BACKGROUND: ERBB2 is a proto-oncogene of multiple cancers including breast and 
gastric cancers with HER2 protein overexpression or gene amplification and has 
been proven clinically as a valid target for these cancers. HER2-targeting 
agents such as Herceptin®, Kadcyla® and ENHERTU® have been approved by the FDA 
for the treatment of breast cancer, but these drugs still face the challenge of 
acquired resistance and/or severe adverse reactions in clinical use. Therefore, 
there is significant unmet medical need for developing new agents that are more 
effective and safer for patients with advanced HER2-positive solid tumors 
including breast and gastric cancers.
METHODS: We report here the making of MRG002, a novel HER2-targeted antibody 
drug conjugate (ADC), and preclinical characterization including pharmacology, 
pharmacodynamics and toxicology and discuss its potential as a novel agent for 
treating patients with HER2-positive solid tumors.
RESULTS: MRG002 exhibited similar antigen binding affinity but much reduced 
antibody-dependent cellular cytotoxicity (ADCC) activity compared to 
trastuzumab. In addition to potent in vitro cytotoxicity, MRG002 showed tumor 
regression in both high- and medium-to-low HER2 expressing in vivo xenograft 
models. Furthermore, MRG002 showed enhanced antitumor activity when used in 
combination with an anti-PD-1 antibody. Main findings from toxicology studies 
are related to the payload and are consistent with literature report of other 
ADCs with monomethyl auristatinE.
CONCLUSION: MRG002 has demonstrated a favorable toxicity profile and potent 
antitumor activities in the breast and gastric PDX models with varying levels of 
HER2 expression, and/or resistance to trastuzumab or T-DM1. A phase I clinical 
study of MRG002 in patients with HER2-positive solid tumors is ongoing 
(CTR20181778).