# Design of de novo interleukin mimics for targeted immunotherapy

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $345,873

## Abstract

PROJECT SUMMARY
Although immunostimulatory cytokines can be used to combat cancer, their poor stability and high off-target
toxicity has limited their application in the clinic. The ​long-term goal of this project is to produce targeted
anti-cancer cytokine mimetics with reduced toxicity. The ​overall objective is to apply recent breakthroughs in ​de
novo protein design to yield a new category of targeted, non-toxic, immunostimulatory proteins. The ​central
hypothesis is that the beneficial stimulatory effects of natural cytokines can be engineered into ​de novo
designed proteins which do not engage in off-target binding, thereby circumventing the dose-limiting toxicities
seen in clinical applications of natural/reengineered cytokines. The ​specific aims are to: (1) use ​de novo protein
design to generate hyperstable, bioactive mimetics of interleukin-2, -4, -12, -15, and -21 which function by
engaging with (i.e. binding to) interleukin receptors ​in vivo​; (2) to split these mimics into inactive parts which
can regain activity by reassembling ​in vivo​; and (3) to fuse each of these inactive parts to specific targeting
domains, thereby yielding conditionally-active cytokine mimics that stimulate T-cells by reassembling only on
the surface of a targeted cells (i.e. cancer cells displaying two specific surface biomarkers). ​As proof of
principle​, the first such ​de novo designed cytokine mimetic has been produced, split, and shown to reduce
tumors in mice without accompanying toxicity or immunogenicity. This research proposal is ​innovative because
it seeks to resolve a long-standing barrier to cancer immunotherapy (namely, the off-target toxicity of
cytokine-based therapeutics) by designing from scratch a new class of non-toxic cytokine mimics. The
proposal is ​significant because it would be the first example of computational protein design yielding targeted,
biosuperior cancer therapeutics. Ultimately, such molecules have the potential to treat a wide range of cancers,
including malignant melanoma, renal cell carcinoma, and more.

## Key facts

- **NIH application ID:** 10232145
- **Project number:** 5R01CA240339-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** DAVID BAKER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $345,873
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232145

## Citation

> US National Institutes of Health, RePORTER application 10232145, Design of de novo interleukin mimics for targeted immunotherapy (5R01CA240339-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10232145. Licensed CC0.

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