Study Design Streptococcal Cell Wall Induced Arthritis - MorphoSys

Development of a HuCAL GOLD ® human monoclonal 

antibody for the therapeutic treatment of inflammatory diseases 

Human Antibodies & Hybridomas, New York, November 12 th -14 th , 2008

Contents 

2 

� Introduction 

� MOR103 anti-GM-CSF antibody program 

� GM-CSF target physiology 

� MOR103 antibody discovery and development 

� Generation 

� Selection 

� Efficacy 

� Safety, Tolerability and Pharmacokinetics 

� MOR103 antibody manufacture 

� PER.C6 ® human cell line 

� Drug product formulation 

� MOR103 antibody clinical trial 

� Phase 1/First in Man 

� Conclusion 

HAH, New York, Nov 2008 | © MorphoSys AG

Introduction 

� MOR103: human monoclonal IgG1 targeting GM-CSF* 

� GM-CSF: proinflammatory cytokine functions 

� Initial indication: Rheumatoid Arthritis (RA) 

3 

� RA patients adequately treated

GM-CSF Target Physiology 

� Structure and Activity 

4 

� Glycoprotein: MW≈15kDa 

� RA synovial fluid concentration

MOR103 Antibody Selection* 

5 

H-CDR2 

Maturation 

Pre-Built Trinucleotide Cassettes 

HCDR1 

HCDR2 

HCDR3 LCDR1 LCDR2 LCDR3 

HuCAL VH HuCAL VL 

Unique Fab panel 

Selection of parental Fabs 

Pannings & Screening 

Antibody Characterization 

H-CDR2-optimized Fabs L-CDR3-optimized Fabs 

CDR Cross-Cloning 

Affinity optimized lead monoclonal antibodies 

L-CDR3 

Maturation 

*Urban, M (2007) HAH 

Steidl et al. (2008) MIMM 46: 135-144 


MOR103 Antibody Characteristics 

6 

Study MOR103 Antibody 

Affinity 

(Fab SET) 

Inhibits 

� Human and rat GM-CSF (K D=0.4pM and 1100pM) 

� Binding of GM-CSF to GM-CSFR-α 

� TF-1 and FDCP-1 cell proliferation 

� GM-CSF induced PMN migration, CD11b expression 

and MHC class II up-regulation 

� GM-CSF mediated PMN Stat-5 phosphorylation* 

SET, solution equilibrium titration 

K D, dissociation constant 

TF-1, Human erythroleukemic cells 

FDCP, Factor dependent cell Paterson (murine bone cells) 

PMN, polymorphonuclear neutrophil 

Stat-5, Signal Transducer Activator of Transcription-5 

* w. GM-CSF 

* w/o. GM-CSF 

* w. GM-CSF and MOR103 


MOR103 Antibody Cross Reactivity 

7 

Study MOR103 Antibody 

Cross 

Reactivity 

� Specific to human GM-CSF cf. IL-3, IL-4, IL-5 & M-CSF 

� Neutralises rat a (IC 50=35nM) GM-CSF 

� Neutralises human b and rhesus b GM-CSF (IC 50 = 11pM to 48pM) 

� No non-specific human or rhesus tissue binding 

a FDCP-1 or b TF-1 cell proliferation assays 

FDCP, Factor dependent cell Paterson (murine bone cells) 

TF-1, Human erythroleukemic cells 

IC 50, Inhibition Concentration at 50% 

MOR103 antibody candidate selected for development in to the clinic 


MOR103 Antibody Stage Outcome 

� Generation of a fully human antibody � 

� High affinity to human GM-CSF � 

� Inhibition of GM-CSF mediated cellular mechanisms � 

� No off target cross-reactivity � 

� Binds rhesus and rat GM-CSF � 

8 


MOR103 In Vivo Antibody Efficacy 

9 

Study Design 

Streptococcal Cell Wall 

Induced Arthritis 

(SCW IA) 

� Treatment: MOR103 dosed at 10, 20 and 50 mg/kg once 

i.p. 2h before intro-articular administration of SCW 

fragments to male Wistar rats (right knee) 

� RA Parameters: Knee joint swelling (right/left knee ratio), 

and histopathology (PMN cell influx), synovial fluid and 

serum cytokine levels 

MOR103 controlled arthritis in the SCW model 

Recognised anti-cytokine inhibitor model for RA therapeutic development* 

*FDA (1997) http://www.fda.gov/cder/guidance/raguide.pdf 


MOR103 Antibody Efficacy 

- Knee Joint Swelling and Histopathology 

10 

2 

1,8 

1,6 

1,4 

1,2 

Right/Left knee ratio Knee joint swelling 

1 

* 

Day 1 Day 2 

3 

2,5 

2 

1,5 

1 

0,5 

Histological scores (0-3) Knee joint histopathology 

0 

Synovium Joint Cavity 

Cell Influx 

Error bars show: ±SD; n=5 rats/group; *P

MOR103 Antibody Efficacy 

- Synovial Fluid and Serum Cytokine Levels 

11 

Cytokines (pg/ml) 


4000 

3500 

3000 

2500 

2000 

1500 

1000 

500 

0 

50000 

40000 

30000 

20000 

10000 

0 

Synovial levels 

IL-1β GM-CSF 

1 2 3 4 5 

IL-6 KC 

Synovial levels 

* 

* * 

1 2 3 4 5 

* 

500 

250 

0 


Serum levels 

Error show bars: ±SD; n=6 knee joints/group *P







� Demonstrable efficacy in an established RA model � 

12 


MOR103 Antibody Toxicology 

13 

Rhesus monkeys (male and female) 

Dose/Route MOR103 at 5, 25 or 100mg/kg by i.v. bolus 

Regimen Repeat dose 4 x 1 per calendar week (4 week recovery) 

Outcomes 

� No adverse clinical signs, BW change or in-study mortality 

� T ½z ≈7d 

� Dose dependent Cmax (142, 626, 4800μg/ml) 

� Some low level immunogenicity observed at 100mg/kg only 

� Humoral immune-response maintained (KLH immunogenicity test) 

� No treatment related changes: histopathology, cytokines, CD marker, 

Coombs test, lymphocyte subsets, haematology, coagulation, clinical 

chemistry, urinalysis, organ weights and macroscopic analysis 

MOR103 showed no relevant toxicological effects (NOAEL=100mg/kg) 









� Safe and well tolerated with dose dependent PK � 

14 


MOR103 Antibody Manufacture 

� PER.C6 ® : human retina cells 

15 

� Immortalized, rapid growth (adherent/suspension) 

� High recombinant protein producing 

� Human post-translational modifications apply 

� Generic 250L fed-batch culture, purification and QC procedures 

� Manufacture platform provided by Crucell and DSM 

� Stable liquid drug product formulation 

� Phosphate buffered saline (pH6.2) 

� No instability trend (12 month at 2-8 C) 

PER.C6 ® suspension culture 

MOR103 drug product 










� PER.C6 ® cell derived drug product � 

16 










� PER.C6 ® cell derived drug product � 

� Phase I study: currently ongoing � 

17 


Conclusion 

18 

MOR103 human anti-GM-CSF antibody selected as a possible anti- 

inflammatory therapy with the required pre-clinical qualities to initiate 

Phase I clinical testing 

Next step: 

Progress with a Phase Ib/IIa clinical trial in Rheumatoid Arthritis (2009) 


Acknowledgments 

19 

MorphoSys, D 

Robert Friesen 

Marco Springer 

Elisabeth Thomassen-Wolf 

Gisele Borelli-Montigny 

Amgad Shebl 

Margit Urban 

Stefan Steidl 

Manuela Dürr 

Olaf Ratsch 

Rainer Boxhammer 

Bettina Swoboda 

MorphoSys, D - continued 

Ralf Ostendorp 

Armin Weidmann 

Andreas Popp 

Bodo Brocks 

Daniela Della-Ducata 

Petra Pfnür 

Meike Eisenmann 

Olaf Broders 

University Nijmegen, NL 

Prof. Leo Joosten 

Marije Koenders 


HAH, New York, 13-Nov-2008 

20 

Development of a HuCAL GOLD ® human monoclonal antibody 

for the therapeutic treatment of inflammatory diseases 

Thank you for your attention 


Thank You 

www.morphosys.com 

Matthew Downham, PhD 

Senior Manager Pre-Clinical & Early Clinical Development 

Phone +49 (0)89 / 899 27-176 

Fax +49 (0)89 / 899 27-5176 

Email matthew.downham@morphosys.com 

HuCAL ® , HuCAL GOLD ® , HuCAL PLATINUM ® , CysDisplay ® , RapMAT ® and AutoCAL ® are registered trademarks of MorphoSys AG.

Study Design Streptococcal Cell Wall Induced Arthritis - MorphoSys

Create successful ePaper yourself

Delete template?

Save as template?