Therapeutic Antibody Engineering
Monoclonal antibodies hold the promise of selective tumor destruction in cancer therapy. Pediatric patients with metastatic neuroblastoma have been shown to benefit from therapeutic monoclonal antibodies directed at the tumor antigen GD2 in minimal residual disease settings. GD2 is a complex acidic glycolipid abundantly found on the surface of neuroblastoma cells and other tumors of neuroectodermal origin, including melanoma, sarcoma, and small cell lung cancer. Building on the favorable clinical results of current anti-GD2 monoclonal antibodies, genetic engineering methods are available to improve their binding to both antigen and Fc receptors. Higher affinity anti-GD2 monoclonal antibodies can have substantially improved tumor-bound to free-unbound ratio and increase T-1/2 of bound antibody, ultimately translating into stronger and sustained anti-tumor effect.
Our approach is to use computational and experimental biophysical methods to guide the design of monoclonal antibodies with enhanced affinity and specificity to several cancer antigens including GD2 and B7H3. Methods of x-ray crystallography and computational chemistry are being utilized to characterize the molecular details of the antibody:antigen binding interface. In silico mutational analyses are then used to design novel monoclonal antibodies with enhanced properties. Antibodies with substantial improvements in affinity and specificity are further tested in therapeutic studies using mouse xenografts and continue onto IND-enabling studies.
Zhao Q, Ahmed M, Guo HF, Cheung IY, Cheung NK (2015). Alteration of electrostatic surface potential enhances affinity and tumor killing properties of anti-ganglioside GD2 monoclonal antibody hu3F8. Journal of Biologial Chemistry. 290(21):13017-27.