2020 Fiscal Year Annual Research Report
Understanding the efficacy of therapeutic antibodies through their interaction with cellular receptors.
| Project/Area Number |
20H03228
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| Research Institution | Kyushu University |
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Principal Investigator |
CAAVEIRO Jose 九州大学, 薬学研究院, 教授 (00536732)
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| Co-Investigator(Kenkyū-buntansha) |
高橋 大輔 九州大学, 薬学研究院, 講師 (70791523)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | antibody / fc receptor / hinge / structure / immunology / glycosylation / protein expression |
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| Outline of Annual Research Achievements |
Key events contributing to the efficacy of therapeutic antibodies, such as the activation of cellular Fcgamma receptors, are still poorly understood. The purpose of this research is to understand the molecular mechanism of antibodies and their interaction with their cellular Fc gamma receptors.
We are applying biophysical and structural techniques to understand it. The constructs (antibodies, Fc receptors, vectors), instruments (such a new purification system and C)2 incubators), and many necessary protocols for protein preparation have been set-up. The expression of some recombinant proteins has been also achieved.
Antibodies with greater affinity for their cognate antigens are highly desirable to achieve the goals of this project. We have developed a new concept resulting in a new modality antibody with greater affinity using site-directed chemical modification. This work resulted in a publication showing increase of potency of up to 700-fold against the target.
A new approach to study the Fc region is also underway, consisting in the simultaneous production of Fc region in the glycosylated as well as in the un-glycosylated fashion. We have been able to obtain recombinant protein in high-yield, and the results have been published.
Finally, attempts to crystallize IgG1 and Fc receptors is also underway.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
Despite the tough working environment at universities in Japan, the project has advanced adequately as demonstrated by the two publications achieved. In addition, we have been able to overcome numerous hurdles to establish a smooth workflow to steadily advance the project. Unfortunately because of the tough circumstances derived from the pandemics I was not able to attend international conferences.
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| Strategy for Future Research Activity |
Basically to continue with the research lines started this year.
(1) preparation of specimens for structural analysis by X-ray crystallography and if possible Cryo-EM
(2) Understand the contribution of glycosylation and other modification in the properties of antibodies
(3) Evaluate the role of the hinge region by mutational analysis
(4) Attempt to quantify the clustering effect in model systems using the membrane portion of the receptor.
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