Plant-Derived Anti-Human Epidermal Growth Factor Receptor 2 Antibody Suppresses Trastuzumab-Resistant Breast Cancer with Enhanced Nanoscale Binding
Chan-Yong Park, Kibum Kim, Yerin Kim, Rong Zhu, Lisa Hain, Hannah Seferovic, Minhyeok Kim, Hyun Joo Woo, Hyun‐Ju Hwang, Seung Ho Lee, Sangmin Kim, Jeong Eon Lee, Peter Hinterdorfer, Kisung Ko, Sungsu Park, Yoo Jin Oh
Abstract
High Resolution Image Download MS PowerPoint Slide Traditional monoclonal antibodies such as Trastuzumab encounter limitations when treating Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer, particularly in cases that develop resistance. This study introduces plant-derived anti-HER2 variable fragments of camelid heavy chain domain (VHH) fragment crystallizable region (Fc) KEDL(K) antibody as a potent alternative for overcoming these limitations. A variety of biophysical techniques, in vitro assays, and in vivo experiments uncover the antibody’s nanoscale binding dynamics with transmembrane HER2 on living cells. Single-molecule force spectroscopy reveals the rapid formation of two robust bonds, exhibiting approximately 50 pN force resistance and bond lifetimes in the second range. The antibody demonstrates a specific affinity for HER2-positive breast cancer cells, including those that are Trastuzumab-resistant. Moreover, in immune-deficient mice, the plant-derived anti-HER2 VHH-FcK antibody exhibits superior antitumor activity, especially against tumors that are resistant to Trastuzumab. These findings underscore the plant-derived antibody’s potential as an impactful immunotherapeutic strategy for treating Trastuzumab-resistant HER2-positive breast cancer.