Computationally Guided Design of Single-Chain Variable Fragment Improves Specificity of Chimeric Antigen Receptors.

ABSTRACT: Chimeric antigen receptor (CAR)-T cell-based immunotherapy of malignant disease relies on the specificity and association constant of single-chain variable fragments (scFvs). The latter are synthesized from parent antibodies by fusing their light (V_L) and heavy (V_H)-chain variable domains into a single chain using a flexible linker peptide. The fusion of V_L and V_H domains can distort their relative orientation, thereby compromising specificity and association constant of scFv, and reducing the lytic efficacy of CAR-T cells. Here, we circumvent the complications of domains' fusion by designing scFv mutants that stabilize interaction between scFv and its target, thereby rescuing scFv efficacy. We employ an iterative approach, based on structural mo

SUBMITTER: Krokhotin A 

PROVIDER: S-EPMC6804740 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature