OP007. Anti-MAdCAM monoclonal antibody PF-00547659 does not affect immune surveillance in the central nervous system of anti-TNF and immunosuppressant experienced Crohn's disease patients who are anti-TNF inadequate responders: Results from the TOSCA stud
G. D'Haens1, S. Vermeire2, F. Cataldi3, H. Vogelsang4, M. Allez5, P. Desreumaux6, A. Van Gossum7, D. Baumgart8, W.J. Sandborn9, K.J. Gorelick3, R. Ransohoff10, O. Stuve11, J. Cheng3, S. Rivers3, G.M. Comer3, B. Jin3, B. Jin3, V. Pradhan3, M. Hassan-Zahraee3, A. Kaminski3, W. Reinisch4, 1University of Amsterdam, Academic Medical Center, Amsterdam, Netherlands, 2University Hospital Leuven, Gastroenterology, Leuven, Belgium, 3Pfizer Inc., Gastroenterology, Cambridge, United States, 4Medical University of Vienna, Internal Medicine/Gastroenterology, Vienna, Austria, 5Hopital Saint-Louis - APHP, Gastroenterologie, Paris, France, 6CHU de Lille, Gastroenterologie, Lille, France, 7Erasme Hospital, Free University of Brussels, Gastroenterology, Brussels, Belgium, 8Humboldt-University of Berlin, Charite Medical School, Berlin, Germany, 9University of California San Diego, Division of Gastroenterolgy, San Diego, United States, 10Cleveland Clinic, Neurology, Cleveland, OH, United States, 11University of Texas, Neurology, Dallas, TX, United States
Therapy that inhibits white blood cell (WBC) trafficking from the bloodstream to the gut has shown promising results in the treatment of inflammatory bowel disease. Its use, however, has been limited by the risk of progressive multifocal leukoencephalopathy (PML) in patients treated with the nonselective anti-α 4 integrin antibody natalizumab. PML is an opportunistic infection caused by the highly prevalent JC virus that attacks the central nervous system (CNS) in immunocompromised hosts. Reduced CNS immune surveillance from inhibition of immune cell trafficking is a likely element in the pathogenic cascade.
PF-00547659 is a human monoclonal antibody that binds to MAdCAM on endothelial cells and blocks its interaction with α 4 β 7-bearing WBC, preventing their entry into gut tissue while sparing the CNS, which is constitutively devoid of MAdCAM. This report is the first to describe effects of an anti-MAdCAM antibody on cellular elements of the CSF.
In 8 European centers, patients with moderate to severe Crohn's disease (CD) (ie, Harvey–Bradshaw Index (HBI) >8 + highly sensitive C-reactive protein (hsCRP) >5.0 mg/L or active lesions on endoscopy or imaging) and prior treatment with both anti-TNF and immunosuppressants (azathioprine, 6-MP or methotrexate), underwent a lumbar puncture (LP) followed by subcutaneous injections of 225 mg PF-00547659 every 4 weeks for 3 doses. 2±1 weeks after the last dose of PF-00547659 a 2nd LP was performed. CSF was analyzed by flow cytometry in a central laboratory adjusting with TruCount beads for enumeration of lymphocytes and T cell subsets.
24 subjects were enrolled (16F/8M). Baseline characteristics mean (sd) were: age: 38.0 (9.7) years; duration of CD: 11.7 (6.1) years; HBI (16 pts without stoma): 8.6 (1.4); and hsCRP: 12.0 (18.7) mg/L. 12 subjects had a 2nd LP after treatment. Cell counts by flow cytometry were not available for 1 subject, and data from another were excluded due to a traumatic tap. Results of flow cytometry are shown in Table 1.
|LP1||24||471 (132%)||435 (132%)||294 (141%)||122 (119%)||2.40 (50%)|
|LP2||12||626 (185%)||595 (188%)||409 (197%)||160 (171%)||2.52 (52%)|
In anti-TNF and immunosuppressant experienced patients with moderate to severe CD, a full induction course of the highest clinical dose of PF-00547659 did not affect CSF lymphocytes. The results of the TOSCA study support the gut selectivity and the CNS-sparing mechanism proposed for PF-00547659.