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1 TIP Vol 21 No3 p21-24 TGN1412 I NPO [1,2] I TGN ICU [3] The Medicines and Healthcare Products Regulatory Agency MHRA [2] TGN1412 TGN1412 CD28-SuperMAB T TGN1412 T superagonistic anti-cd28 antibody ( CD28 CD28 superagonists) [4] B [5] TeGenero Immuno Therapeutics Boehringer-Ingelheim [6] 2005 EMEA [7] [4] [4] 1)superagonistic anti-cd28 mab T signal-1 (T cell antigen receptor T TCR) signal-2 (costimulation ) Signal-1 TCR APC MHC Major Histocompatibility complex :MHC CD28 [4] TCR in vitro TCR anti-tcr signal-1 CD28 T anergy [8] [4] signal-1 CD28 T ( ) anti-tcr T 2 IL-2 TGN1412 superagonistic anti-cd28 antibody anti-cd28 T IL-2 ( ) [4] TGN1412 superagonistic anti-cd28 antibody CD28 superagonists CD28 CD28 C D loop [4] CD28 2 [4] 1

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3 2)B B-CLL [5] B B-CLL APC T TGN1412 CD28 superagonists CLL B APC T TGN1412 CLL [5] 3) T TGN1412 [5] TGN1412 T TCR T TGN1412 T IL-10 TGN1412 regulatory T cell ( T regulatory T cell T ) [5] 3

4 PAREXEL CRO Northwick Park Hospital [1] Raste Khan (23 ) Times Online [9] Ryan Wilson (21 ) 3 [10,11] [11] TGN1412 [11] PAREXEL TeGenero [1] 500 [11-13] Dr. David Glover( ) TGN1412 CD28 [11,14] [11] 2 MHRA I CD4 T CD8 T superagonistic anti-rat CD28 antibody JJ mg/body/ [15] ( ) JJ316 JJ316 CD4 T T CD8 T T [3H] [16] CD4 T 120 CD8 T 30 T T in vitro [16] 1mg JJ316 1 CD4 T B superagonistic anti-cd28 antibody in vitro CD4 T CD8 T 1 - CD4 T B superagonistic anti-cd28 antibody T 4

5 Angus Dalgleish [12] The previous studies which caused similar severe side effects were in patients already suffering from cancer, but [the researchers] should have known they would get a meltdown because this drug was hitting exactly the same immune response pathways, American Society of Clinical Oncology ASCO) TGN1412 NCI Steven Rosenberg [12] T T T IL-2 T PAREXEL TeGenero TGN1412 CD28 CD28 I MHRA MHRA I [17-19] NPO [20] ( 3 ) [21] 5

6 1. PAREXEL ( ). Media Advisory: PAREXEL International Statement Regarding TeGenero AG Phase I Trial at Northwick Park Hospital, U.K BBC News Six taken ill after drug trials 3. Drugs trial men 'still improving' 4. Beyersdorf N, Hanke T, Kerkau T, Hunig T. Superagonistic anti-cd28 antibodies: potent activators of regulatory T cells for the therapy of autoimmune diseases. Ann Rheum Dis Nov;64 Suppl 4:iv TeGenero ( ). Drug Development. TeGenero. development/drug_development/index.php 6. TeGenero ( ). Boehringer Ingelheim and TeGenero sign agreement to develop and manufacture CD28- SuperMAB? TeGenero ( ). TeGenero AG receives EU-orphan drug designation for Humanized Agonistic Anti-CD28 Monoclonal Antibody TGN1412 for the treatment of B-cell Chronic Lymphocytic Leukaemia, B-CLL Wikipedia T helper cell 9. Lister S., and Smith L. Doctors seek international help in treating victims March 17, Alex Peake,?"Ryan: Spare me this pain", The Sun, TGN1412, Wikipedia, the free encyclopedia TGN1412 round-up March 18th, TGN American perspectives March 24th, Flemming N We're praying for them tml 14. "Protein differences may explain drug reaction", Reuters, Sun 19 March :39 PM GMT Rodriguez-Palmero M, Franch A, Castell M et al, Effective treatment of adjuvant arthritis with a stimulatory CD28- specific monoclonal antibody. J Rheumatol Jan;33(1): Tacke M, Hanke G, Hanke T, Hunig T. CD28-mediated induction of proliferation in resting T cells in vitro and in vivo without engagement of the T cell receptor: evidence for functionally distinct forms of CD28. Eur J Immunol Jan; 27(1): PK/PD NPO a)tip 20(7) b No57( ) NPO No64( ) 6

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がん免疫療法モデルの概要 1. TGN1412 第 Ⅰ 相試験事件 2. がん免疫療法での動物モデルの有用性がんワクチン抗 CTLA-4 抗体抗 PD-1 抗体 2

020315 科学委員会非臨床試験の活用に関する専門部会 ( 独 ) 医薬品医療機器総合機構会議室資料 1 2 がん免疫療法モデルの概要川博嘉 1 がん免疫療法モデルの概要 1. TGN1412 第 Ⅰ 相試験事件 2. がん免疫療法での動物モデルの有用性がんワクチン抗 CTLA-4 抗体抗 PD-1 抗体 2 TGN1412 第 Ⅰ 相試験事件 2006 年 3 月 13 日英国でヒトで全く初めての物質が使用された第