In Silico Design of Blinatumomab: A conventional Bispecific T Cell Engager for Targeted Immunotherapy

Blinatumomab is an FDA-approved bispecific T Cell engager(BiTE) that binds CD3 on T cells and CD19 on B cells, redirecting cytotoxic T cell activity to malignant B cells. Blinatumomab has achieved clinical success in treating B-cell acute lymphoblastic leukemia(B-ALL), however, the structural and functional optimization of BiTE molecules remains be active research. In this study, we design and report the de novo in silico design of a functional Blinatumomab molecule using computational modeling techniques, followed by molecular dynamics (MD) simulations to evaluate its structural stability, flexibility, and binding interactions. Using available crystal structures of anti-CD3, anti-CD19 single-chain variable fragments(scFvs), and flexible linkers, we engineered a full bispecific T cell engager in silico. The resulting 3D structure was energy-minimized and put through MD simulations in a solvated environment in order to retrieve conformation stability and inter-domain interactions. Parameters like root mean square deviation (RMSD), radius of gyration, and solvent-accessible surface area (SASA) were additionally monitored from the MD simulations. These energy profiles provided domain stability and interchain interactions. Developing a valid computation model of a BiTE molecule is useful for additional testing in comparison to in vivo and clinical lab tests for improving BiTE Immunotherapy. Computational models are cost-effective and enable faster testing, optimization, and screening prior to in vivo experimental synthesis.