Page 8 - ebook

[E. Immunology] E-4

Antibody-Based Targeting of Cell Surface GRP94 Specifically

Inhibits Cetuximab-Resistant Colorectal Cancer Growth

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Ji Woong Kim¹ , Yea Bin Cho¹ , Kyun Heo¹, Sukmook Lee¹*
¹Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 136-702, Korea

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. Cetuximab, a human/mouse
chimeric monoclonal antibody, is effective in a limited number of CRC patients because of cetuximab resistance.

This study aimed to identify novel therapeutic targets in cetuximab-resistant CRC in order to improve clinical
outcomes. Through phage display technology, we isolated a fully human antibody strongly binding to the

cetuximab-resistant HCT116 cell surface and identified the target antigen as glucose-regulated protein 94 (GRP94)
using proteomic analysis. Short interfering RNA-mediated GRP94 knockdown showed that GRP94 plays a key role

in HCT116 cell growth. In vitro functional studies revealed that the GRP94-blocking antibody we developed strongly
inhibits the growth of various cetuximab-resistant CRC cell lines. We also demonstrated that GRP94 immunoglobulin

G monotherapy significantly reduces HCT116 cell growth more potently compared to cetuximab, without severe
toxicity in vivo. Therefore, cell surface GRP94 might be a potential novel therapeutic target in cetuximab-resistant

CRC, and antibody-based targeting of GRP94 might be an effective strategy to suppress GRP94-expressing
cetuximab-resistant CRC.