MDNA109: Effect of an interleukin-2 superkine on CD8 T-cell properties in the tumor microenvironment.
Bibliographic record
Abstract
e14220 Background: Proleukin (a cysteine-modified variant of interleukin (IL)-2) is the only common-γc cytokine approved for the treatment of metastatic melanoma and renal cell carcinoma. Its therapeutic use is however hampered by its short half-life and severe toxicity. At low doses, Proleukin administration leads to preferential activation of regulatory T cells (Tregs) due to their expression of the high affinity trimeric IL-2 receptor (IL-2R) consisting of CD25, CD122 and CD132 instead of cytotoxic CD8 T cells expressing the intermediate affinity IL-2R (CD122 and CD132). Methods: To bypass these limitations, we evaluated engineered variants of IL-2 (MDNA109 superkine) exhibiting enhanced affinity towards CD122 including their long-acting and bispecific superkine fusions. This approach allows preferential activation of CD8 T cells while displaying reduced adverse effects in vivo. Results: Both Biacore analysis and signaling studies on human peripheral blood mononuclear cells confirmed enhanced binding of MDNA109 to CD122 and STAT5 activation, respectively. When tested in vivo, MDNA109 co-administration with the immune-checkpoint blockers anti-programmed cell death (PD)-1 or anti-cytotoxic T-Lymphocyte-Associated Protein (CTLA)4 cured mice with pre-established MC38 or CT26 colon cancers respectively. In addition, bi-weekly administration of the long-acting MDNA109-Fc fusion led to similar therapeutic outcomes in the B16F10 model when compared to MDNA109 administered daily. Finally, in vitro and in-vivo results using (a) MDNA109 muteins with completely impaired CD25 binding activity and (b) novel bispecific superkine fusions consisting of MDNA109 and a dual IL-4/IL-13 super-antagonist capable of selective CD8 T-cell activation while mitigating the suppressive functions of myeloid-derived suppressor cells and tumor-associated macrophages will be presented. Conclusions: Altogether, these data demonstrate that both MDNA109 and MDNA109-Fc are therapeutically superior to Proleukin. Furthermore, use of MDNA109-based strategies will not only ensure complete abrogation of adverse effects, but will in addition eliminate immunosuppression caused by both Tregs and myeloid cells.
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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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".