Abstract
T-cell-dependent bispecific antibodies (TDBs) are promising cancer immunotherapies that recruit a patient’s T cells to kill cancer cells. There are increasing numbers of TBDs in clinical trials, demonstrating their widely recognized therapeutic potential. Due to the fact that TDBs engage and activate T cells via an anti-CD3 (aCD3) arm, aCD3 homodimer (aCD3 HD) and high-molecular-weight species (HMWS) are product-related impurities that pose a potential safety risk by triggering off-target T-cell activation through bivalent engagement and dimerization of T-cell receptors (TCRs). To monitor and control the level of unspecific T-cell activation, we developed a sensitive and quantitative T-cell-activation assay, which can detect aCD3 HD in TDB drug product by exploiting its ability to activate T cells in the absence of target cells. This assay provides in-vivo-relevant off-target T-cell-activation readout. Furthermore, we have demonstrated that this assay can serve as a platform assay for detecting T-cell-activating impurities across a broad spectrum of aCD3 bispecific molecules. It therefore has the potential to significantly benefit many T-cell-recruiting bispecific programs.
Highlights
Bispecific antibodies are large-molecule therapeutics that target two different antigens simultaneously, maximizing therapeutic efficacy either synergistically or
In addition to quantitating aCD3 homodimer (aCD3 HD), cell-based assays that can measure off-target T-cell activation would be useful for characterizing the biological effects of aCD3 HD and other T-cell-activating impurities that may be present in T-cell-dependent bispecific antibodies (TDBs) drug products
Expression of many of these cytokines occurs via the well-characterized nuclear factor kappa-lightchain-enhancer of activated B cells (NFkB) pathway
Summary
Bispecific antibodies are large-molecule therapeutics that target two different antigens simultaneously, maximizing therapeutic efficacy either synergistically or . It is important to remove and quantitate homodimer impurities in light of their potential safety concerns These concerns are especially clear in T-cell-dependent bispecific antibodies (TDBs)—a promising emerging class of cancer immunotherapy. TDBs engage T cells via an anti-CD3 (aCD3) arm that binds the TCR complex on the surface of T cells For these bispecifics, aCD3 homodimer (aCD3 HD) poses a significant safety risk due to its ability to activate T cells in the absence of target cells by TCR dimerization. In addition to quantitating aCD3 HD, cell-based assays that can measure off-target T-cell activation would be useful for characterizing the biological effects of aCD3 HD and other T-cell-activating impurities that may be present in TDB drug products. This represents the first T-cell-activation assay for detection of T-cell-activating impurities, including aCD3 HD, and provides valuable insight into the overall contribution of impurities to off-target T-cell activation
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