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Comparability presentation


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Comparability of a human IgG1 after cell line switching: 
A retrospective view 
 
Peter Lloyd

Head of PK-PD, Novartis Biologics


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Disclaimer 

    The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated.

 

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Outline of the presentation: 

Introduction to case study: 

IgG PK and mAb-ligand binding models:

      - consequences for characterisation of extent and duration of effect 

Retrospective analysis:

      - can rodent replace NHP in PK studies to explore inherent IgG behaviour?  
 - can immunogenic potential be detected with appropriate PK and PD 
   analytical strategies?

      - can appropriate clinical strategies during clinical development provide 
   more definitive information on comparability? 

Summary: 

- “yes they can”


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Case study: 

  • IgG1 monoclonal Ab
  • binds to and neutralises a soluble cytokine target 
     - target not detected at baseline in systemic circulation
  • cross-reactivity established with marmoset and human target (similar affinity) 
  • PK assay for total drug in serum (marmoset / human)
  • PD assay for total ligand in serum (human)

 


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Product A 

Product B 

Product C 

Product D 

NS0-derived

≥52 mg/mL 

Sp2/0-derived

≥65 mg/mL 

Sp2/0-derived

≥180 mg/mL 

Sp2/0-derived

≥175 mg/mL 

- human and marmoset cross-reactivity 

Comparability exercise:

- phys - chem

- PK (NHP) 

Comparability exercise:

- phys - chem

- PK (NHP) 

Comparability exercise:

- phys - chem 

-marmoset: 4 and 26 wk iv,  
13 wk s.c. toxicology and EFD 

 
 
 
 
 

-  


Clinical studies 

Clinical studies 

 NS0 = expression cell line (mouse myeloma)

Sp2/0 = expression cell line (mouse myeloma)       HSA = Human serum albumin 

Case study:


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Case study: 

       Phase IV 

       Phase III 

       Phase II 

       Phase I 

            Pre-clin       

Research 

cell line switch


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Case study: PK comparability non-human primate 

  – NSO

 – SP2/0    

Time (days) 

Serum mAb concentration (g/mL) 

single sc dose x-over study

n=16 marmosets 

PK comparability established:

- AUC

- Cmax and tmax


www.diahome.org 

Outline of the presentation: 

Introduction to case study: 

IgG PK and mAb-ligand binding models:

      - consequences for characterisation of extent and duration of effect 

Retrospective analysis:

      - can rodent replace NHP in PK studies to explore inherent IgG behaviour?  
 - can immunogenic potential be detected with appropriate PK and PD 
   analytical strategies?

      - can appropriate clinical strategies during clinical development provide 
   more definitive information on comparability? 

Summary:


www.diahome.org 
 

slow clearance 
V ~ 7L 
t ~ 300 h (human) 

iv dose  

elimination  
mAb  

mAb 

FcRn protects IgG from degradation & explains long serum half-life  

    Roopenian and Akilesh.

    Nature Reviews Immunology 2007; 7: 715 
     

A simple mAb PK model:


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mouse 

IgG kinetics scale reasonably  
well using an allometric approach

NB

 

only when target mediated  
      disposition is absent
 

rat 

non-human primate 

Mouse, rat and cyno FcRn recognize human IgG 

man


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mAb – ligand

complex 

elimination  
mAb – ligand 
complex  

ligand 

input ligand  

elimination  
ligand  

+ 
 

slow clearance 
V ~ 7L 
t ~ 300 h 

dose 

elimination  
mAb  

mAb 

A simple mAb PK-PD model:


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  • Inherent pharmacokinetics of the mAb (IgG behaviour): 
     - species differences often well understood and easily characterised; 
       good prediction to man
  • Binding affinity to the target ligand: 
     - species differences understood during characterisation of the mAb
  • Turnover of the ligand and clearance of the mAb-ligand complex: 
     - species differences and behaviour of mAb-ligand complex sometimes not well 
       understood 
     
         - if cell surface ligand is not saturated with mAb then the mAb-ligand complex 
                  may be cleared very quickly
    (target mediated clearance)    
          - for a soluble ligand the mAb-ligand complex will tend to follow IgG clearance 
                   mechanisms (eg case study)
 

Components of the PK-PD model:


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Single dose:

  0.01 mg/kg

 

0.1   mg/kg

 

1.0   mg/kg

10.0   mg/kg 

Assumptions

  mAb with typical IgG kinetics; Kd = 0.37nM; soluble ligand, turnover (half-life 3h) 

soluble ligand 

Case study: PK-PD model


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anti-CD11a mAb – Raptiva (efalizumab) 

Joshi et al An overview of the pharmacokinetics and pharmacodynamics of efalizumab: a monoclonal antibody approved for use in psoriasis 
J Clin Pharmacol 2006; 46: 10-20 

cell surface ligand 

Literature example:


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    • PK of monoclonal antibodies will generally follow “typical IgG behaviour” and scale reasonably well to man and/or exhibit Target Mediated Drug Disposition (TMDD) and be dependent on the amount of target present and its rate of turnover 
    • Once maximum ligand binding is achieved then increasing the dose will primarily increase the duration of response  
    • The shape of the exposure response curve can be simulated from pre-clinical data by adjusting parameters in the model (eg binding affinity, target expression) 
    • The amount of ligand present and the rate at which it can be replaced (turnover) will be key drivers of the extent and duration of response
 

Summary: Ab-ligand PK-PD binding models


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Case study: consequences for comparability testing 

For an antagonistic mAb cleared primarily by IgG mediated clearance pathways, a study with PK endpoints will explore only inherent IgG characteristics

      

this data could be generated equally well in rodents, as rodents clear human 
 IgG by similar pathways to man 

Differences in conventional non-compartmental PK parameters (Cmax, tmax) at high saturating doses may not impact on efficacy 

Binding to target is often not addressed in a PK-only study design


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Literature example: glycosylation pattern (rodent) 

Milward et al Effect of constant and variable domain glycosylation on pharmacokinetics of therapeutic antibodies in mice

Biologicals 2008; 36: 41-47


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Case study: impact of immunogenicity 

drug  

anti-drug antibody  

anti-drug antibody  

mAb “typical IgG kinetics”                      increase in IgG clearance                      increase in IgG clearance

                                                               no effect on target binding                     decrease in target binding

                                                               (total ligand, receptor occupancy)          (decrease in total ligand) 

Target Mediated Disposition        increase IgG clearance                increase/decrease in clearance?            

                                                               (change in inflection point?)                    (change in inflection point?)

                                                               no effect on target binding                      decrease in target binding 
 

non-neutralizing 

neutralizing


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PK 

PD

(soluble target) * 

Immunogenicity 

Analytical strategy: impact of neutralizing immunogenicity 

residual bioactive drug 

anti-human IgG 

residual bioactive drug 

total drug (non-human only) 

mAb (drug) 

ligand 

capture Ab 

NB: capture Ab has different ligand binding epitope compared with the drug and no steric interference

 

* - for cell surface target use receptor occupancy and/or PK profile 

a) 

b) 

c) 

a) 

b) 

c) 

nIG may interfere in the PK and PD assays; detected as short PK t�. Immune complexes may also be cleared more rapidly. Decrease in total target may be apparent 

nIG may intefere in the PK and PD assays; detected as increase / decrease in exposure. Decrease in total target may be apparent 

nIG does not interfere in the PK assay; although immune complexes may be cleared more rapidly.  
Decrease in total target may be apparent 

drug-ligand complex / total target 

or LC-MS


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Case study: population analysis of clinical data 

Phase III clinical study

-

incorporate comparability testing into clinical design;  
  product A (NS0) and B (SP2/0) as covariates (n=35 patients per treatment) 

- serum total mAb and total ligand measured with sparse sampling strategy 
  predict free ligand from PK-PD binding model 

- ligand capture (and therefore ligand suppression) will also detect neutralizing 
  immunogenicity


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Case study: population analysis of clinical data 

       NSO

----- SP2/0    

Time (days) 

Time (days) 

Serum mAb concentration (

g/mL) 

Serum ligand concentration (pg/mL) 

mAb (PK profile) 

Total ligand (PD profile) 

Conclusions for materials derived from both cell lines: 

- similar sc bav 

- similar in-vivo KD derived from clinical PK-PD binding model 

- no loss total ligand over time (ie no evidence of neutralizing immunogenicity) 

Typical PK and PD profile from the PK-PD model


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Case study: summary 

Can rodent replace NHP in PK studies to explore inherent IgG behaviour? 

Industry perception and concern that NHP primate PK studies are necessary is driving acceptance that these will be the norm; 

however, for this case study (mAb targeted against a soluble ligand), pre-clinical studies in NHP with PK-only endpoint could probably be replaced by a PK study in rodent, even when the mAb does not bind the target in rodent (only the inherent IgG behaviour is characterised) 

  

 


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Case study: summary 

Can immunogenic potential be detected with appropriate PK and PD analytical strategies? 

If total ligand capture can be easily measured, then neutralizing immunogenicity should be apparent as a decrease in total ligand; 

this can easily be monitored in Phase III clinical trials; providing a robust assessment of immunogenic potential; 

additional neutralizing immunogenicity assays are probably not required

 


www.diahome.org 

Case study: summary 

Can appropriate clinical strategies during clinical development provide more definitive information on comparability? 

doses are often given at saturation of target ligand binding and differences in dose therefore affect duration of action rather than extent; conventional PK parameters to assess comparability (eg Cmax and tmax) may not be appropriate  

clinical studies with target capture and appropriate analytical strategy are more informative than pre-clinical studies regarding comparability of efficacy and immunogenic potential 

during drug development comparability testing can be built into clinical study design 
 

 


www.diahome.org 

THANK YOU for your attention 

Acknowledgements:

Jennifer Sims

(Head Translational Sciences and Safety, Novartis Biologics)

Phil Lowe

(Modelling and Simulation, Novartis)

Annette Zaar

(Head of Immunogencity, Novartis Biologics)

Fabienne Deckert

(Head of PK-PD Bioanalytics, Novartis Biologics)


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