Challenges in translating
a candidate antibody to
clinical development
Matthias Grossmann, MD PhD
Principal Consultant Early
Phase
© 2013 PAREXEL International
Agenda
Early clinical development of therapeutic antibodies
 Introduction
 Safety aspects
 Regulatory Guidance
 Risk Identification and Mitigation
 PAREXELs experience with therapeutic antibodies
 Summary
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Introduction
What makes therapeutic antibodies unique?
 The manufacturing process involves living organisms 
products are variable
 Difficult to characterize  batch-to-batch differences
(“similar”)
 The binding domain fits perfectly into the receptor 
binds very tight and is cleared by Target Mediated
Disposition
 Almost all safety concerns are related to the
pharmacological mechanism  exaggerated
pharmacology
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Safety Aspects
 Agonist versus Antagonist
 Defining the safe starting dose is challenging (MRSD or
MABEL?)
 Immune response
 Immediate: cytokine storms
 Intermediate: autoimmunity
 Delayed: Immunosuppression
 Organ specific toxicity
 Primary or secondary pharmacodynamics?
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EMA First In Human Guideline (2007)
 Definition of “high-risk IMP”
 mode of action
 nature of the target
 relevance of animal model
 preclinical
 relevant species
 human tissue/cells
 clinical
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study population
study design
starting dose (MABEL)
dose escalation
monitoring (safety)
stopping criteria
study site accreditation
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EMEA/CHMP/SWP/294648/2007
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Risk Identification (Document Part 1)
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Risk Mitigation (Document Part 2)
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Risk Identification and Mitigation
 Joint effort of sponsor and investigator
 Evaluate risk based on scientific knowledge, experience
and preclinical findings
 Identify major safety issues
 Mitigate risk by proper planning of safety monitoring and
selection of study population
 Based on relevant regulatory advice
 EMEA/CHMP/SWP/ 294648/2007
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Challenges
 The RIM process starts very early in the planning of the
FIH study
 often preclinical safety data is limited
 not enough data available to calculate starting dose, especially
not MABEL
 But, this allows sponsor and investigator
 to plan the FIH study jointly
 preparation of scientific advice meeting with CA
 preparation and training of site personnel if High Risk IMP needs
additional safety precautions
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PAREXEL Early Phase – Global Network
Baltimore (90)
Los Angeles (90)
London (50)
Berlin (140)
Bloemfontein (130)
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Early Phase: Therapeutic Antibody
Experience
More than 20% of all studies
involved biopharmaceuticals
Antibody type (since 2008)
 Chimeric mAb
2
 Humanised mAb
10
 human mAb
38
 Fusion Protein
2
 Fragment mAb
1
 Domain Ab
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Study populations
 Healthy subjects (52)
 Patients (12)
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Asthma
COPD
Psoriasis
Rheumatoid arthritis
Crohn’s disease
Hemophilia
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PAREXELs Experience: A case study
GSK1995057
 VH Domain Antibody Antagonist of TNF-α Receptor 1
 RIM STEP1: High Risk
 Single-blind, randomised, placebo-controlled dose
escalation study in which healthy males (n=28)
 Single intravenous infusion of 0.0004, 0.002 and 0.01
mg/kg
 All enrolled subjects pre-screened for human anti-VH
(HAVH) autoantibody status and prospectively stratified
 Serum samples from drugnaïve, HAVH-positive
volunteers were used to investigate the effect of
HAVH/GSK1995057 complexes on the activation of
TNFR1 and cytokine release in vitro.
J Clin Immunol 33(7), 2013:1192-203
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PAREXELs Experience: A case study
GSK1995057
 human anti-VH autoantibodies were detected in
approximately 50 % of drug-naïve subjects
 formation of HAVH autoantibody/GSK1995057
complexes activated TNFR1 and caused cytokine
release in vitro
 When GSK1995057 was administered, clinical and
physiological signs of cytokine release were observed in
two HAVH autoantibody-positive subjects following
GSK1995057 infusion
J Clin Immunol 33(7), 2013:1192-203
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Summary
 mABs are highly specific therapeutics
 Per se, they are not more critical with regard to safety
 Translating data from preclinical to clinical can be more
complicated
 Pleiotropic and secondary PD effects may play a larger
role than expected, especially for Antibody fragments
 A proper Risk Identification and Mitigation plan is
essential before the First in Human study can be initiated
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Thank you very much for your attention!
Matthias.grossmann@parexel.com
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