Combating of non-small-cell lung cancer (NSCLC) through EGFR/PD-L1 bispecific antibody generated by Lock-and-Key method.

e15106 Background: Although monoclonal antibodies (mAbs) are widely used for the treatment of cancer, the acquired resistance is one of the prime obstacles for cancer treatment and development of novel antibodies with potent anti-tumor activities and specificities is urgently needed. Due to complex diseases are often multifactorial in nature, and involve redundant or synergistic action of disease mediators or upregulation of different receptors, bispecific antibodies with the capacity to blockade of multiple targets or binding sites are showing improved therapeutic efficacy against cancer. Although “knobs-into-holes” technique is an efficient way to generate bispecific antibody with whole IgG-architecture, the efficacy of different heavy chain hetero-generation and the thermostability remain questionable. How to efficiently generate bispecific antibodies with more efficiency and stability is critical for the development of novel antibodies against cancer. Methods: By using the structure-based computational design and long-time molecule dynamic simulation (5 µs), we have successfully developed a more efficient technique “Lock-and-key” to produce bispecific antibodies with more efficiency. Based on the parent EGFR antibody cetuximab and PD-L1 antibody atezolizumab, EGFR/PD-L1 bispecific antibody with whole IgG structure was designed. Results: With the benefits of bispecific antibody and whole IgG architecture, the bispecific antibody EGFR/PD-L1 exhibits potent anti-tumor efficacy than the parent antibody Cetuximab, Atezolizumab and the combination of Cetuximab and Atezolizumab. Conclusions: “Lock-and-Key” technique could be a more promising method to produce the herero-generation of antibody heavy chains. More importantly, bispecific antibody with whole intact IgG structure shows the advantages in cancer treatment. Antagonism of EGFR and PD-L1 through bispecific antibody could be a promising anti-tumor strategy against NSCLC.