“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

Immunoglobulin G and antibody fragments

Fab55 kDa

VH VL

scFv30kDa

VH VL

150kDa

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

MPLs Stained with Anti-GPCR IgG-PE

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.

МЕПРОТЕК

Thank You