​Computational Design of Bispecific Antibodies Targeting CD3 and VEGFA Receptors Enhances T-cell Mediated Cancer Therapy

DuoBody antibodies are a type of bispecific antibody designed to target two different antigens or epitopes. These antibodies can simultaneously bind to two targets and enhance CAR T-cell efficacy and specificity. We hypothesize that the bispecific DuoBody antibody can induce potent T-cell-mediated killing of malignant B cells by simultaneously targeting the CD3 receptor on T cells and VEGFA receptors on malignant B cells. The research aims to identify the most promising bispecific antibodies for inducing T-cell-mediated killing of malignant B cells. In this current work, we conducted simulations to design bispecific antibodies targeting CD3 and VEGFA receptors on the surface of CAR T-cell and cancer cells, respectively. AlphaFold 3 was used for the structural elucidation of CD3 and VEGFA receptors, while the antibody structures were sourced from the Protein Data Bank. Molecular docking simulations were performed to investigate receptor-antibody interactions. A total of 30 simulations were conducted, involving 15 antibodies for each receptor. The antibodies were screened based on binding site prediction using a graph neural network, binding energy calculations, and the number of hydrogen bonds formed between the receptor-antibody complexes. The results demonstrated that the antibodies bind to the specific region of the receptors, as predicted by the graph neural network. Further interaction analysis pinpointed the 1IL1 antibody as the most effective for the CD3 receptor and 2HRP antibodies for the VEGFA receptor. The designed DuoBody antibody targeting B-cell malignancies holds promise for treating complex diseases by improving specificity and efficacy while minimizing off-target effects.