Using trastuzumab and high-HER2-expressing breast cancer cells, this study provided for the first time in vitro and in vivo experimental evidence that proteinase cleavage of trastuzumab at the lower hinge compromised its Fc-mediated immune effector functions such as ADCC in vitro, which resulted in reduced anti-tumor efficacy in vivo. Here, ERBB2 is linked to neoplasm.