853 Design of a next generation tumor targeted masked IL-12Fc for enhanced tolerability and localized anti-tumor activity
Bibliographic record
Abstract
Background IL-12 is a potent immunostimulatory cytokine whose use as an anti-tumor therapeutic has been limited by severe toxicities associated with systemic administration. Tumor targeting and conditional activation in the tumor microenvironment (TME) are two alternative, potentially complementary, strategies to increase therapeutic index of cytokines. To improve the pharmacokinetics and tolerability of IL-12, we have engineered a masked, protease activated human IL-12Fc with attenuated potency (ZW270). ZW270 is engineered with an internally developed, highly efficient cleavage sequence to provide conditional activation of IL-12Fc in a protease-rich tumor environment. Previous data has shown efficient masking of IL-12Fc activity, improved pharmacokinetics and an expanded therapeutic index of ZW270 in vivo compared to wild type IL-12Fc. ZW270 was well tolerated in non-human primates (>30mg/kg) with slow extended release in the serum.1 While this data demonstrates the benefits of the above combined strategies, additional benefit could be gained by targeting ZW270 to the tumor environment, increasing retention time and further localizing IL-12 activity.Methods To delineate the advantages of targeting a conditionally masked IL-12Fc to the tumor environment, with a tumor targeting Fab, we developed a surrogate masked, protease activated, potency attenuated, mouse IL-12Fc, mZW270. The potency, efficacy and tolerability of a targeted mZW270 was evaluated in vitro and in syngeneic tumor models.Results Targeted mZW270 demonstrated efficient masking and attenuated potency, similar to ZW270, in in vitro splenocyte and reporter gene assays. In vivo, compared to wild type mouse IL-12Fc (no masking, attenuation or targeting), it was better tolerated with no early severe bodyweight loss, highlighting the advantage of combined masking and attenuation strategies. In syngeneic and transgenic models, with varying tumor antigen densities, targeted mZW270 activated a local tumor immune response, leading to strong anti-tumor activity, lowering the minimum effective dose without decreasing the tolerability. Initial characterization of a targeted ZW270 indicated translatability of these observations to a human therapeutic.Conclusions Overall, our combined strategies of masking, potency attenuation and tumor targeting can be incorporated to widen the therapeutic index of an IL-12 based therapeutic.Reference Poffenber, et al. ZW270, a conditionally masked IL-12 cytokine fusion protein displaying potent anti-tumor activity absent systemic toxicity. Cancer Res. 2023;83(7_Supplement):2935. https://doi.org/10.1158/1538-7445.AM2023-2935. AACR 2023
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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".