Abstract: The present disclosure relates to the application of a shielded and homing bispecific antibody as an effective and tissue specific treatment of cancers such as breast, lung, gastric cancers, and other HER2 over-expressed cancers. The homing domain increases the local concentration of the bispecific antibody in the tumor microenvironment, and the shielding employs masking domains that are fused via protease-cleavable linkers to the Fab domains targeting a human epidermal growth factor receptor 2 family protein and Fab domains targeting an angiogenic vascular endothelial growth factor pathway associated target. The unmasking of the shielded bispecific antibody occurs predominantly by proteases and enzymes in the tumor microenvironment. The application of such bispecific antibody minimizes systemic toxicity and expands the therapeutic index.