Abstract
Bispecific T cell engaging antibodies (BiTEs) address tumor associated antigens that are over-expressed on cancer but that can also be found on healthy tissues, causing substantial on-target/off-tumor toxicities. To overcome this hurdle, we recently introduced hemibodies, a pair of complementary antibody fragments that redirect T cells against cancer-defining antigen combinations. Here we show that hemibodies addressing CD38 and SLAMF7 recruit T cells for the exquisite elimination of dual antigen positive multiple myeloma cells while leaving single antigen positive bystanders unharmed. Moreover, CD38 and SLAMF7 targeting BiTEs, but not hemibodies induce massive cytokine release and T cell fratricide reactions, a major drawback of T cell recruiting strategies. Together, we provide evidence in vitro and in vivo that hemibodies can be developed for the effective and highly specific immunotherapy of multiple myeloma.
Highlights
Bispecific T cell engaging antibodies (BiTEs) address tumor associated antigens that are overexpressed on cancer but that can be found on healthy tissues, causing substantial ontarget/off-tumor toxicities
To investigate the potential benefit of combinatorial targeting of tumor cells using the complementing hemibody technique, we resorted to an MM model system focusing on three antigens that are clinically addressed by monoclonal antibodies and T cellredirecting strategies in ongoing trials
In line with previously established results, we found B cell maturation antigen (BCMA) largely restricted to the B cell compartment
Summary
Bispecific T cell engaging antibodies (BiTEs) address tumor associated antigens that are overexpressed on cancer but that can be found on healthy tissues, causing substantial ontarget/off-tumor toxicities. To overcome this hurdle, we recently introduced hemibodies, a pair of complementary antibody fragments that redirect T cells against cancer-defining antigen combinations. We show that hemibodies addressing CD38 and SLAMF7 recruit T cells for the exquisite elimination of dual antigen positive multiple myeloma cells while leaving single antigen positive bystanders unharmed. A hemibody pair addressing CD38 and SLAMF7 redirects T cells against dual antigen-positive myeloma cells in vitro and in vivo, while sparing single antigen-positive bystanders. The results presented here provide experimental evidence for a precise and highly potent treatment of MM
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