# Development of Antibody-RNAi Conjugates (ARCs) to Treat Lung Cancer

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $171,281

## Abstract

ABSTRACT
Lung cancer (small cell and Non-Small Cell Lung Cancer [NSCLC]) is the number one cause of cancer
death in men and women in the US with more people dying of lung cancer than the combined total from
colon, breast and prostate cancer (>150K deaths/year). While newer chemotherapeutic approaches
have shown some improvements, ~70% of NSCLC patients escape all of these therapies and succumb
to the disease. Consequently, there is a great need to develop novel genetic precision medicine
therapeutics that specifically target and kill lung cancer cells based on their oncogenic mutations, while
sparing normal cells. siRNA-induced RNA interference (RNAi) responses have great potential to develop
truly precision genetic medicines that can target the entire “undruggable” genome. Indeed, RNAi
targeting of the otherwise undruggable KRASMut and cMYC master oncogenes that drive cancer growth
and survival can induce a synthetic lethal RNAi response that selectively kills lung cancer cells, while
leaving the surrounding normal cells unharmed. Unfortunately, despite its promising therapeutic
features, due to their requisite negatively charged phosphate backbone, siRNAs have no ability to enter
cells and require a delivery agent. Consequently, siRNA delivery remains the technological problem to
solve for development of RNAi therapeutics to treat lung cancer. To tackle the RNAi delivery problem,
we pioneered development of a next-generation RNAi trigger, called RiboNucleic Neutral (siRNN)
prodrugs. siRNNs represent a “Prodrug” approach where the negative charge is directly neutralized by a
bioreversible phosphotriester chemical group that allows for self-delivery of monomeric RNAi molecules
into cells. Once inside cells, thioesterase enzymes only present inside of cells, convert neutral siRNNs
into charged siRNAs that induce RNAi responses. Unlike siRNAs, siRNNs have many drug-like
properties, including extreme stability, enhanced delivery and synthetic scalability. The goal of this high
risk/high gain exploratory R21 proposal is treat preclinical mouse models of lung cancer by developing
Antibody-RNAi Conjugates (ARC) that target KRASMut and cMYC oncogenes to induce a synthetic lethal
RNAi response in lung cancer cells. To develop ARCs, we will conjugate our next-generation siRNN
RNAi precision medicine triggers to antibodies targeting the NaPi2b, which is overexpressed on lung
cancer cells. Delivery of RNAi triggers remains the technological problem to solve. Our proposal directly
addresses the delivery problem and targets the otherwise undruggable KRASMut and cMYC driver
oncogenes.

## Key facts

- **NIH application ID:** 9840889
- **Project number:** 5R21CA234740-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** STEVEN F DOWDY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $171,281
- **Award type:** 5
- **Project period:** 2018-12-19 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840889

## Citation

> US National Institutes of Health, RePORTER application 9840889, Development of Antibody-RNAi Conjugates (ARCs) to Treat Lung Cancer (5R21CA234740-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840889. Licensed CC0.

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