Inducing tolerance to Campath 1H (alemtuzumab) in the treatment of multiple sclerosis

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1 Inducing tolerance to Campath 1H (alemtuzumab) in the treatment of multiple sclerosis Alasdair Coles Herman Waldmann & Geoff Hale Universities of Cambridge & Oxford

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3 Alemtuzumab (Campath 1H) Humanised antibody against CD52 depletes lymphocytes Licensed in 2001 for chronic lymphocytic leukaemia Exploratory trials in autoimmunity& transplantation Herman Waldmann Nicola Cole & Geoff Hale Cesar Milstein ( ) Nobel Prize 1985

4 Multiple Sclerosis 3 women : 1 man 120 /100,000 prevalence 100,000 affected in the UK Commonest cause of neurological disability amongst young adults in UK Relapsing remitting phase Secondary Progressive Phase

5 Alemtuzumab (Campath 1H) in multiple sclerosis: efficacy CAMMS year data: relapse accumulation 68 % reduction p< Coles NEJM 2008, Coles (Neurology, in press)

6 CAMMS year data: risk of accumulating fixed disability 71 % reduction p< Coles NEJM 2008, Coles (Neurology, in press)

7 Alemtuzumab: Clinical Trial Program in MS Phase 3 Phase 2 CARE MS I N=581 Treatment naïve vs. SC IFNB 1a 44 µg 2 years COMPLETED: Summer 2011 CAMMS223 N=334 Treatment naïve vs. SC IFNB 1a 44 µg 3 years & extension (2+ years) COMPLETED: 2007 CARE MS II N=840 Treatment experienced and relapsed on prior therapy vs. SC IFNB 1a 44 µg 2 years COMPLETED: Autumn 2011 Extension study CARE-MS Extension Protocol 3 years ONGOING RRMS=relapsing, remitting MS; SC IFNB=subcutaneous interferon beta

8 Anti alemtuzumab antibodies in a phase 2 trial (n=223) 100% Alemtuzumab Alemtuzumab Alemtuzumab % of Patients with Detectable Antialemtuzumab Antibodies 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Time point after Campath 1H treatment

9 CD4 T cell counts after 4 cycles of alemtuzumab Anti alemtuzumab antibodies 40,000 U/mL

10 High zone tolerance

11 Cytokine release with alemtuzumab infusions 20mg alemtuzumab induces a significant cytokine response: Pyrexia, tachycardia, raised CRP Raised TNF α, IFN γ

12 Waldmann group's mutants of alemtuzumab

13 SM3 Campath 1H Campath 1H hucd52 transgenic mouse SM3 mutant of Campath 1H reduces immunogenicity of Campath 1H Anti Campath 1H Ab Gilliland J Immunol 1999

14 SM3 Trial Design N=20 patients with multiple sclerosis SM3 Test dose of 50mg on day 1 Full dose of 450mg on day 2 1 st cycle of alemtuzumab day 7 2 nd cycle of alemtuzumab Month 0 Month 12 Month 24 Anti alemtuzumab antibodies at month 1 and 13

15 % of patients with detectable anti alemtuzumab antibodies Mean concentration of antialemtuzumab antibodies (U/ml) *** 10,000,000 1,000,000 1,235,072 *** ,000 *** 1,254 1,000 0 Month 1 post alemtuzumab 21 Month 13 post alemtuzumab 100, *** Month 1 post alemtuzumab 3,640 Month 13 post alemtuzumab CAMMS223 trial: alemtuzumab only (n=223) SM3 & alemtuzumab (n=19) Campath 1H Sample Campath 1G

16 IgM Campath 1H Sample Anti hu IgM Mean optical density of absorbance p<0.05 IgG1 Anti hu IgG1 Sample Campath 1G Max velocity (mod/min) of absorbance P< Month 1 Month 13 0 Month 1 Month 13 Alemtuzumab only (n=4) SM3 & alemtuzumab only (n=4)

17 Did SM3 compromise assays? Goat anti human Ig SM3 Anti Campath idiotype The estimated mean concentration of SM3 at 1 month was 30.3 μg/ml and at 13 month was 0.01 μg/ml.

18 Conclusions from formal trial Apparent lack of anti alemtuzumab antibodies after one cycle of SM3 and alemtuzumab might be an artefact due to persistence of SM3 Low rate of anti alemtuzumab antibodies after second cycle of alemtuzumab could be due to: Long lasting tolerance induction to alemtuzumab, with a minority generating a secondary response to second cycle Masking of first cycle of alemtuzumab; now seeing a primary response with second cycle What has happened subsequently?

19 Percentages of patients with anti alemtuzumab antibodies before and after 3 rd cycle After 2 nd cycle Before 3 rd Cycle After 3 rd cycle Before 4 th cycle After 4 th cycle Before 5 th cycle After 5 th cycle Non SM3 7/30 14/30 5/8 7/8 1/1 1/1 SM3 1/5 0/5 2/5

20 anti alemtuzumab antibody concentration after 3 rd cycle (SM3 and non SM3) P=0.08

21 anti alemtuzumab antibody concentration comparing non SM3 after 2 nd cycle and SM3 after 3 rd cycle P=0.9

22 Conclusions Insufficient data to be conclusive Rate of conversion after 3 rd cycle in SM3 patients is still lower than after 2 nd cycle in non SM3 patients Level of anti alemtuzumab antibodies after 3 rd cycle in SM3 patients is equivalent to that after 2 nd cycle in non SM3 patients

23 Therapeutic Immunology Group Department of Clinical Neurosciences University of Cambridge Genzyme / Sanofi Aventis Cambridge Centre for Biomedical Research Multiple Sclersosis Society of GB and N Ireland MRC Grand Charity of the Freemasons UCB Celltech