2021
DOI: 10.1158/1538-7445.am2021-1890
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Abstract 1890: A solution to T-cell engager toxicity: An anti-CD3 Prodrug DARPin (CD3-PDD) shows no toxicity, but potent anti-tumor activity in a humanized mouse model

Abstract: T-cell engagers (TCEs) direct cytotoxic T-cell response towards tumor cells by binding simultaneously to a tumor-associated antigen (TAA) on target cells and to CD3 on T-cells, thereby forming an artificial immune synapse. They have been shown to be very potent anti-tumor drugs, as exemplified by blinatumomab, an α-CD19 x α-CD3 bispecific. However, the development of TCEs for hematological and solid tumors has been hampered by several factors, amongst them severe toxicity, elicited by on-target/off-tumor recru… Show more

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“…161 This concept has recently been applied to a DARPin based CD3-binding T cell engager in which the CD3 effector function is masked until being activated in the tumor microenvironment. 162 The anti-CD3 prodrug molecule is composed of four distinct DARPin domains: an EGFR-and a CD3-binder as the core T cell redirecting entity, connected by a protease-cleavable linker to a DARPin domain that occupies the CD3-binding interface through intramolecular interactions. A fourth anti-HSA domain ensures prolonged blood circulation.…”
Section: Multi-specific Darpins In Cancer Therapymentioning
confidence: 99%
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“…161 This concept has recently been applied to a DARPin based CD3-binding T cell engager in which the CD3 effector function is masked until being activated in the tumor microenvironment. 162 The anti-CD3 prodrug molecule is composed of four distinct DARPin domains: an EGFR-and a CD3-binder as the core T cell redirecting entity, connected by a protease-cleavable linker to a DARPin domain that occupies the CD3-binding interface through intramolecular interactions. A fourth anti-HSA domain ensures prolonged blood circulation.…”
Section: Multi-specific Darpins In Cancer Therapymentioning
confidence: 99%
“…upon cleavage), the HSA domain is lost and, consequently, the T cell engager entity is quickly eliminated from circulation by renal clearance if not bound to its target, minimizing the exposure of the activated drug outside the tumor. 162 It will be interesting to see how this DARPin-based prodrug compares to 'muted' T cell bispecific antibodies (TCBs) that are similarly activated by cleavage of an anti-idiotypic anti-CD3 mask through tumor-associated proteases. 163…”
Section: Multi-specific Darpins In Cancer Therapymentioning
confidence: 99%