А.Улитин, ООО "Мепротек"
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Transcript of А.Улитин, ООО "Мепротек"
“Терапевтические моноклональныеантитела - основной базис современных биологических
лекарств”.
Улитин А.Б., директор по науке компании «Мепротек», Пущино, Россия
# Product (Company) WWSales($ m)
1 Enbrel (Amgen) 5,982
2 Rituxan (Genentech) 5,082
3 Humira (Abbott) 4,521
4 Avastin (Genentech) 4,479
5 Herceptin (Genentech) 4,394
6 Remicade (J&J) 3,748
7 Gleevec (Novartis) 3,700
8 Neulasta (Amgen) 3,318
9 Lantus (Sanofi-Aventis) 3,159
10 Aranesp (Amgen) 3,137
# Product (Company) WWSales($ m)
1 Avastin (Roche) 9,232
2 Humira (Abbott & Eisai) 9,134
3 Rituxan (Roche) 7,815
4 Enbrel (Wyeth, Amgen & Takeda)
6,583
5 Lantus (Sanofi-Aventis) 6,386
6 Herseptin (Roche) 5,796
7 Crestor (AstraZeneca) 5,739
8 Spriva (Boehringer Ing.) 5,552
9 Remicade (SGP, J&J, MTP) 5,220
10 Gleevec (Novartis) 5,136
TOP BIOTECH DRUGSSold in 2008 Estimated for 2014
Source: FierceBiotech, BioWorld, EP Vantage
Antibody companies
• Big Pharma• Pfizer• Hoffmann–La Roche
(Genentech) • Sanofi (Genzyme)• Novartis• Merck Co• Amgen• AstraZeneca (Medimmune)• Biogen Idec• Abbott Labs• Merck Serono• Bristol-Myers Squibb
(Medarex)• Takeda Pharmaceutical
(Millennium) • Chugai Pharmaceutical Co• Centocor Ortho Biotech Inc.• and other
• Antibody Technology• PDL Biopharma• Morphosys• Regeneron• Seattle Genetics• Kirin• Lonza• Elan Co• Ablynx• Dyax• Xoma• Xencor• Celltech• Micromet• Affimed• ImmunoGen Inc.• MSM/Meprotek• and many other
Infliximab and adalimumab
ADCС by macrophagesand NK
Macrophage or NK
Rituximab
B-cell
Complement-mediated lysis
CD20
Signalling leadingto apoptosis
Rituximab
Treatment of rheumatoidarthritis, psoriatic arthritis, Crohn’s disease
Treatment of B-cell lymphomas, leukemiasand rheumatoid arthritis
Antibody therapy mechanisms of action
TNF receptor
Infliximab or adalimumab
Soluble TNF ligand
Blocking of TNF ligand- receptorinteraction
Immune or endothelian cell
IL6 receptor
Tocilizumab
Immune or endothelian cell
IL6 ligand
Blocking of IL6 receptor- ligandinteraction
Treatment of rheumatoidarthritis, psoriatic arthritis,Crohn’s disease
CH1
VL
VH
paratope
Affinity and specifityoptimization
Decreasing of immunogenicityCL
CH2
CH3Enhancing effectorFunction (ADCC and CDC)by improved binding to FcγIIIaand FcγIIa affinity
Increasing serum half-life by altering the FcRn binding affinity
Enhancing thermostability, solubility and aggregation resistance
Next generation antibody properties
Improve anti-cancer therapy by enhancing innate effector function and adaptive anti-tumor responses
Improved dosing and frequencyof administration
Decreasing of side effects and increasing the therapy efficiency
Increased therapeutic benefits and decreased side effects
Improving the production and keeping of antibody drug
Antibody fragment drug format – “magic bullet”
scFv
VH VL
Radionuclide conjugate
Immunotoxin
scFv1 scFv2
Bispecific format
Ig Oligomers
Immunocytokine
paratope
Fab
IgG
Nano-delivery conjugate
Antibody gene
scFvor Fab
900 nm
12 nm
Phage antibody particle
Phage display libraries
1011 antibody structures
~1 ml tube
immune potential of hundreds people
Sources of new antibody drugs –antibody phage display libraries.
• World class expertise for the discovery of functional humanantibodies directed to multi-spanning membrane proteins
• Discovery platform based upon world-class scFv and Fab phagelibraries and the MPL and SIMPL® presentation of the target.
• Science team: 20 People (18 hold Dr. Sci., Ph.D. or M.S. degree)
• Laboratories: Pushchino, Moscow Region, Russia; fully enabledfor molecular biology, cell biology, biochemistry, and phagedisplay technologies. Pushchino is a Russian Center for BiomedicalStudies
• Established 2006
Company Overview:
MAB Drug Discovery CollaborationsPartner Company Year Status
1. Cambridge Antibody Technologies (CAT)
2005 Delivered
2. Astra Zeneca 2006 Delivered3. ESBAtech 2007 Delivered4. Cystic Fibrosis Therapeutics
Foundation (CFFT) 20082009
Completed, Ph.ILaunched, Ph.II
5. Merck Serono 2009 Ongoing6.7.
DebioPharmMicrogen
20092010
OngoingCompleted
Meprotek (Puschino)Antibody EngineeringPhage display
MSM ProteinTechnologies (Boston)Cell biologyBiochemistry
Meprotek (Puschino)15 highly qualified scientists
MSM ProteinTechnologies (Boston)12 highly qualified scientists
Cross Training and Sharing of Technologies
Meprotek’s Cell lines over-expressing GPCRs (>1 mln copies/cell)SIMPL platform technology
Staining with fully humanIgGs generated by Meprotek(followed by IgG-FITC or PE)
Target Presentation: Magnetic ProteoLiposome (MPL)GOLIK platform technology
CellAntigen: 1/10,000of total protein
Membrane1/500 of total protein
MPLEssentially pure antigen
MSM-protein antigen in MPL:- In the native state- In the right orientation- Pure - Highly concentrated
Proprietary State of the Art scFv and Fab Libraries
Complexity: ~1011(scFv), and ~ 1011 (Fab)
Type: Synthetic, major VH and VK human germline framework.
Design: Specifically designed to target GPCRs, ion channels and transporters
Easy affinity maturation
Validation: Five major drug target multi-spanners, few water-soluble targets. Sub-nanomolar affinities with few targets in initial screenings (before affinity maturation). Cross-reactivity – Human-cyno-mouse cross-reactive MABs have been selected for several under validation targets
# Company LibraryFormat
Repertoire Affinities, Primary, Kd (M) a)
Affinities, Maturated, Kd (M) a)
1 Genentech, (Roche) Synthetic, Fab 1011 10-8-10-10 10-10-10-11
2 GSK, (Domantis) Synthetic, VH >1010 unknown unknown
3 AstraZeneca (CAT) Natural, ScFv 1011 10-7-10-9 10-9-10-11,
4 Morphosys(Novartis)
Synthetic, Fab >1010 10-8-10-10 10-10-10-12
5 Dyax Semisynthetic, Fab ~1011 10-7-10-10 unknown
6 Ely Lilly (ImClone) Natural, Fab >1010 10-7-10-8 10-9-10-10
7 BioInvent Semisynthetic, scFv >109 10-6-10-9 unknown
8 Merck Synthetic, Fab 1010 10-7-10-10
9 Pfizer (Rinat) Native, scFv, 4x1010 unknown unknown
10
MEPROTEK Synthetic, scFvSynthetic, Fab
1011
101110-7-10-9
10-7-10-9 (GPCRTargets)
10-8-10-10
10-8-10-10(GPCRTargets)
Principal Antibody Libraries in Pharma Industry
Different functional (epitope) IgGcandidates against any GPCR target
Chem-1 cells were grown overnight 37°C, 5%CO2 (cell culture media – DMEM/F12 with G418 and 10% serum).
Before the Ca-flux measuring cells were starved in serum-free media (CHO-S-SFM II) 3h, 37°C, 5%CO2, and then were loaded with dye (Calcuim-5 kit) with (squares and circles) or without (triangles) IgG 30min, 37°C, 5%CO2.
Ligand1 and 2 (R&D) in TBS was added to dye-loaded cells to reach concentrations 15nM or 30nM respectively.
Inhibition was calculated as function:
where I – mean peak value in inhibited samples, C – mean peak value in control samples.
1 μM R1IgG1 μM R2IgG
1 μM R3IgG
1 μM R4IgG
1 μM R1IgG1 μM R2IgG
1 μM R3IgG
1 μM R4IgG
Ligand1 inhibition
Ligand2inhibition
Mol BiolMol Biol
Polimorph.Syn Genes:HumanCynoMouseLigandsVectors
Cell BiolCell Biol
Cell Lines:3-5 Human1 Cyno1 Mouse
BiochemBiochem
Target Presentation:MPLsSIMPL
F library scFvFab selectionF library scFvFab selection IgGIgG Affinity
Maturat.Affinity
Maturat.
Final 3-5 IgGs:
1. Functional antagonists/agonists2. Cyno cross-reactivity3. High affinity (10-9-10-10 M range)4. Thermo-, Proteolytic, & Aggregation Stable5. High specifity6. Well expressed7. 20-200 mgs
Final 3-5 IgGs:
1. Functional antagonists/agonists2. Cyno cross-reactivity3. High affinity (10-9-10-10 M range)4. Thermo-, Proteolytic, & Aggregation Stable5. High specifity6. Well expressed7. 20-200 mgs
30-250 Unique binders
20-50Unique IgGs
5-10 IgGsusing MPLs
Antibody Generation Work Flow
~18 months,~10 FTE
(Depends on target)
~18 months,~10 FTE
(Depends on target)
Proven TechnologyStage MAB format
Pre-Clinical 3 IgGs
Selection of LeadCandidates
5 ScFv/Fab/IgG
Generation of Lead Candidates
6 ScFv/Fab
Meprotek – Summary
• Validated platform technology: World-class Fab and scFvLibraries and unique GOLIK and SIMPL® presentations for GPCRsand other complex membrane proteins.
• We deliver functional fully human monoclonal antibodies targeting GPCRs at the level of lead drug candidates.
• Skilled scientific team trained in Boston in the company’s proprietary technology.
• Fully equipped labs in Pushchino, Russia.
• Matrix management between Puschino and Boston with frequent interactions and information exchange.
• Meprotek has played a major role in successful collaborations with major international biopharmaceutical companies.