30

Japan Academy Prize to:
Ryuzo Ueda
Designated Professor, Graduate School of Medicine,Nagoya University
Emeritus Professor, Nagoya City University
Emeritus Professor, Aichi Medical University
for “Translational Research on Antibody Drug
Development for Adult T-cell Leukemia andLymphoma”

Outline of the work:
Dr. Ryuzo Ueda graduated from Nagoya University School of Medicine in 1969 and beganclinical research, focusing on chemotherapy for leukemia. In 1976, he worked at the Sloan
Kettering Cancer Institute in New York to study tumor immunology and conducted research todiscover human tumor antigens.
Dr. Ueda conducted tumor antigen analysis (autologous-serum typing) to examine the reaction between kidney cancer patient serum and cultured cancer cells derived from the samepatient, to find out whether the human body can recognize its cancer as a foreign substance. He
was successful in identifying kidney cancer-specific antigens. Furthermore, he was a pioneer
in identifying a human kidney cancer-specific antibody using a monoclonal antibody production
method that had been newly developed. He was convinced that cancer immunotherapy targeting cancer-specific antigens is eﬀective in cancer treatment, and hence he immersed himself intranslational research (TR), from basic cancer research to clinical application, upon his return toJapan.
After returning to Japan in 1980, he initiated research on adult T-cell leukemia/lymphoma(ATLL) at the Aichi Cancer Center Research Institute. ATLL is an incurable leukemia causedby the human T-cell leukemia virus type 1 (HTLV-1), which was discovered in 1977 by Japanese
researcher Dr. K. Takatsuki. There is an ATLL endemic region in southwestern Japan. At thetime, there were no eﬀective treatments for ATLL.
Since the late 1990s, Dr. Ueda’s laboratory at Nagoya City University School of Medicine
has been involved in pathological analysis of more than 100 ATLL patients specimens alongwith the mouse monoclonal antibody, developed by Dr. K. Matsushima and his colleagues. Theyobserved an elevated expression of the chemokine receptor 4 (CCR4) molecule on the surface ofATLL cells in more than 90% of patients diagnosed with ATLL. They identified CCR4 to be a
specific marker molecule for ATLL and also a factor responsible for the poor prognosis of ATLL
patients, and further identified it as an optimal target molecule for ATLL tumor treatment.
Since the year 2000, Dr. Ueda has been actively engaged in ATLL TR in collaboration
with a company. During his tenure, the company successfully produced antibodies with high31

potency and antibody-dependent cell cytotoxicity (ADCC) by developing a technology known
as the Poteligio technology, involving the removal of sugar chains from the Fc (fragment crystallizable) region of antibodies. Dr. Ueda’s laboratory was the first in the world to demonstratethat after administration of this fucose-depleted chimeric anti-CCR4 antibody, lymphocytes fromATLL patients were able to destroy their own ATLL cells in vitro.
Dr. Ueda then directed the company to formulate a humanized anti-CCR4 antibody as atherapeutic antibody drug. After verification of the activity, safety, and stability of the antibody
by the company, Dr. Ueda’s group initiated a first-in-human trial to administer the antibody(mogamulizumab) to ATLL patients. In the phase 1 trial, the drug was administered to 16 CCR4positive relapsed or refractory cases. As a result, the trial was safe and two ATLL patientsachieved complete remission (CR), and three patients achieved partial remission (PR), resulting
in an overall response rate (ORR) of 31%. Based on the results of the phase 1 trial, Dr. Ueda’sgroup immediately initiated a phase 2 clinical trial involving 26 patients with relapsed ATLL. The
results of this trial were amazing, with eight patients achieving CR and five patients achieving
PR, resulting in an ORR of 50%.
These clinical trials resulted not only in the creation of Japan’s first self-created anti-cancer
antibody drug in 2012, as an orphan drug for recurrent ATLL, but also in the first simultaneous
approval of the first companion diagnostic drug in Japan. In Japan, this drug was approved in2014 for expanded indications to treat untreated ATLL, relapsed CCR4-positive peripheral T-celllymphoma (PTCL), and cutaneous T-cell lymphoma (CTCL). Overseas, in 2018, the drug wasapproved by the U.S. Food and Drug Administration and the European Medicines Agency forthe treatment of mycosis fungoides (MF), relapsed and refractory skin lymphoma, and Sézary
syndrome (SS).
Following the launch of the anti-CCR4 antibody, Dr. Ueda continues the physician-led
drug development research to examine the optimal way to use this drug, as well as to clarify themechanisms of recurrence and resistance development for this antibody drug.
As mentioned above, Dr. Ryuzo Ueda discovered a therapeutic target for ATLL and developed a therapeutic drug in collaboration with a pharmaceutical company. Furthermore, hesupervised every step, right from the preclinical research to the clinical trials, and successfullylaunched Japan’s first monoclonal antibody drug for cancer. He is an outstanding researcher who
can be labeled as a role model for physician-scientists, as he has proved the clinical eﬃcacy ofthe drug and successfully delivered an eﬀective drug to ATLL patients around the world. Thisis a remarkable achievement in the history of cancer research and cancer treatment in Japan,and even today, Dr. Ueda continues to make several contributions to cancer immunotherapy andcancer TR.

List of Main Publications
1. Ishida T and Ueda R. Immunopathogenesis of lymphoma: focus on CCR4. Cancer Sci.,
2011; 102: 44–50. (review article)
2. Ishida T and Ueda R. Antibody therapy for Adult T-cell leukemia-lymphoma. Int. J. Hematol., 2011; 94: 443–452. (review article)

32

3. Ueda R., Shiku, H., Pfreundschuh, M., Takahashi, T., Li, I.T.C., Whitmore, W.F., Oettgen,
H.F. and Old, L.J. Cell surface antigens of human renal cancer defined by autologous typing.
J. Exp. Med., 1979; 150: 564–579.
4. Ueda R., Ogata, S., Morrissey, D.M., Finstad, c.L., Szkudlarek, J., Whitmore, W.F., Oettgen,H.F., Lloyd, K.O. and Old, L.J. Cell surface antigens of human renal cancer defined by mousemonoclonal antibodies: Identification of tissue-specific kidney glycoproteins. Proc. Natl.
Acad. Sci. USA., 1981; 78: 5122–5126.
5. Ueda R., Tanimoto, M., Takahashi, T., Ogata, S., Nishida, K., Namikawa, R., Nishizuka,
Y. and Ota, K. Serological analysis of cell surface antigens of null cell acute lymphocytic
leukemia by mouse monoclonal antibodies. Proc. Natl. Acad. Sci., U.S.A., 1982; 79:4386–4390.
6. Motoi, T., Uchiyama, T., Hori, T., Itoh, K., Uchino, H. and Ueda R. Elevated serum-solubleinterleukin-2 receptor (Tac antigen) levels in chronic myelogenous leukemia patients withblastic crisis. Blood, 1989; 74: 1052–1057.
7. Ishida T, Utsunomiya A, Iida S, Inagaki H, Takatsuka Y, Kusumoto S, Takeuchi G, Shimizu
S, Ito M, Komatsu H, Wakita A, Eimoto T, Matsushima K and Ueda R. Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association withskin involvement and unfavorable outcome. Clin. Cancer Res., 2003; 9: 3625–3634.
8. Niwa R, Shoji-Hosaka E, Sakurada M, Shinkawa T, Uchida K, Nakamura K, Matsushima K,Ueda R, Hanai N and Shitara K. Defucosylated chimeric anti-CC chemokine receptor 4 IgG1
with enhanced antibody-dependent cellular cytotoxicity shows potent therapeutic activity toT-cell leukemia and lymphoma. Cancer Res., 2004; 64: 2127–2133.
9. Ishida T, Iida S, Akatsuka Y, Ishii T, Miyazaki M, Komatsu H, Inagaki H, Okada N, Fujita T,Shitara K, Akinaga S, Takahashi T, Utsunomiya A and Ueda R. The CC chemokine receptor
4 as a novel specific molecular target for immunotherapy in adult T-Cell leukemia/lymphoma.
Clin. Cancer Res., 2004; 10: 7529–7539.
10. Yamamoto K, Utsunomiya A, Tobinai K, Tsukasaki K, Uike N, Uozumi K, Yamaguchi K,Yamada Y, Hanada S, Tamura K, Nakamura S, Inagaki H, Ohshima K, Kiyoi H, Ishida T,
Matsushima K, Akinaga S, Ogura M, Tomonaga M and Ueda R. Phase I study of KW0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cellleukemia-lymphoma and peripheral T-cell lymphoma. J. Clin. Oncol., 2010; 28: 1591–1598.
11. Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S, Saburi Y, Miyamoto T,Takemoto S, Suzushima H, Tsukasaki K, Nosaka K, Fujiwara H, Ishitsuka K, Inagaki H,Ogura M, Akinaga S, Tomonaga M, Tobinai K and Ueda R. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter
phase II study. J. Clin. Oncol., 2012; 30: 837–842.
12. Ogura M, Ishida T, Hatake K, Taniwaki M, Ando K, Tobinai K, Fujimoto K, Yamamoto K,Miyamoto T, Uike N, Tanimoto M, Tsukasaki K, Ishizawa K, Suzumiya J, Inagaki H, Tamura
K, Akinaga S, Tomonaga M and Ueda R. Multicenter phase II study of mogamulizumab(KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed
peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J. Clin. Oncol., 2014; 32:

33

1157–1163.
13. Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K, Uike N, Saburi Y,Nosaka K, Utsunomiya A, Tobinai K, Fujiwara H, Ishitsuka K, Yoshida S, Taira N, Moriuchi Y, Imada K, Miyamoto T, Akinaga S, Tomonaga M and Ueda R. Dose-intensified
chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive
adult T-cell leukaemia-lymphoma: a randomized phase II study. Br. J. Haematol., 2015;
169: 672–682.
14. Kurose K, Ohue Y, Wada H, Iida S, Ishida T, Kojima T, Doi T, Suzuki S, Isobe M, FunakoshiT, Kakimi K, Nishikawa H, Udono H, Oka M, Ueda R and Nakayama E. Phase Ia study ofFoxP3+ CD4 Treg depletion by infusion of a humanized anti-CCR4 antibody, KW-0761, incancer patients. Clin. Cancer Res., 2015; 21: 4327–4336.
15. Sakamoto Y, Ishida T, Masaki A, Murase T, Yonekura K, Tashiro Y, Tokunaga M, Utsunomiya A, Ito A, Kusumoto S, Iida S, Ueda R and Inagaki H. CCR4 mutations associatedwith superior outcome of adult T-cell leukemia/lymphoma under mogamulizumab treatment.
Blood, 2018; 132: 758–761.
16. Maeda Y, Wada H, Sugiyama D, Saito T, Irie T, Itahashi K, Minoura K, Suzuki S, Kojima T,Kakimi K, Nakajima J, Funakoshi T, Iida S, Oka M, Shimamura T, Doi T, Doki Y, Nakayama
E, Ueda R and Nishikawa H. Depletion of central memory CD8+ T cells might impede theantitumor therapeutic eﬀect of Mogamulizumab. Nat. Commun., 2021; 12: 7280.