COBRA™: a highly potent conditionally active T cell engager engineered for the treatment of solid tumors.

MAbs
Anand PanchalRobert B DuBridge

Abstract

Conditionally active COBRA™ (COnditional Bispecific Redirected Activation) T cell engagers are engineered to overcome the limitations of inherently active first-generation T cell engagers, which are unable to discern between tumor and healthy tissues. Designed to be administered as prodrugs, COBRAs target cell surface antigens upon administration, but engage T cells only after they are activated within the tumor microenvironment (TME). This allows COBRAs to be preferentially turned on in tumors while safely remaining inactive in healthy tissue. Here, we describe the development of the COBRA design and the characterization of these conditionally active T cell engagers. Upon administration COBRAs are engineered to bind to tumor-associated antigens (TAAs) and serum albumin (to extend their half-life in circulation), but are inhibited from interacting with the T cell receptor complex signaling molecule CD3. In the TME, a matrix metalloproteinase (MMP)-mediated linker cleavage event occurs within the COBRA construct, which rearranges the molecule, allowing it to co-engage TAAs and CD3, thereby activating T cells against the tumor. COBRAs are conditionally activated through cleavage with MMP9, and once active are highly potent, displ...Continue Reading

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Citations

Jan 16, 2021·Advanced Healthcare Materials·Anthony BrouillardAshish A Kulkarni
Jan 21, 2021·British Journal of Cancer·Ajit SinghIqbal S Grewal
Jan 21, 2021·Cancers·Jim MiddelburgThorbald van Hall
May 29, 2021·Molecular Cancer Therapeutics·Alison Crawford, Danica Chiu

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Methods Mentioned

BETA
biolayer interferometry
electrophoresis
enzyme-linked immunosorbent assay
ELISA
fluorescence-activated cell sorting
FACS
flow cytometry
size
light scattering
size exclusion chromatography

Software Mentioned

GraphPad
Octet
GraphPad Prism

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