Keppel Ltd. 1Q 2024 Business Update Presentation Slides
А.Улитин, ООО "Мепротек"
1. “Терапевтические моноклональные
антитела - основной базис
современных биологических
лекарств”.
Улитин А.Б., директор по науке компании «Мепротек», Пущино, Россия
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 NK
Signalling leading Macrophage or NK
IL6 ligand
to 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 lysis
Treatment of B-cell Treatment of rheumatoid Treatment of rheumatoid
lymphomas, leukemias arthritis, psoriatic arthritis, psoriatic
and rheumatoid arthritis arthritis, Crohn’s disease arthritis,Crohn’s disease
6. Next generation antibody properties
Affinity and specifity Increased therapeutic benefits and
optimization decreased side effects
paratope
VL
Decreasing of immunogenicity VH Enhancing thermostability,
CL solubility and aggregation
CH1 resistance
Decreasing of side effects and
increasing 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 conjugate
Nano-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
Antibody
900 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 M.S.
degree)
• 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 Status
1. Cambridge Antibody 2005 Delivered
Technologies (CAT)
2. Astra Zeneca 2006 Delivered
3. ESBAtech 2007 Delivered
4. Cystic Fibrosis Therapeutics 2008 Completed, Ph.I
Foundation (CFFT) 2009 Launched, Ph.II
5. Merck Serono 2009 Ongoing
6. DebioPharm 2009 Ongoing
7. 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 protein
Cell
Antigen:
1/10,000
of total
protein
MPL
Essentially
pure antigen
MSM-protein antigen in MPL:
- In the native state
- In the right orientation
- Pure
- Highly concentrated
15. 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
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 10-10-10-11
2 GSK, (Domantis) Synthetic, VH >1010 unknown unknown
3 AstraZeneca (CAT) Natural, ScFv 1011 10-7-10-9 10-9-10-11,
4 Morphosys Synthetic, Fab >1010 10-8-10-10 10-10-10-12
(Novartis)
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
1 MEPROTEK Synthetic, scFv 1011 10-7-10-9 10-8-10-10
0 Synthetic, Fab 1011 10-7-10-9 (GPCR 10-8-10-10(GPCR
Targets) Targets)
17. Different functional (epitope) IgG
candidates 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
Mol Biol Cell Biol Biochem F library scFv
IgG Affinity
Fab selection Maturat.
Polimorph. Cell Lines: Target 30-250 20-50 5-10 IgGs
Syn Genes: 3-5 Human Presentation: Unique Unique using
Human 1 Cyno MPLs binders IgGs MPLs
Cyno 1 Mouse SIMPL
Mouse
Ligands
Vectors
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 Technology
Stage MAB format
Pre-Clinical 3 IgGs
Selection of Lead 5 ScFv/Fab/IgG
Candidates
Generation of Lead 6 ScFv/Fab
Candidates
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.