Monoclonal Antibodies For Cancer Therapeutics LG CDR Variable

Monoclonal Antibodies For Cancer Therapeutics LG생명과학연구소 박영우

항체 CDR Variable region (V) C C 1 sc. Fv C 1 C C 2 C 3 Constant region (C) C C 1 Fab

Specific Targeting Macrophage Attack (ADCC) Complement Attack (CDC) Stability Ig. G 1: 23 days New Function

Therapeutic Effect of Monoclonal Antibody • Blocking cell activity and immune functions • Activating cell activity and immune functions • Delivering therapeutic agents

ANTIBODY의 작용 기작 Isotope Toxin Chemicals Cytokine (ex. IL 2 등) Killing effect (Herceptin, Retuxan) host immune system kine 의 활성억제 및 제거 icade, Xolair, Anti-VEGF) B Neutralizing antibody 타겥 분자를 inactivation 시킴 (Antagonistic Ab) 타겥 분자를 activation 시킴 (Agonistic Ab) livery A

Technology Improvement From Mouse Ab Chimeric Ab Mouse Ab From Humanized Ab Human Ab

항체 제조 핵심기술 보유회사 HYBRIDOMA (Standard) 면역 (쥐) B CELL Mouse m. Ab Humanize 면역 (쥐) Transgenic Mouse 면역 (쥐) Human Naive LIBRARY HYBRID m. Ab (mouse) B CELL HYBRID m. Ab (human) CDR graft (Modeling)

시장 및 개발현황 Anti-EGFr Anti-VEGF HUMIRA 2003 2002 Zevalin 2001 Campath 2000 Mylotarg 1998 Simulect Synagis 1997 Rituxan Zenapax 1995 Panorex 1994 Reo. Pro Humanization 1986 OKT 3 Chimerization 1985 Hybridoma 1975 Yeast Display Transgenic Mice Phage Display Anti-cancer mab RA Affinity increase Yeast Display Fully Human Phage Display Remicade Herceptin

FUTURE TREND FULLY HUMAN ANTIBODY

LG ANTIBODY LIBRARY HIGH QUALITY, ULTRADIVERSITY GENE POOL 100, 000, 000 TRANSFORMANTS -ⅱ-

sc. Fv HIGH QUALITY 1011 different phage pool

PANNING OPGL

BINDING OPGL

WASHING OPGL

ELUTION OPGL

AMPLIFICATION

OPGL PANNING RESULT OPGL 3. 50 3. 00 ELISA signal 2. 50 2. 00 1. 50 1. 00 0. 50 0. 00 1 st 2 nd Panning 3 rd 4 th MYC control

INDIVIDUAL CLONE ANALYSIS (4 TH PANNING) Fully Human Anti-OPGL sc. Fv fragment 6. 000 5. 000 4. 000 3. 000 Hybridoma clones 2. 000 ~109 n. M 1. 000 0. 000 #1 #3 #8 #9 #12 #21 #22 #23 2 E 2 7 A 2

Anti Cancer Targets

Target Discovery by Genome-Wide Expression Profiling

Target Discovery by Expression Profiling Tissue Samples Expression Database Data Analysis Gene List Target Prioritization Expression Validation Target Validation

Affymetrix Gene. Chip Technology Human Genome U 133 Probe Set PM : perfectly complementary to a target sequence MM : identical to PM except for a single base mismatch in its center Probe pair Cell * The difference in hybridization signals between PM and MM serve as indicators of specific target abundance.

LG GI Cancer Database LGLS Proprietary Gastrointestinal Tract Cancer Genome DB (106 tissue samples). Gene. Chip Analysis Clinical Samples LG GI Cancer Database Stomach Liver Pancreas Normal Hyperplastic Polyp Epithelial Dysplasia Early Gastric Cancer Advanced Gastric Cancer Normal Chronic Hepatitis Liver Cirrhosis Hepatocellular Carcinoma IH Cholangiocarcinoma GB Cancer Normal Chronic Pancreatitis Adenocarcinoma IPMT Solid Papillary Neoplasm

PCA of Liver Samples Normal Hepatocellular Carcinoma Chronic Hepatitis Liver Cirrhosis

PCA of Stomach Samples Normal Adenocarcinoma Chronic inflammation Epithelial dysplasia Signet ring cell carcinoma Hyperplastic polyp

Novel Genes Associated with Cancers LBFL 109 : GTPase activating protein LBFL 110 : Receptor LBFL 123 : Transporter LBFL 131 : Membrane protein LBFL 164 : Kinase LBFL 167 : Intracellular signaling molecule LBFL 169 : Transporter LBFL 301 : Secreted protein LBFL 302 : Transcription factor LBFL 303 : Transporter LBFL 304 : Protease ? LBFL 305 : Kinase LBFL 306 : ANK repeat LBFL 307 : Membrane protein LBFL 308 : Transferase LBFL 309 : Membrane protein LBFL 310 : Membrane protein LBFL 312 : Similar to rat embigin (proliferation / differentiation) LBFL 313 : Secreted protein LBFL 314 : Calpain homolog (migration / proliferation) LBFL 315 : Isomerase

Human Cancer Genome DB Processed DB of Gene Logic’s Oncology Datasuite (1, 094 tissue samples). Breast Cervix Colon Duodenum Endometrium Esophagus Kidney Liver Lung Lymph Node Myometrium Ovary Pancreas Prostate Rectum Skin Stomach Gene. Chip Analysis Normal vs Cancer Oncology Datasuite* Data Mining Cancer Related Genes

Tissue samples used in Gene Logic’s Oncology Datasuite

IL 2 R (LYMPHNODE) IL 2 RG Immunotoxin approach to anti. IL 2 RA in HD BREAST CERVIX DUOD ESOPH COLON ENDOM IL 2 RA IL 2 RB KIDNEY LUNG LIVER LYMPH OVARY MYOM PANC RECTUM PROST SKIN STOMACH

KIDNEY Clear Cell & Renal Cell Carcinoma specific N CCA OC RCC KIDNEY TNFAIPx Clear Cell Carcinoma Renal Cell Carcinoma BREAST CERVIX DUOD ESOPH COLON ENDOM GPRxx KIDNEY LUNG LIVER LYMPH OVARY MYOM PANC RECTUM PROST SKIN STOMACH

KIDNEY Oncocytoma specific N CCA OC RCC KIDNEY gene 1 BREAST CERVIX DUOD ESOPH COLON ENDOM gene 2 gene 3 KIDNEY LUNG LIVER LYMPH OVARY MYOM PANC RECTUM PROST SKIN STOMACH

LYMPHNODE PANCREASE KIDNEY LUNG LIVER N AC BREAST CERVIX DUOD ESOPH COLON ENDOM KIDNEY N HD ML DUOD N CCA OC RCA BREAST N ID IDL IL CXCR family LYMPH OVARY MYOM PANC RECTUM PROST SKIN STOMACH

GENE 1 (BREAST)

LG ANTIBODY LIBRARY & Related Platform Technology LG GI Cancer Database Gene Logic’s Oncology Datasuite Bioinformatics Target Selection & Validation Collaboration 서울대 암연구소 유전체 사업단 Therapeutic and diagnostic Antibody