Treatment of Autosomal Recessive Interleukin-7 Deficiency with NT-I7 (Efineptakin Alfa), Long-Acting Recombinant Human Interleukin-7: An Expanded Access Protocol
Bibliographic record
Abstract
Background Interleukin-7 (IL-7) is a cytokine required for T cell development and homeostasis. IL-7 signal transduction is mediated by STAT5 phosphorylation and results in cell proliferation and anti-apoptotic effects. While genetic deficiencies in any of the components of IL-7 receptor (IL-7Rα or γ-chain) result in severe combined immunodeficiency, the recently discovered autosomal recessive IL-7 cytokine deficiency presents with a less severe phenotype characterized by T cell lymphopenia, recurrent HPV diseases complicated by cutaneous squamous cell carcinomas, and other opportunistic infections. NT-I7 is a long-acting human recombinant IL-7, and we hypothesize that treatment of patients with autosomal recessive IL-7 deficiency with NT-I7 will result in T cell expansion, regression of HPV-related diseases, and prevention of HPV-related cancers and opportunistic infections. Methods Peripheral blood mononuclear cells (PBMCs) from 2 patients with IL-7 deficiency were studied. Flow cytometric assays were used to evaluate the integrity of the IL-7 signaling axis and its downstream effect on T cell survival and proliferation by measuring the expression of CD127 (IL-7Rα), STAT5-phosphorylation, and BCL-2 and Ki-67 expression in response to IL-7 stimulation. Results Patients with IL-7 deficiency were found to have preserved expression of CD127 on CD4+ but not on CD8+ T cells. Accordingly, STAT5-phosphorylation in response to IL-7 stimulation was reduced in CD8+ T cells compared with healthy subjects. Nevertheless, prolonged ex vivo IL-7 stimulation increased BCL2 and Ki67 expression in both CD4+ and CD8+ T cells to a level comparable with that observed in healthy subjects. Furthermore, a preferential proliferation of CD31+ CD4+ naive T cells was noted. These ex vivo data supported the development of an investigational new drug expanded access clinical protocol using NT-I7, which was designed, approved, and launched. NT-I7 will be given up to 5 injections: 12 weeks apart for the first 3 doses, then every 24 weeks for the final 2 doses, allowing for dose escalation based on safety and clinical response. Conclusions The ex vivo anti-apoptotic and proliferative effect of IL-7 on T cells from patients with IL-7 deficiency raises the promising possibility that NT-I7 will have a similar effect in vivo in this as well as other inborn errors of immunity associated with impaired T cell homeostasis. Figure 1. Baseline CD127 expression, phosphorylated STAT5 and BCL2 signal transduction with IL-7 stimulation, and T cell proliferation assays in IL-7–deficient patients as compared with healthy controls. (a) Expression of CD127 on CD4+ and CD8+ T cells. (b) Phosphorylated STAT5 percent in response to stimulation with IL-7 (1 ng/ml). (c) BCL2 expression after incubation of CD4+ and CD8+ T cells with IL-7. (d) CD4+ and CD8 + T cell proliferation in response to IL-7 incubation as measured by Ki67 expression. (e) Proliferation of naive CD4+ T cells in response to IL-7 incubation as measured by Ki67 expression. Figure 2. Timeline of expanded access protocol screening, NT-I7 dosing, and laboratory monitoring. (a) Timeline of expanded access protocol screening, NT-I7 dosing, and laboratory monitoring. (b) Structure of NT-I7 demonstrating N terminus human IL-7 fused to a hyFc long-acting platform that combines the hinge flexibility of IgD and recycling of IgG4 to minimize protein–protein interactions and increase serum half-life. Table 1. Baseline clinical features of two patients with IL-7 deficiency.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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) | 0.003 | 0.000 |
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".