審議結果報告書 - pmda.go.jp

1 27 50mg 26 19 27 28 10 1 27 5 19 50mg 26 9 19 1 10mL 50mg 1 T -4 IgG1 448 H 1 2 215 L 2 148,000 Ipilimumab is a recombinant human IgG1 monoclonal antibody against human cytotoxic T-lymphocyte-associated antigen 4.

2 Ipilimumab is produced in Chinese hamster ovary cells. Ipilimumab is a glycoprotein (molecular weight: ca. 148,000) composed of 2 H-chains ( 1-chains) consisting of 448 amino acid residues each and 2 L-chains ( -chains) consisting of 215 amino acid residues each. 2 C215 C221 C227 C227 C230 C230 Q1 K44 8 N298 Gal GlcNAc N- Man Fuc C6472H9972N1732O2004S40 148,000 25 300 25 3 15 0315 2 3 27 5 19 50mg 26 9 19 infusion reaction 1 1 3mg/kg 3 4 1.

3 2. 4 1 27 4 2 I 50mg 26 9 19 1 10mL 50mg 1 3mg/kg 3 4 II 1 1 Medarex Bristol-Myers Squibb BMS CD152 T -4 CTLA-4 Ig G1 T T CTLA-4 CD80 CD86 T 2 Medarex BMS 20

4 I MDXCTLA4-01 20 I MDXCTLA4-02 Medarex BMS 20 III MDX010-20 EU MDX010-20 2010 6 2010 5 2011 3 YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma. EU 2011 7 YERVOY is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy. EU 2012 8 2013 10 YERVOY is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults. 2015 2 51 20 10mg/kg 5 DTIC II CA184202 4 iii 2 CA184202 10mg/kg DTIC 20 3mg/kg II CA184396 MDX010-20 CA184396 2012 3 11 2012 4 2013 3 25 300 2 1 1 CD152 T -4 CTLA-4 CTLA-4 Ig G1

5 CHO MCB WCB MCB WCB in vitro CAL cDNA MCB WCB CAL / in vitro in vivo in vitro XC Mus dunni MCB WCB MCB WCB 2 6 2 8 C QbD CQA DNA CPP KPP 3 CHO MCB WCB CAL 1 in vitro in vitro log10 1 3 * * 4 / A B L B L C B L

6 C A B L 7 B L B L B L C C / A B L * 3 ii 5 1 A B L 3 iii 2 3 3 B L C 3. ii 5 2 B L C 3. iii 7 9 B L C 4 i 3 I / * L B L 5 Asp -N LC-MS/MS N C Lys -C CD DSC HDX -MS LC-ESI -MS ESI -Q/TOF-MS IEF iCIEF CEX SDS - SDS -PAGE SDS -PAGE SDS -PAGE SDS CE-SDS SEC

7 ELISA CTLA-4 8 SPR CTLA-4 ELISA SPR CDC ADCC / HCP DNA 6 pH SEC SDS -PAGE ELISA UV 7 4 5 3 C 36 * 2 C 5%RH 2 C 5%RH 2 C %RH B L 1 120 lux h 200W h/m2 * 36 C SDS -PAGE SDS -PAGE C C SEC 2 8 C 9 2 1 1 10mL 50mg D- 80 mol/L mol/L 2 3 / / / 4 pH SEC SDS -PAGE ELISA UV 5 C 3 5 3 C 36 2 30 * 2 C 5%RH

8 2 C 5%RH 2 C 5%RH B L 1 120 lux h 200W h/m2 * 36 C SDS -PAGE SDS -PAG C C SEC 2 8 C 24 3 10 C pH SEC SDS -PAGE ELISA UV mol/L mol/L mol/L mol/L mol/L mol/L 3 i CD152 T -4 CTLA-4 Ig G1 CTLA -4 1 1 CTLA-4 CTLA-4 9D9 IgG2 b UC10 IgG 1 1 1 CTLA-4 930019518 930019520 930021444 930043090 MDX-010- 011- R MDX-010- 013-R CTLA-4 IgG1 Fc KD n 4 in vitro FCM CTLA-4 CTLA-4 CTLA-4 T BW-mCTLA-4/CD3 CHO 11 CTLA-4 L

9 FCM in vitro CTLA-4 CTLA-4 FCM 2 CTLA-4 MDX-010 -008- R CTLA-4 FCM CTLA-4 T -Fc Fc 50% EC50 3 930031729 TIB -06-001 MDX-1106/010-006-R MDX-1106/010-007-R 930031040 SIV T B HBsAg SK-mel SK-mel T KLH iii 2 2 1 CTLA-4 T T CTLA-4 IgG Fc FC R IIb 9D9 2 6 ANA FC RIIb ANA non -obese diabetic NOD 9D9 PD-1 4H2 2 5 9D9 4H2 4H2 UC10 20 40mg/kg 3 1 3 4 MDX-010-006- R 930025694 STR -131 930023602 CTLA-4 T CDC ADCC CTLA-4 PBMC T T CDC 12 FC R FC RI EC50 FC RII FC RIII EC50 EC50 mol/L

10 PBMC T PBMC in vitro ADCC 51Cr 1%* 1 8%* 8 55%* ADCC * 1%Triton X-100 100% in vivo CTLA-4 CTLA-4 T