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P234. Vedolizumab does not reduce the CD4+:CD8+ ratio in the CSF of healthy volunteers

C. Milch1, T. Wyant2, J. Xu3, W. Kent3, J. Berger4, I.H. Fox1

1Millennium Pharmaceuticals, Inc./Takeda Pharmaceuticals, Inflammation Clinical Research, Cambridge, United States; 2Millennium Pharmaceuticals, Inc./Takeda Pharmaceuticals, Department of Molecular Medicine, Cambridge, United States; 3Millennium Pharmaceuticals, Inc./Takeda Pharmaceuticals, Cambridge, United States; 4University of Kentucky, Dept of Neurology, Lexington, United States

Background: Vedolizumab (VDZ) (previous versions MLN0002, MLN02, LDP-02) is a gut-selective integrin antagonist in phase 3 development for ulcerative colitis and Crohn's disease (CD). VDZ binds to the GI-homing integrin α4β7, antagonizing its interaction with MAdCAM‑1 and thereby preventing migration of memory T lymphocytes into the gut. Natalizumab (NTZ), an integrin antagonist that binds to both α4β7 and α4β1, is approved for multiple sclerosis (MS) and CD (US only), and is believed to exert its effect by blocking migration of white blood cells (WBCs) into the central nervous system (CNS) and GI tract. NTZ is associated with progressive multifocal leukoencephalopathy (PML), thought to be caused by NTZ's inhibition of WBC migration into the CNS. NTZ decreases WBCs and helper (CD4+) and cytotoxic (CD8+) T lymphocytes, and reduces CD4+:CD8+ ratio to <1 in cerebrospinal fluid (CSF) of MS patients. VDZ does not decrease WBCs, CD4+ or CD8+ T lymphocytes, or the CD4+:CD8+ ratio in CSF of rhesus monkeys. We studied the effects of VDZ on CD4+:CD8+ lymphocyte ratio and cell counts in CSF of healthy volunteers.

Methods: Healthy subjects ages 18–45 underwent lumbar puncture (LP) before and after a single 450 mg dose of VDZ. Each subject served as his/her own control. ∼15 mL CSF was obtained from each subject for immunophenotyping. CSF samples had to meet the following criteria: ≤10 RBCs/µL per sample (to minimize peripheral blood contamination), negative CSF culture, adequate T‑lymphocyte numbers in each flow cytometry sample, and no serum antibodies to VDZ detected.

Results: 14 subjects underwent LP; 13 were eligible for analysis (1 excluded due to VDZ antibodies). Mean (SD) CD4+:CD8+ ratios were 3.59 (0.985) at baseline and 3.61 (0.956) post-VDZ. Mean ratio difference (SD; 90% CI) pre- and post-VDZ was 0.01 (0.709; −0.337, 0.363). No subject had a postdose CD4+:CD8+ ratio <1. No significant changes in CSF % CD4+ and % CD8+ T lymphocytes were observed after VDZ dosing: mean % CD4+ predose, 75%; postdose, 74%; mean % CD8+ predose, 22%; postdose, 22%.

Conclusions: These data show that VDZ does not affect CSF CD4+ and CD8+ cell counts or CD4+:CD8+ ratio in healthy volunteers. These results are consistent with VDZ's lack of effect on physiologic CNS immune surveillance and pathologic CNS inflammation in monkeys. VDZ's gut selectivity, including lack of observed effect on lymphocytes in CSF, may translate to lower risk of opportunistic CNS infections such as PML.