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А.Улитин, ООО "Мепротек"
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А.Улитин, ООО "Мепротек"


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  • 1. “Терапевтические моноклональные антитела - основной базис современных биологических лекарств”.Улитин А.Б., директор по науке компании «Мепротек», Пущино, Россия
  • 2. TOP BIOTECH DRUGS Sold in 2008 Estimated for 2014# Product (Company) WW # Product (Company) WW Sales Sales ($ m) ($ m)1 Enbrel (Amgen) 5,982 1 Avastin (Roche) 9,2322 Rituxan (Genentech) 5,082 2 Humira (Abbott & Eisai) 9,1343 Humira (Abbott) 4,521 3 Rituxan (Roche) 7,8154 Avastin (Genentech) 4,479 4 Enbrel (Wyeth, Amgen & 6,583 Takeda)5 Herceptin (Genentech) 4,394 5 Lantus (Sanofi-Aventis) 6,3866 Remicade (J&J) 3,748 6 Herseptin (Roche) 5,7967 Gleevec (Novartis) 3,700 7 Crestor (AstraZeneca) 5,7398 Neulasta (Amgen) 3,318 8 Spriva (Boehringer Ing.) 5,5529 Lantus (Sanofi-Aventis) 3,159 9 Remicade (SGP, J&J, MTP) 5,22010 Aranesp (Amgen) 3,137 10 Gleevec (Novartis) 5,136 Source: FierceBiotech, BioWorld, EP Vantage
  • 3. Antibody companies• Big Pharma • Antibody Technology• Pfizer • PDL Biopharma• Hoffmann–La Roche • Morphosys (Genentech) • Regeneron• Sanofi (Genzyme) • Seattle Genetics• Novartis • Kirin• Merck Co • Lonza• Amgen • Elan Co• AstraZeneca (Medimmune) • Ablynx• Biogen Idec • Dyax• Abbott Labs • Xoma• Merck Serono • Xencor• Bristol-Myers Squibb • Celltech (Medarex) • Micromet• Takeda Pharmaceutical • Affimed (Millennium)• Chugai Pharmaceutical Co • ImmunoGen Inc.• Centocor Ortho Biotech Inc. • MSM/Meprotek• and other • and many other
  • 4. Antibody therapy mechanisms of action Rituximab Infliximab and adalimumab Tocilizumab Blocking of TNF ligand- receptor Blocking of IL6 receptor- ligand ADCС by macrophages interaction interaction and NKSignalling leading Macrophage or NK IL6 ligandto apoptosis TNF receptor Infliximab or adalimumab B-cell IL6 receptor CD20 Immune or Immune or Rituximab endothelian cell endothelian cell Soluble TNF ligand Complement-mediated lysisTreatment of B-cell Treatment of rheumatoid Treatment of rheumatoidlymphomas, leukemias arthritis, psoriatic arthritis, psoriaticand rheumatoid arthritis arthritis, Crohn’s disease arthritis,Crohn’s disease
  • 5. Immunoglobulin G and antibody fragments VH VL VH VL scFv 30kDa 150kDa Fab 55 kDa
  • 6. Next generation antibody properties Affinity and specifity Increased therapeutic benefits and optimization decreased side effects paratope VLDecreasing of immunogenicity VH Enhancing thermostability, CL solubility and aggregation CH1 resistanceDecreasing of side effects andincreasing the therapy efficiency CH2 Improving the production and keeping of antibody drug Enhancing effector CH3 Function (ADCC and CDC) Increasing serum half-life by by improved binding to FcγIIIa altering the FcRn binding and FcγIIa affinity affinity Improve anti-cancer therapy by Improved dosing and frequency enhancing innate effector function of administration and adaptive anti-tumor responses
  • 7. Antibody fragment drug format – “magic bullet” paratope IgG Fab Ig Oligomers VH VL scFv Radionuclide conjugateNano-delivery conjugate Immunotoxin scFv1 scFv2 Bispecific format Immunocytokine
  • 8. Sources of new antibody drugs – antibody phage display libraries. Phage antibody particle Phage display libraries scFv or Fab 1011 antibody structures immune potential of hundreds people Antibody900 nm gene 1 ml tube ~ 12 nm
  • 9. Company Overview:• World class expertise for the discovery of functional human antibodies directed to multi-spanning membrane proteins• Discovery platform based upon world-class scFv and Fab phage libraries and the MPL and SIMPL® presentation of the target.• Science team: 20 People (18 hold Dr. Sci., Ph.D. or• Laboratories: Pushchino, Moscow Region, Russia; fully enabled for molecular biology, cell biology, biochemistry, and phage display technologies. Pushchino is a Russian Center for Biomedical Studies• Established 2006
  • 10. MAB Drug Discovery Collaborations Partner Company Year Status1. Cambridge Antibody 2005 Delivered Technologies (CAT)2. Astra Zeneca 2006 Delivered3. ESBAtech 2007 Delivered4. Cystic Fibrosis Therapeutics 2008 Completed, Ph.I Foundation (CFFT) 2009 Launched, Ph.II5. Merck Serono 2009 Ongoing6. DebioPharm 2009 Ongoing7. Microgen 2010 Completed
  • 11. Cross Training and Sharing of Technologies Meprotek (Puschino) MSM Protein Antibody Engineering Technologies (Boston) Phage display Cell biology Biochemistry Meprotek (Puschino) MSM Protein 15 highly qualified scientists Technologies (Boston) 12 highly qualified scientists
  • 12. Meprotek’s Cell lines over-expressing GPCRs (>1 mln copies/cell) SIMPL platform technology Staining with fully human IgGs generated by Meprotek (followed by IgG-FITC or PE)
  • 13. Target Presentation: Magnetic ProteoLiposome (MPL) GOLIK platform technology Membrane 1/500 of total proteinCellAntigen:1/10,000of totalprotein MPL Essentially pure antigenMSM-protein antigen in MPL:- In the native state- In the right orientation- Pure- Highly concentrated
  • 14. MPLs Stainedwith Anti-GPCR IgG-PE
  • 15. Proprietary State of the Art scFv and Fab LibrariesComplexity: ~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 maturationValidation: 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
  • 16. Principal Antibody Libraries in Pharma Industry# Company Library Repertoire Affinities, Affinities, Format Primary, Kd (M) a) Maturated, Kd (M) a)1 Genentech, (Roche) Synthetic, Fab 1011 10-8-10-10 10-10-10-112 GSK, (Domantis) Synthetic, VH >1010 unknown unknown3 AstraZeneca (CAT) Natural, ScFv 1011 10-7-10-9 10-9-10-11,4 Morphosys Synthetic, Fab >1010 10-8-10-10 10-10-10-12 (Novartis)5 Dyax Semisynthetic, Fab ~1011 10-7-10-10 unknown6 Ely Lilly (ImClone) Natural, Fab >1010 10-7-10-8 10-9-10-107 BioInvent Semisynthetic, scFv >109 10-6-10-9 unknown8 Merck Synthetic, Fab 1010 10-7-10-109 Pfizer (Rinat) Native, scFv, 4x1010 unknown unknown1 MEPROTEK Synthetic, scFv 1011 10-7-10-9 10-8-10-100 Synthetic, Fab 1011 10-7-10-9 (GPCR 10-8-10-10(GPCR Targets) Targets)
  • 17. 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. Ligand1 Ligand2 Inhibition was calculated as function: inhibition inhibition 1 μM R1IgG 1 μM R1IgG 1 μM R2IgG 1 μM R2IgG where I – mean peak value in inhibited samples, C – mean 1 μM R3IgG 1 μM R3IgG peak value in control samples. 1 μM R4IgG 1 μM R4IgG
  • 18. Antibody Generation Work Flow F library scFv AffinityMol Biol Cell Biol Biochem Fab selection IgG Maturat.Polimorph. Cell Lines: Target 30-250 20-50 5-10 IgGsSyn Genes: 3-5 Human Presentation: Unique Unique usingHuman 1 Cyno MPLs binders IgGs MPLsCyno 1 Mouse SIMPLMouseLigandsVectors Final 3-5 IgGs: ~18 months, 1. Functional antagonists/agonists ~10 FTE 2. Cyno cross-reactivity (Depends on target) 3. High affinity (10-9-10-10 M range) 4. Thermo-, Proteolytic, & Aggregation Stable 5. High specifity 6. Well expressed 7. 20-200 mgs
  • 19. Proven TechnologyStage MAB formatPre-Clinical 3 IgGsSelection of Lead 5 ScFv/Fab/IgGCandidatesGeneration of Lead 6 ScFv/FabCandidates
  • 20. Meprotek – Summary• Validated platform technology: World-class Fab and scFv Libraries and unique GOLIK and SIMPL® presentations for GPCRs and 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.
  • 21. Thank YouМЕПРОТЕК