Immunogenicity in rheumatology

38 Pages·2017·3.07 MB·English

Immunogenicity: Antibodies to
biologicals:
Symptoms and clinical value of
their determination and
Relevance in clinical practice
Bern : 23 March 2017
Pascal Zufferey MER/PD
CHUV Lausanne Switzerland
Biologics in inflammatory arthritis
NonBiologic Era Biologic Era
Leflunomide (1998)
MTX
Etanercept(1998)
Rituximab
SSZ
ustekimumab
HCQ
Secukimab
Infliximab
Abatacept
CQ
Gold
Adalimumab
Cyc-A Biologic Golimumab
AZA drug Certolizumab
clinical Anakinra
PNC Tocilizumab
trials
belimumab
1990 2000 ‘01 ‘03 ‘05 ‘06 ‘09 12 16
Year of Approval
Nomenclature and structure of Biologics
Cosentyx
stelara
Classes of ADABs
Neutralising
antibodies
•Binds to
Fab region
Detected using in
vitro assays
•Activity in vitro does not
always correspond with
activity in vivo
•In vivo, both may impact
Non-
on safety and clearance
neutralising
antibodies
•Binds to
any other
region
Factors affecting
immunogenicity
Factors affecting immunogenicity
• Idiotypic region,
• mode of action
• Glycosylation pattern
• Allotype (IgG4 is non-allotypic)
• Pegylation
• Joining sequences on fusionproteins
• Formulation, packing, impurities
• Intra articular> sc administration > immunogenic than iv
• Lower dose > immunogenic higher dose
• Intermittent > immunogenic maintenance
Size of biologic compounds
Anakinra certolizumab
19,000 Dalton 47,000 Dalton
Etanercept , Abatacept
Methotrexate
150,000 Dalton
453 Dalton
Pharmacology of biologic agents
Not eliminated by kidney or metabolized by the liver
Degradated but also recycled by reticulo-endothelial
cells.
Half life depending of several factors
sc
Factors affecting trough levels
None had ADABS
Serial determinations of TCZ were made in five patients
Three patients had detectable levels at day 10 but
undetectable levels at days 20 and 28.
The other two patients had adequate TCZ levels in all
determinations.
The level of the target at start of biologic could be
important (loading dose : cimzia)
Trough serum levels of tocilizumab in rheumatoid arthritis: relationship
with disease activity and remission in a clinical setting
Virginia Ruiz Esquide, Pascal zufferey : EULAR 2015
Auto –immunity versus ADABs
F. Atzeni , R. Talotta Autoimmunity Reviews 12 (2013) 703–708