Fingolimod synergizes with anti-PD-1 radioimmunotherapy in an experimental multiple sclerosis model through enhanced lymph node retention and CD8+ T cell depletion
Bibliographic record
Abstract
Introduction Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease caused by inappropriate activation of the immune system that targets central nervous system antigens, such as myelin. Some MS therapies control the disease through the depletion of CD20+ B cells and the sequestration of T lymphocytes in lymph nodes. A targeted approach aimed at depleting only activated T lymphocytes, which play a key role in disease progression, would be optimal. Programmed cell death protein 1 (PD-1) is an inhibitory receptor expressed on exhausted and recently activated T cells. We have previously reported success with [177Lu]Lu-anti-PD-1 (177Lu-αPD-1) radioimmunotherapy (RIT) as a standalone treatment in experimental autoimmune encephalomyelitis (EAE), which is the most common preclinical model of MS. In this study, we present the synergistic effect of fingolimod (FTY720/Gilenya™) in combination with [177Lu]Lu-αPD-1 in EAE. Methods [177Lu]Lu-αPD-1 and [111In]In-αPD-1 were prepared by conjugating a commercial anti-murine PD-1 antibody with a DOTA bifunctional chelating agent. Therapy using [177Lu]Lu-αPD-1 ± FTY720 was initiated at the EAE symptom onset in MOG 35–55 immunized C57Bl/6 mice. ImmunoSPECT/CT imaging utilizing [111In]In-αPD-1 was performed with or without FTY720 administration at the symptom onset in EAE mice. Flow cytometry was performed on spinal cord mononuclear cells isolated from EAE mice 7 days post treatment with RIT ± FTY720. Results [177Lu]Lu-αPD-1 in combination with FTY720 administration significantly reduced long-term paralysis in EAE mice. ImmunoSPECT/CT imaging revealed enhanced lymph node retention of [111In]In-αPD-1 antibody in conjugation with FTY720, corresponding to the presence of activated lymphocytes in lymph nodes. Flow cytometry performed on isolated spinal cord mononuclear cells demonstrated a significant reduction in CD8+ T cell counts in the spinal cords of animals treated with [177Lu]Lu-αPD-1 and [177Lu]Lu-αPD-1 + FTY720. Immunofluorescent microscopy of thoracic spinal cord sections from treated animals demonstrated reduced demyelination and moderate infiltration of CD3+ lymphocytes in the [177Lu]Lu-αPD-1 + FTY720 group at study termination. Conclusion [177Lu]Lu-αPD-1-targeted radioimmunotherapy was synergistically enhanced utilizing the approved MS therapeutic FTY720 through increased lymph node retention and irradiation of activated T lymphocytes. This study paves the way for the application of PD-1+ T cell-targeted radioimmunotherapy as a potential theranostic agent for MS.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".