Computational design of novel tetra-specific antibody (PD-1/CD47/VEGF/TGF-ß) with IgG-like architecture against non-small cell lung cancer (NSCLC).

e14002 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. There is an urgent need to development of novel antibodies with potent anti-tumor activities and specificities against cancer. Due to the complexity and heterogeneity of cancer, mAb with a single target could not be significantly improved to combat cancer. Nowadays, bispecific antibodies with the capacity to blockade of multiple targets or binding sites are showing improved therapeutic efficacy against cancer both in clinical trials and preclinical studies, suggesting that multi-specific antibodywith great potential for administration of cancer in near future. Although more than 30 bispecific antibodies with IgG architecture are being explored in clinical trials, tetra-specific antibody with IgG-like architecture against NSCLC has not been reported. Methods: Recently, we have successfully solved the correct assembling of heavy-heavy chain and heavy-light chain of multi-specific antibody through the Lock-and-Key and FabX technologies we have previously described. By using these two technologies, we have designed the tetra-specific antibody with IgG-like architecture against NSCLC. Then, we have performed long-time molecule dynamic simulation (6 µs) to evaluate and improve the structure stability of tetra-specific antibody. Results: With the benefits of tetra-specific antibody and whole IgG architecture, the tetra-specific antibody PD-1/CD47/VEGF/TGF-ßexhibits potent anti-tumor efficacy than the parent antibody Atezolizumab, Hu5F9-G4, Bevacizumab or Fresolimumab and the combination of these parent antibodies. Conclusions: Tetra-specific antibody with IgG-like structure shows the advantages in cancer treatment. Antagonism of PD-1, CD47, VEGF and TGF-ß through multi-specific antibody could be a promising anti-tumor strategy against NSCLC.