(

(

2

3

4

Sx x C 2 C 2 5

6

Arnold Demain: TIBTEC JAUARY 2000) 7

8

2 2 Duocarmycin B2 Mitomicin C Br ES-242-1 RES-1149-1 DC102 DC14E Kaprimycin A1 Staurosporine Manumycin A Clecarmycin wortmannin Saintopin DC92-B 2 Tetrocarcin A Sapurimycin 2 RES-1214-1 MS-681a 2 2 Fortimicin A K-252a GE3 - Secanacarcin A + 2 UC-01 UCE6 KS-501 UCA1064A Cl 2 Limphostin 2 Calphostin C AS-186a RP-1551-1 RES-701-1 Trioxoacarcin 2 2 Belactosin A UCS1025 2 Gilvocarcin V MS-444 2 2 2 Sagamicin erboxidiene Pyrronamycin A Cl Cl Cl Cl Cl Cl KS-504a 2 Cl MY336 UC9 Leinamycin Q uinocarcin Destruxin EI-1507-1 β1 6 Glucose Glucose n-1 S S + 3 C - (Caproic acid) m S-142 3 C C 3 S 9 PS-996 n=10-30 m=5-15

1920-30 1940 1950 1960 1970 Penicillin Penicillin Amino Fradiomycin Kanamycin Gentamicin Micronomicin - glycoside Streptomycin Tobramycin Astromicin Tetracyclin Tetracyclin Erythromycin Josamycin Macrolide Spiramycin Kitasamycin Peptide Gramicidin Bacitracin Vancomycin Enramycin thers Cycloserine Fosfomycin Clavulanic acid Polyene ystatin Azalomycin F -macrolide Amphotericin B Pentamycin thers Griseofulvin Aureothricin Siccanin Actinomycin D Carzinophilin Doxorubicin Aclarubicin Chromomycin A3 Bleomycin Peplomycin eocarzinostatin *Mitomycin C 58, 17, 2000 10

1970 1980 1990 Mizoribine(Bredinin) Tacrolimus(FK-506) Ciclosporin(Cyclosporin A) Gusperimus(15-deoxyspergualin) Pravastatin (Mevalotin) Simvastatin Acarbose Voglibose 58, 17, 2000 11

20g/L 70%) Mortierella alpina 12

& 13

L- L-

D-p- -carbamoyl D-p-hydroxy-PhenylGlycine D- D- Pseudomonas sp. D-p-hydroxy PhenylGlycine 15

8 2 Rhodococcus rhodochrous 16

C 2 - L-Proline trans-4-yp C 2 17

+ + + + + Glucose ATP ADP ATP ADP 2 C 2 Glucose Acids 2 C 2 Acids 18

19

E.coli sugartransferase sugarnucleotide biosynthesisgenes E.coli sugartransferase sugarnucleotide biosynthesisgenes E.coli sugar Transferase sugarnucleotide biosynthesisgenes β β α β β ABC GMP 1,4-Galactosyl Transferase 1,3-Galactosyl Transferase 1,4-Galactosyl Transferase 1,4-GalAc Transferase 1,3-GalAc Transferase C. ammoniagenes ABC α2,3-siaryl Transferase α2,6-siaryl Transferase α1,2-fucocyl Transferase α1,3-fucosyltransferase etc. ABC 2'-Fucosyl-lactose 3-Fucosyl-lactose 3'-Sialyl-3-fucosyllactose Lacto-di-fuco-tetraose Lacto--fuco-pentaose I Lacto--fuco-pentaose II Lacto--fuco-pentaose V LS-Tetra-saccharide a LS-Tetra-saccharide b 20 GM1 GD1 etc.

ED MGF MGF Minimum Genome Cell 21 ED)

22 ED)

TG Y Y Y Y 23

2004

/ P 25

( 26

( 18 19 20 20 IgE 20 27

( (1) (2) B 28

( 29

( 2,000 1,500 1,000 500 384 ReoPro Synagis 668 1,607 Rituxan 1,261 Remicade 694 erceptin Zevalin Mylotarg Campath - 50 KT-3 70 Zenapax 50 Simulect 30 44 19 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2003 umira 30 Xolair

31 Stage Phase III Phase II Phase I Total 11 3 20 60 35 129 4 0 1 7 5 17 5 1 9 25 13 53 0 1 2 15 6 24 2 1 8 4 6 21 0 0 0 9 5 14 Chimera umanized uman Mouse thers PharmaProject (2003 1 (

32 (

( 33

( ADCC Asn - - 34

ADCC ( 35

( 36

/ ( vial MCB/WCB 37

( 38

4 kl Pacific Biologics ( 39

( 40

( 8 kl CM 0.9 kl x 7 2.5 kl x 2 10 kl x 8 Pacific Biologics CM 4 kl 41

42

43