Immunity [Innate and Acquired Immunity]

Biotechnology

RED: Medical Area

GREEN: Agriculture/Food Science

WHITE: Bioprocess Engineering

20th Century: Physical Science

21st Century: Life Science

21st Century: Integrated Science

BIO is at the core !

Areas at the interface

BIO

Physics

Chemistry

Mathematics

Nanotechnology

IT & ETEngineering

Drug Development- clinical trials

phase I: 25-45 healthy volunteers [safety evaluation] phase II: 20-150 diseased individuals

[safety and efficacy]phase III: hundreds to thousands patients

multi-center, double-blind, placebo-controlled randomized clinical trial (RCT)

protocol phase IV: vigilant post-marketing surveillance

- toxicity : major cause of drug rejection

Biotech. Industry

Revenue($b)

Year% ofHealth caretotal

% ofPharmaceuticals

% ofBiotechnology

Growth rate

Health care total 2,467 (2003)

Pharmaceuticals 592 (2003) 24.0 8.8 (02-03)

Biotechnology 41 (2002) 1.7 6.9 15.0 (01-02)

Antibody 7 (2003) 0.3 1.2 17.1 38.0 (01-02)

Biotech. & Pharm.

Revenue($m)

Revenueperemployee($000)

R&Dexpenses($m)

R&Dexpensesperemployee($000)

R&Dexpenseas %of revenue

Netincome(loss)($m)

Employees

Marketcap12.31.02($m)

Marketcap/revenue

BiotechAmgen 5,523 547 1,117 111 20 1,600 10,100 62,217 11.3Genentech 2,618 498 623 119 24 64 5,252 17,067 6.5Genzyme 1,329 237 308 55 23 -13 5,600 6,477 4.9Chiron 1,172 290 326 81 28 226 4,044 7,037 6.0Biogen 1,148 436 368 140 32 199 2,633 5,972 5.2Medimmune 848 528 144 90 17 81 1,605 6,820 8.0Gilead Sciences 467 374 135 108 29 72 1,250 6,687 14.3Biovail 788 415 52 27 7 256 1,900 4,146 5.3Weighted average 429 95 22 8.4

PharmaBristol-Myers Squibb 18,119 412 2,218 50 12 2,235 44,000 44,843 2.5Eli Lilly 11,078 254 2,149 49 19 2,792 43,700 71,334 6.4J onhson & J ohnson 36,298 335 3,957 37 11 6,786 108,300 159,550 4.4Merck & Co 21,631 356 2,677 44 12 6,786 60,800 127,121 5.9Pfizer 32,373 360 5,176 58 16 9,126 90,000 188,337 5.8Weighted average 345 47 14 4.9

CJ ($, 2003) 3,927 140 3,719 0.9

Beyond Borders

The Global Biotechnology Report 20003

Ernst & Young

Biotech. & Pharm.

Biological drugs in Pharm.

Drug approvals

Antibody drugs항체약품 저분자 화합물 약품

전임상 이전 개발 기간 1-2 년 5 년개발 비용 2 백만불 20 백만불부작용 예측 쉽다 . 어렵다 .개발 실패 드물다 . 가끔 있다 .

전체적 특성독성 드물다 . 예측하기 힘들다 .라이선스판매 임상 I 이후 임상 II 이후성공율 20% 5% 이하

한 공장에서여러 약품 생산긴 반감기 .

생산비 $100-300 /g 매우 낮다 .

Biological drugs

ClassSales(2001 $ m)

Sales(2002 $ m)

Growth(01-02, % )

MarketShare(2002)

Erythropoietin 6702 8426 26 25

Interferons 3923 5731 46 17

Insulin 3949 4400 11 13

Monoclonal antibodies 2997 4150 38 12

Blood factors 3188 3565 12 11

Colony stimulating factors 2059 2739 33 8

Growth hormones 1652 1703 3 5

Interleukins 173 213 23 1

Growth factors 108 123 14 0

Therapeutic vaccines 50 68 36 0

Others(calcitonins, enzymes, TNF)

2080 2222 7 7

Total 26881 33340 24 100

Antibody industry

Revenue($b)

Year% ofHealth caretotal

% ofPharmaceuticals

% ofBiotechnology

Growth rate

Health care total 2,467 (2003)

Pharmaceuticals 592 (2003) 24.0 8.8 (02-03)

Biotechnology 41 (2002) 1.7 6.9 15.0 (01-02)

Antibody 7 (2003) 0.3 1.2 17.1 38.0 (01-02)

Antibody industry

• More than 400 antibodies are in clinical trial currently.

• The annual sale of biological drugs in 2003 was $30 billion.

• The annual sale of therapeutic antibodies in 2003 was $7.2 b

illion. (Monoclonal Antibody Therapeutics - Current Market Dynamics & Future Outlook, AS Insights, June 1, 2004)

• More than 100 antibodies will be approved before 2010. (V. Bryan Lawlis, Diosynth ATP in Cary, NC)

• The market size of antibodies will be $26 billion in 2010. (Monoclonal Antibody Therapeutics - Current Market Dynamics & Future Outlook, AS Insights, June 1, 2004)

0

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Adams, Harkness & Hill (2001)

허가 받은 항체 약품 수 판매액 (백만불)

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Approved Therapeutic Abs

Antibody Target Indication Sales Producer (million $)

OKT3 CD3 Acute kidney transplantation rejection (Ortho Biotech/J & J)Digibind Digoxin Digoxin poisoning (Glaxo/Welcome)Herceptin HER- 2 Metastatic.breast cancer 424.8 (03) (Genentech/MedImmune)

117.7(2Q/04)Zenapax IL2 R-a Kindney transplantation rejection (Protein Design Labs/Roche)Simulect IL2 R-a Acute organ rejection (Norvatis)

Rituxan CD20 Non-Hodgkin’s lymphoma 1,489.1 (03) (Genentech/Roche) * 424.7(2Q/04)

Panorex CA17-1A Colorectal cancer (GlaxoSmithKline / Centocor)Remicade TNFa Crohn’s disease & Rheumatoid arthritis 409.0 (02) (Centocor/Schering-Plough) *Reopro Platelet Ischemic cardiac complications 431.0 (02) (Centocor/Eli Lilly) * Synagis RSV RSV infection 849.0 (03) (MedImmune)

Mylotarg CD33 Relapsed CD33-positive AML (calicheamin) (Celltech/Wyeth-Ayerst)Campath CD52 B cell CLL (Millenium Ph/Schering AG)Zevalin CD20 Non-Hodgkin’s lymphoma (I111 & Y90) (IDEC)Humira TNF Rhematoid arthritis 149.0(1Q/04)(Abbot)Xolair IgE Asthma 30.0(1Q/04)(Genentech/Novartis)

Bexxar CD20 Non-Hodgkin’s lymphoma (I131) 132.0 (03) (Corixa/Glaxo-SmithKline) Raptiva CD11a Mod.. severe plaque psoriasis, psoriatic arthritis 6.3(1Q/04)(Xoma/Genentech)Avastin VEGF Metastatic carcinoma of the colon or rectum 133.0(2Q/04)(Genetech)Erbitux EGFR EGFR-expressing, metastatic colorectal cancer 17.5(1Q/04)(Brystol-Myer-Squibb, Imclone)

Embrel TNF RA, Polyarticular juvenile RA, psoriatic arthritis, 397,0(1Q/04)(Amgen)ankylosing spondylitis, psoriasis

Murine Antibody Chimeric AntibodyHumanized Antibody

Hypervariable and framework regions --- Complementarity determining regions (CDR)

The market for therapeutic The market for therapeutic

antibodies is exponentially antibodies is exponentially

growing !!growing !!

Chronicle of Therapeutic Abs

Source: Duckworth J, Fisken J, “Investing in new therapeutic technologies.” Current Drug Discovery. 2002;2:29–32. Reprinted with permission.

Sources of Therapeutic Abs

1.1. Human B cell (Recombinant DNA technology)Human B cell (Recombinant DNA technology)• Source of B cell (amount, validation)

• Ethical Issues on Immunization

2. Hybridoma technology2. Hybridoma technology• Mouse immunization

• Limited Screening

• HAMA (human anti-mouse antibody response) effect Ab engineering required

3. Phage display3. Phage display• Naive, immunized and synthetic libraries

4. Immunized animal4. Immunized animal• Immunogenecity problem

Phage display

• Higher chance of good clone selection

Process for Ther. Ab develop.Target Discovery

- Genomics- Proteomics

Antibody Generation

- Naïve- Immunized

- Fab- scFv- Domain

New format - Andrea’s group - Plastibody

Conformationof antigen

Polishing

- Phage- Phagemid- Non-biological

Affinity maturation

Localization

Half life extension

- Drug conjugate- Isotope labeling- Enzyme labeling (ADEPT)- Bispecific

Production

Mammalian - Prokaryotic- Plant- Transgenic chicken

- Cell panning (Raven, Affitech’s CBAS, Health Canada)- Antibody repertoire directed- Animal model based (Lexicon)

Pre- & clinical TrialEvery good antibody can be a drug!

Humanization