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Advanced Control of Reaction Selectivity via High-speed Micromixing Flow Processes : A Breakthrough Approach to Protein Functionalization

中原, 祐一 北海道大学

2023.09.25

概要

1. Flow micro-process technology: importance in process chemistry
The remarkable progress of mankind has been substantially aided by advances in science and technology.
Chemical materials serve an indispensable role in numerous sectors, including automotive, electronics,
pharmaceuticals, consumer goods, and construction. Not only do these novel materials enhance human living
standards, but they also increasingly address the rising demand for energy conservation and environmental harmony.
As technology advances, a shift is observed from basic chemical substances towards functional substances. This
implies an industrial use of high-molecular-weight compounds and biomacromolecules such as proteins and nucleic
acids, extending beyond just simple low-molecular-weight compounds. A movement towards more complex
functional chemicals, including composites, inorganic hybrids, and protein conjugates, is also evident.
In the context of semiconductor materials, miniaturization, a crucial factor for improving the performance of
smartphones and semiconductors, necessitates the functionalization of chemical products. This emphasizes the
importance of precision synthesis processes, such as elevating yields and curbing impurities. The escalation in
energy costs and the evolution of environmentally sustainable processes are also significant considerations.
Another noteworthy advancement in functional chemicals is visible within the pharmaceutical industry. Proteins
and their functional conjugates are rapidly becoming standard as biotechnological materials. The introduction and
functionalization of new materials through chemical processes, like PEGylated drugs such as Pegasys and antibodydrug conjugates (ADCs) like Enhertu, have been creating blockbuster products consistently. The key to these
achievements lies in the stable production of these complex biomolecules.
Reports on continuous manufacturing specific to the drug manufacturing process have been issued by the FDA.
In parallel, the Japanese PMDA has established a working group on continuous manufacturing, indicating a shift
towards this production model. ...

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参考文献

1)

Nagaki, A., Ishiuchi, S., Imai, K., Sasatsuki, K., Nakahara, Y., & Yoshida, J.-I.

Micromixing

enables chemoselective reactions of difunctional electrophiles with functional aryllithiums. Reaction

Chemistry and Engineering, (2017), 862-870, 2(6)

2)

Endo, Y., Furusawa, M., Shimazaki, T., Takahashi, Y., Nakahara, Y., & Nagaki, A.

Molecular

Weight Distribution of Polymers Produced by Anionic Polymerization Enables Mixability Evaluation.

Organic Process Research and Development, (2019), 635-640, 23(4)

https://doi.org/10.1021/acs.oprd.8b00403

3) Nakahara, Y., Metten, B., Tonomura, O., Nagaki, A., Hasebe, S., & Yoshida, J.-I. Modeling and

Design of a Flow-Microreactor-Based Process for Synthesizing Ionic Liquids. Organic Process

Research and Development, (2019), 635-640, 23(4)

https://doi.org/10.1021/acs.oprd.8b00436

4) Nakahara, Y.; Endo, Y.; Takahashi, K.; Kawaguchi, T.; Kato, K.; Matsuda, Y.; Nagaki, A. A

Manufacturing Strategy Utilizing a Continuous Mode Reactor toward Homogeneous PEGylated

Bioconjugate Production

Synthesis, (2023), In press. DOI: 10.1055/a-2077-6187

190

Other Publications

1)

Nagaki, A., Nakahara, Y., Furusawa, M., Sawaki, T., Yamamoto, T., Toukairin, H., Tadokoro,

S., Shimazaki, T., Ito, T., Otake, M., Arai, H., Toda, N., Ohtsuka, K., Takahashi, Y., Moriwaki, Y.,

Tsuchihashi, Y., Hirose, K., & Yoshida, J.-I.

Feasibility Study on Continuous Flow Controlled/Living

Anionic Polymerization Processes. Organic Process Research and Development, (2016), 1377-1382,

20(7)

https://doi.org/10.1021/acs.oprd.6b00158

2)

Nakahara, Y., Furusawa, M., Endo, Y., Shimazaki, T., Ohtsuka, K., Takahashi, Y., Jiang, Y., &

Nagaki, A. Practical Continuous-Flow Controlled/Living Anionic Polymerization. Chemical

Engineering & Technology, (2019), 2154-2163, 42(10)

https://doi.org/10.1002/ceat.201900160

3)

Inoue, I., Chiba, M., Ito, K., Okamatsu, Y., Suga, Y., Kitahara, Y., Nakahara, Y., Endo, Y.,

Takahashi, K., Tagami, U., & Okamoto, N.

One-step construction of ferritin encapsulation drugs for

cancer chemotherapy. Nanoscale, (2021), 1875-1883, 13(3)

https://doi.org/10.1039/d0nr04019c

4)

Nakahara, Y., Inoue, I., Endo, Y. Construction protocol of drug-protein cage complexes for drug

delivery system. Methods in Molecular Biology, (2022), Article in Press

191

5)

中原祐一. 連続フロー生産に向けたプロセスモニタリング技術の適用, 化学工学,

(2021), 627-630, 85(11)

6)

Nakahara, Y., Mendelsohn, B. A., Matsuda, Y. Antibody–Drug Conjugate Synthesis Using

Continuous Flow Microreactor Technology. Organic Process Research and Development, (2022), 27662770, 26(9) https://doi.org/10.1021/acs.oprd.2c00217

7) フローマイクロ合成の実用化への展望

(吉田潤一監修), シーエムシー出版, p. 73-84 (2017)

8) マイクロリアクター/フロー合成による反応条件を最適化した導入と目的に応じた実生産へ

の適用、サイエンス&テクノロジー, p195-216 (2020)

9) 月刊ファームステージ, 技術情報協会, p7-12 (2020)

192

List of patents

Domestic patents

1)

複合素子及びセンサ 特願 2019-8897

2)

圧電シートおよびその製造方法 特願 2019-9797

3)

ポリマーの製造方法 特願 2020-33034

4)

有機化合物封入フェリチンの製造方法 特願 2020-553874

5)

フローマイクロリアクターを用いるリフォールディングされたタンパク質の製造方法

及びタンパク質のリフォールディング装置 特願 2020-556076

International patents

6)

位置選択的に修飾された抗体中間体、および生体直交性官能基または機能性物質を位

置選択的に有する抗体誘導体の製造方法 PCT/JP2022/033613

7)

抗体薬物複合体の製造方法 PCT/JP2021/039001

8)

相性予測方法、相性予測装置および相性予測プログラム PCT/JP2021/018932

9)

品質予測方法、品質予測装置および品質予測プログラム PCT/JP2021/024864

10)

L-アミノ酸の製造方法 PCT/JP2010/051071

193

List of presentations at conferences

Invited presentations

1)

化学工学会関西支部

(2017 年 10 月 31 日)

2)

The First International Conference on Automated Flow and Microreactor Synthesis (ICAMS-1),

マイクロプロセス最前線シリーズ

January 18-20, 2018 (Osaka, Japan)

3)

化学工学会関西支部

(2018 年 11 月 20 日)

4)

近畿化学協会フロー・マイクロ合成研究会

5)

京都大学マイクロ化学生産研究コンソーシアム講演会

6)

岡山マイクロリアクターネット 第 35 回例会 (2021 年 12 月 3 日)

7)

近畿化学協会フロー・マイクロ合成研究会

マイクロプロセス最前線シリーズ

第 81 回研究会(2019 年 2 月 8 日)

(2021 年 7 月 8 日)

第 93 回研究会(2022 年 1 月 28 日)

Oral presentations

1)

日本化学会

第 98 春季年会 2018, フローマイクロリアクタを用いた選択性制御有機リ

チウム種と二官能性求電子剤の反応

2)

日本化学会

第 99 春季年会 2019, マイクロリアクタによるイオン液体合成におけるモ

デリングとプロセス設計

194

Poster presentations

1)

14th International Conferences on MicroREaction technology (IMRET14)

(September 12-14, 2016, Beijing, China)

2)

日本プロセス化学会 2017 サマーシンポジウム

フローマイクロリアクタによる有機リチウム種の官能基選択性制御

Seminar Presentations

1)

シーエムシー出版 フローマイクロ合成の基礎・反応制御と応用技術動向

(2019 年 03 月 13 日)

2)

技術情報協会 フロー合成の装置選定と条件設定、トラブル対策

(2021 年 10 月 19 日)

3)

サイエンス&テクノロジー マイクロリアクター/フロー合成による反応条件を最適化し

た導入と目的に応じた実生産への適用(2020 年 12 月 4 日)

4)

サイエンス&テクノロジー

マイクロリアクターにおける合成操作で起こる

不具合とトラブル対策および活用に向けた課題(2022 年 1 月 20 日)

195

Other books and chapters

1)

フローマイクロ合成の実用化への展望

(吉田潤一監修), シーエムシー出版,

p. 73-84

(2017)

2)

マイクロリアクター/フロー合成による反応条件を最適化した導入と目的に応じた実生

産への適用、サイエンス&テクノロジー, p195-216 (2020)

3)

月刊ファームステージ, 技術情報協会, p7-12 (2020)

Press release

1)

Ajinomoto OmniChem Launches Flow Chemistry for API Commercial Manufacturing

https://www.ajibio-pharma.com/news-post/ajinomoto-omnichem-launches-flow-chemistry-for-apicommercial-manufacturing/

2)

ADC 迅速製造装置の実現 -フローリアクタによる抗体薬物複合体の迅速合成-

https://www.chem-station.com/blog/2023/03/adc.html

196

Acknowledgement

Firstly, I would like to express my sincerest gratitude to Professor Aiichiro Nagaki for his excellent guidance,

valuable discussions, and warm words of encouragement throughout this work. The studies presented in this

thesis were carried out during 2011-2023 in Ajinomoro Co., Inc., as part of investigations on novel applications

of flow flash chemistry for biopharmaceutical compounds.

Some studies were completed as collaborations with members of Micro Chemical Production Study

Consortium in Kyoto University and Ajinomoto Omnichem and Ajinomoto Althea. I am grateful to Ms. Mai

Furusawa (TOHO CHEMICAL INDUSTRY COMPANY, LIMITED), Mr. Toshiya Shimazaki (TACMINA

CORPORATION), Dr. Bert Metten, Dr. Eric De Vos (Ajinomoto Omnichem) and Assistant Professor Osamu

Tonomura (Kyoto University), Professor Shinji Hasebe (Kyoto University) and Professor Kazuhiro Mae (Kyoto

University).

I am greatly indebted to all former/present members of the management at Ajinomoto Co. Inc., during my

research period. Notably, Dr. Yutaka Matsuda (currently director antibody-drug conjugate chemistry at Exelixis

Inc.,), Dr. Ippei Inoue (currently senior principal researcher at Suntory Global Innovation Center), Mr. Keisuke

Kato, Dr. Yuta Endo, Dr. Kazutoshi Takahashi, Mr. Takahiro Okasora, Dr. Masoyo Date, Dr. Naoyuki Yamada

(currently chief technology officer at Synplogen), Dr. Daisuke Ejima (currently senior director at Sysmex), Dr.

Yoshimi Kikuchi, Dr. Teruhisa Mannen, Dr. Akira Okano, Dr. Fumihiko Takatsuki, and Dr. Atsushi Konishi,

Mr. Takahiro Terawaki, Mr. Kazuhiro Hioki, and Mr. Junya Wakuda, Mr. Osamu Nishikawa, Dr. Kazuhiro

Hasegawa, Dr. Shinrtaro Iwatani, Dr. Akito Chinen, Dr. Hiroshi Itaya, Dr. Takayuki Ito, Mr. Ryuichi Sasaki,

197

Dr. Tomoyuki Ohnishi, Dr. Tatsuya Okuzumi and Mr. Yosuke Koyama, Dr. Hiroshi Miyano, Dr. Kazuya

Onomichi, Dr. Toshihisa Kato for his technical, linguistic and for their invaluable contributions.

I would also like to express my sincere thanks to Professor Masaya Sawamura of Hokkaido University,

Professor Takanori Suzuki of Hokkaido University, Associate Professor Hisanori Senboku of Hokkaido

University, Ms. Tomoko Kawaguchi of Hokkaido University, Associate Professor Minami Atsushi of Hokkaido

University and Lecturer Kazuhiro Okamoto of Hokkaido University and Lecturer Yosuke Ashikari of Hokkaido

University for all their valuable discussions and encouragement.

Furthermore, I wish to express sincere thanks to my manager and colleagues at Ajinomoto Co. Inc., Dr. Ikuo

Kira, Dr. Masaru Takayanagi, Dr. Kazuhiro Nakanishi, Dr. Takashi Kayahara, Mr. Hirohisa Narahashi and Mr.

Masahiro Karakawa, Mr. Kenichi Kasumi, Ms. Megumi Kaneko, Mr. Hiroshi Umishio, Mr. Takumi Yoshida,

Mr, Shota Ino, Ms. Kaori Kobayashi, Ms. Kaoru Ogawa and Mr. Hiroshi Orikabe.

I gratefully dedicate the achievements of my studies to Emeritus Professor Jun-ichi Yoshida of Kyoto

University and express my deepest appreciation for his extremely valuable guidance over many years, especially

for establishing the concept of Flash Chemistry.

Last but not least, I wish to express my deepest appreciation to my family, Ms. Yukiko Nakahara, Mr. Yuki

Nakahara, Ms. Miku Nakahara, Ms. Natsuki Nakahara, Mr. Akio Nakahara, Ms. Yasuko Nakahara and Ms.

Harue Kitagawa, for their affectionate encouragement and constant assistance throughout this work. Without

their support and love, I could not have completed the doctoral thesis.

198

Yuichi Nakahara

Hokkaido University

199

...

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