1. 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

3. Biotech. Industry

4. Biotech. & Pharm.

6. Biological drugs in Pharm.

7. Drug approvals

8. Antibody drugs 항체약품 저분자 화합물 약품 전임상 이전 개발 기간 1-2 년 5 년 개발 비용 2 백만불 20 백만불 부작용 예측 쉽다. 어렵다. 개발 실패 드물다. 가끔 있다. 전체적 특성 독성드물다. 예측하기 힘들다. 라이선스판매 임상 I 이후 임상 II 이후 성공율 20% 5% 이하 한 공장에서 여러 약품 생산 긴 반감기. 생산비 $100-300 /g 매우 낮다.

9. Biological drugs

11. Antibody industry

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

14. Approved Therapeutic Abs AntibodyTarget IndicationSalesProducer (million $) OKT3CD3Acute kidney transplantation rejection (Ortho Biotech/J & J) DigibindDigoxinDigoxin poisoning (Glaxo/Welcome) Herceptin HER- 2 Metastatic.breast cancer 424.8 (03) (Genentech/MedImmune) 117.7(2Q/04) ZenapaxIL2 R-aKindney transplantation rejection (Protein Design Labs/Roche) SimulectIL2 R-aAcute organ rejection (Norvatis) RituxanCD20Non-Hodgkin’s lymphoma1,489.1 (03) (Genentech/Roche) * 424.7(2Q/04) PanorexCA17-1AColorectal cancer (GlaxoSmithKline / Centocor) RemicadeTNFaCrohn’s disease & Rheumatoid arthritis 409.0 (02)(Centocor/Schering-Plough) * ReoproPlateletIschemic cardiac complications 431.0 (02)(Centocor/Eli Lilly) * SynagisRSVRSV infection 849.0 (03)(MedImmune) MylotargCD33Relapsed CD33-positive AML (calicheamin) (Celltech/Wyeth-Ayerst) CampathCD52B cell CLL (Millenium Ph/Schering AG) Zevalin CD20Non-Hodgkin’s lymphoma (I111 & Y90) (IDEC) HumiraTNFRhematoid arthritis 149.0(1Q/04)(Abbot) Xolair IgEAsthma 30.0(1Q/04)(Genentech/Novartis) BexxarCD20Non-Hodgkin’s lymphoma (I131) 132.0 (03)(Corixa/Glaxo-SmithKline) RaptivaCD11aMod.. severe plaque psoriasis, psoriatic arthritis 6.3(1Q/04)(Xoma/Genentech) AvastinVEGFMetastatic carcinoma of the colon or rectum 133.0(2Q/04)(Genetech) ErbituxEGFREGFR-expressing, metastatic colorectal cancer 17.5(1Q/04)(Brystol-Myer-Squibb, Imclone) EmbrelTNFRA, Polyarticular juvenile RA, psoriatic arthritis, 397,0(1Q/04)(Amgen) ankylosing spondylitis, psoriasis Murine Antibody Chimeric Antibody Humanized Antibody

15. The market for therapeutic antibodies is exponentially growing !!

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

17. Sources of Therapeutic Abs 1.Human B cell (Recombinant DNA technology) Source of B cell (amount, validation) Ethical Issues on Immunization 2. Hybridoma technology Mouse immunization Limited Screening HAMA (human anti-mouse antibody response) effect  Ab engineering required 3. Phage display Naive, immunized and synthetic libraries 4. Immunized animal Immunogenecity problem

18. Higher chance of good clone selection

19. Process for Ther. Ab develop. Target Discovery - Genomics - Proteomics Antibody Generation - Naïve - Immunized - Fab - scFv - Domain New format - Andrea’s group - Plastibody Conformation of 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 Trial Every good antibody can be a drug! Humanization