Drug delivery system for malignant tumors using carbohydrate mimetic peptides.

   Glycans are involved in the onset, progression, and metastasis of various types of cancers. The large number of unsolved problems in glycobiology is due to the difficulty of their structural analysis and chemical synthesis. Biosynthesis, chemical synthesis, and quality control of glycans are also difficult, resulting in few examples of glycans being utilized in drug discovery. To solve these problems, our laboratory employs an alternative approach: phage display technology.

   Dr. Michiko N. Fukuda in the Sanford-Burnham Research Institute, USA, screened a phage library consisting of short random peptide and identified a series of peptides that mimic the structure of carbohydrates. One of the peptides, designated as IF7, was shown to bind to annexin A1 expressed on the surface of tumor blood vessels. Surprisingly, IF7 accumulated at the tumor site, and IF7-binding anticancer drugs were shown to eliminate malignant tumors in mice at low doses (Hatakeyama et al, PNAS, 108:19587-92, 2011). Since IF7 peptide migrated from the vasculature surface to the basolateral side via transcytosis pathway, we thought that the peptide might also cross the blood-brain tumor barrier. After I joined Michiko’s lab, we demonstrated that IF7 accumulates specifically in brain tumors (Nonaka et al, Br J Cancer, 123: 1633-43, 2020). We also showed that D-peptide (a peptide composed of D-amino acids) is more stable in vivo and targets brain tumors (Nonaka et al, PLos One, 16: e0241157, 2021). We are now focusing on the function of annexin A1 to elucidate the detailed mechanism how this peptide accumulates in malignant tumors.

Development of therapeutic antibody-like molecules with low immunogenicity.

   The various types of biological agents in clinical use have brought tremendous benefits in the treatment of disease. However, administration of such agents in the body over a long period of time often results in a gradual loss of their effectiveness. One of the main reasons for this is the formation of anti-drug antibodies in the body. To date, humanized antibodies have been developed to circumvent the immunogenicity of biotherapeutics. However, even the latest humanized antibodies remain immunogenic. Our laboratory is conducting basic research to develop biotherapeutics that prevent the formation of such anti-drug antibodies in the body.

   Drug discovery research is difficult to conduct in a single research area alone and requires fusion research that crosses the boundaries between fields. Our project is conducted in collaboration with the Graduate School of Pharmaceutical Sciences and other laboratories specializing in organic chemistry.

Development of diagnostic and therapeutic methods for allergy and autoimmune diseases.

   Self-reactive autoantibodies secreted in autoimmune diseases target a variety of biological macromolecules including proteins, nucleic acids, carbohydrates, and lipids. Allergic diseases are known to be caused by the binding of foreign antigenic proteins to immunoglobulin E (IgE). Our laboratory is interested in the epitopes of these autoantigens. Our goal is to determine the autoantigen proteins from their sequences and to obtain peptides that mimic the epitope structures. We believe these approaches will lead to technologies for early diagnosis and treatment of diseases.