Biography

Tsuchikama Research Group Website
https://www.tsuchikamalab.org

Antibody–drug conjugates (ADCs) represent an emerging class of cancer chemotherapy agents. The striking success of ADCs, as demonstrated with 4 FDA-approved ADCs and more than 60 ADCs in clinical trials, has inspired scientists and clinicians to further advance this molecular format towards effective therapeutics for cancers. ADCs enable pinpoint delivery of highly potent antitumor drugs selectively to tumor cells while avoiding healthy tissues. The ADC chemical linker between the antibody and the drug molecule critically impacts ADC potency, safety, and durability profiles. Thus, the use of proper ADC linkers is a key to successfully implement ADC-based chemotherapy.

Our primary interest is in developing novel ADC linker technologies by taking advantage of the power of organic chemistry, medicinal chemistry, and chemical biology. One example is branched ADC linkers that can be equipped with multiple drug molecules. Most ADC linkers developed to date accommodate only single cytotoxic drugs. The clinical potential of such multiloading ADC linkers had remained unexplored because of the lack of efficient and versatile methods. We developed efficient methods for installing dual-loading ADC linkers in a simple and quantitative manner. Based on this success, we are currently advancing the multi-loading strategy to produce next-generation ADCs for combating the cancer drug resistance and heterogeneity. These are unsolved issues in cancer chemotherapy leading to discontinuation of medication and recurrence of malignancy. We envisage that our ADC technologies will provide innovative approaches for overcoming such unsolved issues and establish a novel technology platform providing a number of valuable additions to the current list of drug candidates for the future clinical studies.

Research Projects

  • Design, synthesis, and evaluation of novel branched chemical linkers for constructing multiloading antibody–drug conjugates (ADCs)
  • Structural optimization of ADC linkers for high plasma stability and rapid drug release
  • Quorum sensing-guided drug delivery

Publications

  • Anami, Y., Yamazaki, C. M., Xiong, W., Gui, X., Zhang, N., An, Z., Tsuchikama, K.* Glutamic acid–valine–citrulline linkers ensure stability and efficacy of antibody–drug conjugates in mice. Nature Commun. 9:2512 (2018). DOI: 10.1038/s41467-018-04982-3.
  • Tsuchikama, K.*, An, Z. Antibody-drug conjugates: recent advances in conjugation and linker chemistries, Protein Cell, 9, 33–46 (2018). DOI:10.1007/s13238-016-0323-0.
  • Anami, Y., Xiong, W., Gui, X., Deng, M., Zhang, C. C., Zhang, N., An, Z., Tsuchikama, K.* Enzymatic Conjugation Using Branched Linkers for Constructing Homogeneous Antibody–Drug Conjugates with High Potency. Org. Biomol. Chem. 15, 5635–5642 (2017).
  • Tsuchikama, K.*, Shimamoto, Y., Anami, Y. Truncated Autoinducing Peptide Conjugates Selectively Recognize and Kill Staphylococcus aureus. ACS Infect. Dis. 3, 406–410 (2017).