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* = Presenting author

P002. The gastrointestinal-selective biologic vedolizumab does not impair immune surveillance of the central nervous system in non-human primates

E.R. Fedyk1, V. Csizmadia1, W. Shyu2, L. Yang3, T. Wyant3, D. Estevao4, S. Hofman4, B. 't Hart4, K. Haanstra4

1Department of Drug Safety Evaluation, Millennium Pharmaceuticals, Cambridge, MA, United States; 2Department of Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals, Cambridge, MA, United States; 3Department of Molecular Medicine, Millennium Pharmaceuticals, Cambridge, MA, United States; 4Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands

Purpose: Crohn's disease (CD) and ulcerative colitis (UC) are chronic disabling inflammatory bowel diseases (IBDs) of unknown etiologies. Biological therapies that antagonize specific molecules have demonstrated efficacy in IBD, but sizable unresponsive patient populations and safety issues underscore the need for novel therapy. The therapeutic antibody natalizumab antagonizes the α4β1 and α4β7 integrins and provides efficacy in multiple sclerosis and CD, by blocking migration of inflammatory cells into the central nervous system (CNS) and gastrointestinal tract. Natalizumab is also associated with an opportunistic infection of the brain, progressive multifocal leukoencephalopathy (PML), which is believed to be caused by impaired immune surveillance of the CNS. Vedolizumab (former versions known as MLN0002, MLN02, and LDP-02) is an investigational humanized monoclonal antibody in Phase III clinical development for UC and CD that binds the gastrointestinal-homing integrin α4β7, and not the α4β1 integrin, and thus may not impair immune surveillance of the CNS.

Methods: A model of PML does not exist. This investigation therefore induced experimental autoimmune encephalomyelitis (EAE), which is caused by immune surveillance of the CNS, in the pharmacologically responsive Rhesus macaque and investigated the potential effects of vedolizumab and natalizumab on EAE. Animals received an initial intravenous bolus of vehicle, natalizumab (30 mg/kg) or vedolizumab (30 mg/kg) before intracutaneous immunization with recombinant human myelin/oligodendrocyte glycoprotein (rhMOG) and were dosed once weekly thereafter. Vehicle control animals (n = 8) were grouped 1:1 or 1:2 with natalizumab- or vedolizumab-treated animals (n = 7 in each group) before disease induction, to ensure time-matched comparators for subsequent post-mortem analyses of samples. An entire group of animals was therefore euthanized once one animal in the group reached a humane endpoint, based on clinical symptoms of EAE, as assessed by blinded observers.

Results: Animals that developed clinical EAE also exhibited inflammatory infiltrates in cerebral spinal fluid and brain, whereas asymptomatic animals did not exhibit CNS inflammation. Natalizumab inhibited leukocytic infiltration of cerebral spinal fluid and the cerebrum/cerebellum. Natalizumab also prevented formation of demyelinated lesions in the cerebrum/cerebellum relative to time-matched vehicle control animals. Vedolizumab in contrast did not elicit these effects. A pharmacodynamic response was observed for each antibody in vivo, and comparable levels of antigen-specific (anti-rhMOG), autoimmune T lymphocytes and anti-MOG antibodies were detected in the peripheral blood of all animals.

Conclusion: The results demonstrate that vedolizumab does not inhibit infiltration of the CNS by leukocytes in EAE. This suggests that vedolizumab does not impair immune surveillance of the CNS and thus may have a lower risk of predisposing IBD patients to PML than natalizumab.