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PML development:Risk factors and predictive biomarkers
- limitations and perspective -
Heinz Wiendl
University of Münster, Germany
PML workshop 07_2011
1) Biomarkers for Mab therapy: what do we have?2) „The german pharmacovigilance natalizumab study“: an
academic approach by the KKNMS3) Immunological consequences of long-term Efalizumab and
Natalizumab therapy: insights from our cohorts4) Summary and outlook
Hypothesis: PML is Caused By A Convergence of Multiple Risk Factors
Candidates for additive risk factors
Duration of therapy
Biomarker – identifying the risk group
© Kompetenznetz Multiple Sklerose
2-Step Assay Demonstrates Anti-JCV Antibody Prevalence of 54% in MS Patients in STRATA Study1
Gorelik L et al. Ann Neurol. 2010;69:295-303.
450
Step 1: ELISA
40% Positive
30% Negative
30% Indeterminate
48% Confirm Positive
52% Confirm Negative
Step 2: Confirmation test
54% Positive
46% Negative
Overall Result:
negative
JCV-Antibody status
positive
Prior immune suppression
No Yes
Natalizumab therapy duration
JCV-seronegative JCV-seropositive
No prior immune suppression
Prior Immune suppression
0-2 years
0,11/1000(95% CI: 0-0,59)
~1:9000
0,35/1000(95% CI: 0,19-0,60)
~1:2900
1,2/1000(95% CI: 0,58-2,2)
~1:800
>2 years 2,8/1000(95% CI: 2,0-3,8)
~1:350
8,1/1000(95% CI: 5,4-11,6)
~1:120
Sandrock A et al. AAN 2011; Poster P03.248.
PML incidence / 1000
A possible risk calculation algorithm?
What should a “biomarker” for Mab-associated PML be like?
1) Biomarkers for Mab therapy: what do we have?2) „The german pharmacovigilance natalizumab study“: an
academic approach by the KKNMS3) Immunological consequences of long-term Efalizumab and
Natalizumab therapy: insights from our cohorts4) Summary and outlook
German “Natalizumab Pharmakovigilance Study”
© Kompetenznetz Multiple Sklerose
• Aim 1: To identify risk factors that predispose to the development of PML during long-term therapy with Natalizumab
• Aim 2: To better understand the immunomodulatory and immunosuppressive effects of Natalizumab.
Approach: multiparametric, multicentric (Münster, Bochum, Düsseldorf, Munich), crossectional + longitudinal
1.Thera py history: previous immunosuppressive/modulatory conditions,
2.Genetics: individual genetic predisposition
3.Pathogen-host interaction: preexisting JC-virus specific antibodies
4.Virology: presence of JCV in biofluids
5.Bioenergetics: altered bioenergetic values and
6.Immunephenotyping
7.Functional assessments of immune components (e.g. migration, TCR repertoire etc.)
Objectives
© Kompetenznetz Multiple Sklerose
PML risk assessment
• !"#$#%&'(#!)'%*+!+,*-!'(!.+, , -/!!0#%1&/!234!*(-!1%'(#!5"67!
• !"#$#%&'(#!*($'. , -?!$'$#%!*<*'(0$!8*$@,<#(0!5A67!
• !"#$#%&'(#!0#%,8,0'$')'$?!5"67!
• !D($'<#(!08#9'E'9!FG9#++!8%,+':#%*$', (!5A37!
• !HID!$?8'(<!5A37!
• !D(*+?;#!F2J!%#8#%$, '%#!5"67!
• !D(*+?;#!. ',#(#%<#$'9!8*%*&#$#%0!5=>7!
Natalizumab mechanism of action
• !"#$#%&'(#!8%#0#(9#!, :!(#1$%*+';'(<!*($'. , -'#0!'(!.+, , -!5=>/!"67!
• !2,&8+#$#!8@#(,$?8'(<!, :!'&&1(#!9#++!8,81+*$', (0!'(!.+, , -!*(-!234!5A6/!A3/!"67!
• !B#%:,%&!C*$*+';1&*. !. '(-'(<!*00*?!*(-!0'<(*+'(<!0$1-'#0!5A37!
• !2*%%?!,1$!:1(9$', (*+!*00*?0!, (!(#1$%,8@'+!<%*(1+,9?$#0!5A37!
• !"#$#%&'(#!*($'. , -?!8%,E'+#0!10'(<!8%,$#,&'9!&'9%,*%%*?!*88%,*9@#0!5=>7!
• !"#$#%&'(#!&'$,9@,(-%'*+!3CB0K@*8+,<%,180!5=>7!
0 126Months Longitudinal studies
CSF
Blood
X
X
Urine
XX
Project phase
MS: Nat. therapy 0. point
MS: Nat. therapy ≥
18 months
MS: Interferon therapy
Healthy donorMS: Nat therapy 6 months follow-
up
MS: No therapy
MS: Nat. therapy 12 months follow-
up
X X
X
X
X
X
X
Patient groups
© Kompetenznetz Multiple Sklerose
30-50 Natalizumab patients/center (total appr. 120-200 patients)
1) Biomarkers for Mab therapy: what do we have?2) „The german pharmacovigilance natalizumab study“: an
academic approach by the KKNMS3) Immunological consequences of long-term Efalizumab and
Natalizumab therapy: insights from our cohorts4) Summary and outlook
PML associated with Efalizumab (anti-LFA-1/CD11a)
• 4 confirmed cases of PML associated with Efalizumab (Raptiva®) (Major et al., 2010)
• incidence ca. 1 in 500• withdrawn from the market 2009
Serial „immunological“ assessments of one Efalizumab-PML patient:
Schwab et al., Neurology in pres
- Serial analysis of peripheral blood and parallel CS- Functional analysis of immune cells (e.g. migration- Detailed CNS tissue analysis- Immune repertoire and antigen-specific T cell ana
LFA1-blockade blunts T cell activation and maturation development of effector/memory populations over time
What should a “biomarker” for Mab-associated PML be like?
And how can one get there?- Currently 3 risk parameters are available:
1) duration of treatment, 2) prior immune suppression, 3) JC antibody status
- Due to the multifactorial nature of the rare event (PML), a „dynamic“ biomarker ofPML risk is probably needed
- A „biosignature“, including „functional components“ is probably more likely to reflethe complex nature of disease pathogenesis
- Partly, these are highly difficult to standardize (e.g. migration, flow cytometry)
- Biological plausibility is important! (e.g. dynamic aspects, reversibility)
- Larger consortia have be established, that cooperate and independently validatedifferent aspects of Mab-associated changes and PML pathogenesis
- The KKNMS has already established a structure, IT platform, different biorepositorieand common SOPs for sampling of different biospecimens
Wiendl-Lab
Stephan BittnerNicole BobakJohanna BreuerAngela DreykluftPetra EhlingKerstin GöbelCatharina GroßAlexander HerrmannNico MelzerSven Meuth Suse PankratzVilmos PosevitzTobias RuckOle SimonTilman SchneiderMichael SchumannNicholas SchwabMax-Philipp Stenner
Collaborators
Laura Airas (Turku)Amit Bar-Or, Jack Antel (Montreal)Christian Bien, Christian Elger (Bethel/Bonn)Wolfgang Brück, Christine Stadelmann (Göttingen)Thomas Budde, Christian Pape (Münster)Lieping Chen (Baltimore) Ralf Gold (Bochum)Bernhard Hemmer (München)Reinhard Hohlfeld, Klaus Dornmair (München) Thomas Hünig (Würzburg)Helmut Jonuleit, Ari Waisman (Mainz)Bernd Kieseier, Hans-Peter Hartung (Düsseldorf)Monique Lafon (Paris)Joel Le-Maoult, Edgardo Carosella (Paris)Rudolf Martini (Würzburg)
Funding:DFG, SFB 581, KFO421, IZKF Münster, IMF MünsterBMBF, Hertie-Foundation, Thyssen, DMSG, American Myositis Association, Industry
Alumni
Ute FegerYu-Hwa HuangSonja OrtlerAlla ZozulyaChristoph LederAnne Waschbisch
Klinik für Neurologie – Abtl. Entzündliche Erkrankungen
und Neuroonkologie
Westfälische Wilhelms Universität Münster