Mr DE GARIDEL - Ingenierie Moleculaire - Forum Santé 11
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Ingénierie Moléculaire GIPSO 3 EME FORUM NATIONAL DE SANTE BORDEAUX 11 DECEMBRE 2008 Marc de Garidel VP Amgen international Region Sud L‘ innovation en biotechnologie avance vite et prend différentes formes 1) Modification d’une protéine existante 2) Assemblage de molécules 3) Développement de nouvelles molécules 1) Modification d’une protéine existante Darbepoetin αlpha Molecular Structure rHuEPO Darbepoetin Darbepoetin alfa has: Two additional sialic acid–containing carbohydrates (red) Up to 8 additional sialic acids Increased molecular weight (~37,100 daltons) Darbepoetin αlfa Unique molecular structure1 Longer half-life2–4 Greater in vivo biological activity2,5,6 Potential for extended and more convenient dosing schedules2,5,7 associated with possible dose savings ( nephrology) 1. Egrie J et al. Br J Cancer 2001;84(suppl 1):3–10 2. Glaspy J et al. Br J Cancer 2002;87:268–76 3. Heatherington A et al. Br J Cancer 2001;84(suppl 1):11–6 4. Macdougall I et al. J Am Soc Nephrol 1999;10:2392–5 5. Heatherington A et al. Proc ASCO 2001;20:119A 6. Smith R et al. Br J Cancer 2001;84(suppl 1):24–30 7. Vansteenkiste J et al. J Natl Cancer Inst 2002;94:1211–20 Darbepoetin αlfa QW significantly reduced RBC transfusion requirements p<0.001 p<0.001 Patients transfused (%) 70 60 57 50 40 n=158 n=149 52 n=148 n=156 30 20 27 28 10 0 Week 5–EOTP Week 1–EOTP Vansteenkiste J et al. J Natl Cancer Inst 2002;94:1211– 2002;94:1211–20 Darbepoetin alfa (2.25 µg/kg QW) Placebo Li He ght av y What is a Peptibody? vy a He ght Li pe pt id e e d i pt e p 2 Assemblage de molécules Fc Fc • Bioactive peptide fused to human IgG1 Fc Fc Fc • Produced in E. coli Peptibody Resembles antibody in structure but no effector functions Antibody AMG 386 is peptibody designed to neutralize angiopoietins Ang1 Ang2 AMG 386 Tie2 p AMG 386 Angiopoietin Inhibiting Peptibody Hypothesis Angiopoietin axis, like the VEGF axis, is critical for angiogenesis Targeting Ang in combination with chemotherapy or VEGF blockade further improves the benefit/risk ratio in cancer patients Existing evidence/data AMG 386 demonstrated anti-tumor effect in preclinical models either alone or in combination with VEGF inhibitors No MTD established in P1 study Promising clinical activity seen in P1 studies. L S Rosen ASCO 2007 A C Mita ASCO 2007 Le développement de nouvelles molécules peut se faire sous différentes formes Antagoniste d’une cible connue Antagoniste d’une nouvelle cible Agoniste d’une cible connue Agoniste d’une nouvelle cible 3 Antagoniste d’une cible connue: Panitumumab Fully Human MoAb anti-EGFr TGF-2 Panitumumab EGF 100% human protein Cell Proliferation and survival signals, Metastatic potential A fully human lgG2 monoclonal antibody to EGFR ↓ Cell Proliferation High Affinity, KD= 5 x 10-11 M ↓ Cell Survival Inhibits ligand-induced EGFr ↓ Angiogenesis tyrosine phosphorylation ↓ Metastatic spread Fully Human MAbs Are a Recent Development in Hybridoma Technology Mouse Chimeric Humanized Fully Human 100% Mouse Protein 34% Mouse Protein 10% Mouse Protein 100% human Protein Panitumumab + Best Supportive Care vs Best Supportive Care Alone in metastatic ColoRectal Cancer: Progression-Free Survival Event-Free Probability 1.0 0.9 Mean 0.8 Panitumumab + BSC (n=231) 96 days 0.7 BSC (n=232) 60 days 0.6 0.5 0.4 Hazard Ratio = 0.54 (95% CI 0.44, 0.66) 0.3 P < 0.0001 0.2 0.1 0.0 0 Patients at risk: panitumumab 231 BSC 232 8 118 75 16 24 32 40 Weeks from Randomization 49 17 31 7 13 3 5 1 48 1 1 Primary analysis, all randomized analysis set, central radiology. Stratified Log-rank test P <.000000001 Peeters M, et al. Proc Am Assoc Cancer Res. 2006;47:A CP-1; Presentation available at http://www.aacr.org/page6026.aspx# 12 56 4 Antagoniste d’une nouvelle cible RANKL: Denosumab ● Investigational, fully human monoclonal antibody to RANKL ● IgG2 ● High affinity for human RANKL (Kd 3x10–12 M) ● Does not bind to human TNFα, TNFß, TRAIL, or CD40L ● Formerly referred to as AMG 162 ● DENse OSteo (bone) hUman Monoclonal AntiBody Bekker PJ et al. J Bone Miner Res 2004;19:1059–1066 Boyle WJ et al. Nature 2003;423:337–342 Amgen, data on file Mechanism of Action for Denosumab Y Osteoclast Formation, Function and Survival Inhibited by Denosumab denosumab CFU-M Osteoprotegerin Y RANKL Multinucleated Osteoclast Y Growth Factors Hormones Cytokines Y RANK Pre-Fusion Osteoclast Mature Osteoclast Osteoblast Bone Adapted from Boyle WJ, et al. Nature. 2003;423:337-42. RANK ligand is implicated in bone loss across a broad range of conditions Pathological bone loss Treatment-induced bone loss Cancerrelated bone destruction Aromatase inhibitors Glucocorticoids PostMale menopausal osteoporosis osteoporosis Rheumatoid arthritis Glucocorticoidinduced osteoporosis Androgen deprivation therapy Cancer therapy-related bone loss Bone metastases/ multiple myeloma 5 Agoniste Agoniste d’une nouvelle cible connue AMG 531 is a Recombinant Peptibody Stimulates platelets production FC Carrier Domain Peptide Receptor Binding Domain • Comprised of multiple copies of an Mpl-binding peptide that imparts the biological activity • Mpl-binding end is linked to a carrier Fc domain that increases serum half-life • No sequence homology to native TPO • Clearance is by endothelial FcRn and regulated by platelet mass. AMG 531 is being developed for three major health concerns • Immune (idiopathic) Thrombocytopenic Purpura (ITP) • Myelodysplastic Syndrome (MDS) • Chemotherapy-Induced Thrombocytopenia (CIT) 6 Agoniste d’une cible nouvelle: AMG 655 TRAIL Receptor-2 Agonist Fully Human Monoclonal Antibody Induce Apoptosis Existing data: Preclinical single agent activity in multiple tumor models (NSCLC, colorectal, pancreas) and cooperativity with chemotherapy TR-2 Ab TR-1 TR-2 Encouraging First-in-Human data P LoRusso ASCO 2007 FADD Caspase-8, 10 Caspase-3, 9 Apoptosis Tumor Necrosis Factor – Related Apoptosis – Inducing Ligand AMG 655 Apo2L/TRAIL Y TR-1 TR-2 TR-3 TR-4 DR4 DR5 DcR1 DcR2 Death Receptors “death domains” OPG Decoy Receptors FADD Caspase-8, 10 TR-1 and TR-2 Contain death domains Induce apoptosis Caspase-3, 6, 7 Apoptosis TR-3, TR-4 and OPG Lack death domains La galénique de ces produits de Biotech Lors de la fabrication tenir compte des spécificités de ces produits ( cycle de lyophilisation , temps de stockage ; filtration ) En majorité des solutions sensible à la chaleur , a la lumière et à l’agitation L’apparition possible d’agrégat peut exiger l’utilisation de filtres lors de l’administration Dispositif de sécurité d’aiguille pour éviter tout risque de contamination
