mechanisms may have been responsible for the @entity137 observed in prior clinical studies.

Anti-CD3-based bispecific antibody designed for therapy of XXXX B-cell malignancy can induce T-cell activation by antigen-dependent and antigen-independent mechanisms.

@entity1 :: ('9606', 'Species') :: ['patients'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicity', 'cytotoxicity'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'malignancies'] @entity368 :: ('CHEBI:25017', 'Chemical') :: ['leucine']
@entity1 :: (9606,Species) :: ['human']
