Bispecific molecules redirecting the cytotoxicity of T-cells are a growing class of therapeutics with numerous molecules being tested in clinical trials. However, it has been a long way since the proof of concept studies in the mid 1980's. In the process we have learnt about the impact of different variables related to the bispecific molecule and the target antigen on the potency of this type of drugs. This work reviews the insights gained and how that knowledge has been used to design more potent bispecific T-cell engagers. The more recent advancement of antibodies with this modality into safety studies in non-human primates and as well as in clinical studies has revealed potential toxicity liabilities for the mode of action. Modifications in existing antibody formats and new experimental molecules designed to mitigate these problems are discussed.
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