Chemistry/Biology/Medical Care

Shin-Ichiro Nishimura

Drug Discovery from Chemical Glycobiology -Developing New Antibody Drugs

Shin-Ichiro Nishimura , Professor

(Department of Biological Sciences, School of Science (Area of expertise: Macromolecular Function))

High school : Hokkaido Chitose High School

Academic background : Graduate School of Science, Hokkaido University

Research areas
Bioorganic Chemistry (Glycotechnology, Medicinal Chemistry)
Research keywords
lycans, Medicinal Chemistry, Protein, Biopolymers, Disease-Specific Antigen, Antibody Drug
Website
http://altair.sci.hokudai.ac.jp/g4/

Creating New Antibody Drugs with High Unmet Needs

An antibody is a protein generated by lymphoid cells in our body to protect our body from various invading antigens (foreign objects), and it is the most important biopolymer which plays a role in humoral immunity. This antibody has been used at clinical sites as an excellent therapeutic or diagnostic medicine for some diseases such as cancers or immunological diseases. It is widely recognized as an “antibody drug” these days. The presence of the antibody drugs is increasing more and more in the global market of drugs. The following five antibody drugs are all among “the top 10 blockbuster drugs that are sold most in the world”: Humira and Remicade which are therapeutic medicines for rheumatism, Rituxan for lymphoma, Herceptin for breast cancer, and Avastin for metastatic colon cancer. They are said to have sales between 600 billion to 1 trillion yen annually (data from 2012). There are no effective therapeutic or diagnostic medicines that exist for not only various types of cancer but also for many diseases ranging from neurodegenerative diseases such as Alzheimer's disease, to lifestyle-related diseases such as diabetes, to infectious diseases. As a result, there are greater expectations for more research and development of new antibody drugs which can meet these needs.

 

Lack of Disease-Specific Epitope Information is the Biggest Obstacle

The development of antibody drugs requires antigen molecules such as proteins existing in target cancer cells. Particularly, the structure of the disease-specific epitope (antigenic determinant) in antigen molecules is critical information because it determines specificity and affinity when the antibody binds to target antigen molecules. However, the structure of all of the human proteins is directly governed (determined) by the structure of the gene (base sequence), and almost no changes are seen in the basic structure other than expression level, regardless of the disease onset or its advancement. This means the protein molecules themselves cannot become a disease-specific epitope when no significant change occurs between the disease and the expression level of the specific gene. Recently, it is said that this severe “lack of disease-specific epitope information” makes the research and development of new antibody drugs extremely difficult. The technological innovation in the manufacturing processes of antibody drugs has advanced so much, for example, the preparation methods of human antibodies for treating people or the improvement of the function in antibody molecules as drugs for antibody-dependent cellular cytotoxicity (ADCC activity). Therefore, it's not an exaggeration to say that the biggest issue in the research and development of antibodies for new drugs is all summed up in “finding disease-specific epitopes.”

 

Posttranslational Modification = Focusing on the Relationship between Disease and glycan Modification of Protein


Glycoprotein Called MUC4 Existing in Pancreas
Cancer Cells

There are many cases where the structures and functions of the proteins existing in our body (in internal organs or tissues, in all kinds of cells constituting the organs and tissues, and in blood) significantly change due to posttranslational modification, such as dynamical glycan modifications. For example, it is known that the CA15-3 used widely as a biomarker (diagnostic drug) of breast cancer or the KL-6 used for diagnostics of interstitial pneumonia is a peptide fragment (glycopeptide) which is partially cut from the gigantic protein called MUC1, which exists on the cell surface at the affected area, and is modified by the glycan with a unique structure which is leaked into blood. These molecules are nothing other than good “disease-specific epitopes” which are not found in healthy people. They directly reflect specific structural information of the cell membrane glycoproteins existing in the affected area of patients with breast cancer or with pneumonia. Needless to say, they are prospective targets for antibody drug development.

 

Was There a Breakthrough?


Image of Antibody Attacking “Disease-Specific Epitope”
Existing on Cancer Cell Surface

There was a “big obstacle specific to the glycan structure” in the structural analysis or chemical synthesis of glycoproteins or the partial structures, glycopeptides, which are potential disease-specific epitopes. A new technology called the Glycoblotting method, which we developed at Hokkaido University, became a “breakthrough.” We were able to perform large-scale and high-speed glycan analysis using patients’ blood for the first time in the world, and we were able to achieve a basic study of “disease-specific epitope.” Due to so much joint research with clinical groups, the relationship between the mechanisms of posttranslational modification by glycans and the diseases has been gradually made clearer. We all are “ambitious” for the future day when an antibody drug becomes available which meets patients’ unmet needs, thanks to the results of this fundamental research.

 

References

(1)   Isao Ishida, “Development Trend of Antibody Drug (Kotai Iyaku no Kaihatsu Doko)”, Development and Market of Antibody Drug (Kotai Iyakuhin no Kaihatsu to Shijo), CMC Publishing, p1-11, 2011.

(2) Shin-Ichiro Nishimura, Development and Clinical Application of Automatic glycan Analytical System (Zen Jido Tosa Kaiseki System no Kaihatsu to Rinsho Oyo), Rinsho Kagaku (Clinical Chemistry), Vol. 41, p257-258, 2012.

(3) Shin-Ichiro Nishimura, Molecular Design and Drug Development of Glycopeptide (To Toupepuchido no Bunshi Sekkei to Iyakuhin Kaihatsu), Front Line of Peptide Medical Care (Peptide Iyaku no Saizensen), CMC Publishing, p25-35, 2012.