# Endothelial Cell-Targeted Amatoxin Conjugates for Effective Therapy of Breast Cancer

> **NIH NIH R01** · PROTEOGENOMICS RESEARCH INSTIT/SYS/ MED · 2020 · $735,974

## Abstract

SUMMARY
The overall objective of the proposed project is to harness a newly discovered, active transendothelial
transport pathway, the caveolae pumping system, to provide an effective solution to the delivery and toxicity
problem of chemotherapeutics in metastatic breast cancer treatment. We propose to develop novel antibody-
drug conjugates (ADCs) that exploit our newly discovered endothelial cell (EC) caveolae targeting system in
order to improve the delivery and targeting of modern chemotherapeutics. We have established that EC
caveolae in preclinical models can rapidly and specifically pump Annexin A1 (AnnA1) antibodies and attached
cargo across the vascular endothelial barrier directly into solid tumors. Based on this discovery, we propose to
design novel EC caveolae-targeted ADCs that may revolutionize treatments for metastatic breast cancer. We
have created a robust delivery platform by arming hAnnA1 with amatoxins, a class of ultra-potent toxins that
can effectively kill both rapidly dividing and dormant tumor cells. These include α-Amanitin, a toxin derived
from the “death cap” mushroom and Chaetocin, an anti-proliferative, broad-spectrum toxin derived from the
filamentous fungus Chaetomiun sp. Our main hypothesis is that caveolae-targeted antibody-drug conjugates
(CTAs), will dramatically increase delivery of ultra-potent toxins specifically into tumors, thereby requiring much
lower dosages and dramatically enhancing efficacy of cancer treatment. This hypothesis will be tested by the
following specific aims: In Aim 1, we will design and characterize novel hAnnA1-toxin CTAs. We will optimize
their physicochemical properties, stability, release kinetics in the tumor interstitium, and binding affinity towards
the human Annexin A1 protein. In Aim 2, we will evaluate therapeutic efficacy, drug delivery and off-target
effects of candidate CTAs in human tumor models of breast cancer using intravital microscopy (IVM). In Aim 3,
we will examine the therapeutic efficacy of the select CTAs in metastatic tumor models and in patient-derived
xenograft (PDX) models. We will also prepare a foundation for clinical testing, where successful targeted
therapeutics will be selected as candidates for future Phase 1 safety trial. Tumor targeting, delivery and
accumulation of these novel therapies will be assessed in rodents using x-ray/CT imaging, IVM, and histology.
The long-term goal is to translate our key basic discoveries into a unique, innovative delivery platform that may
vastly improve treatments for solid cancers.

## Key facts

- **NIH application ID:** 9954072
- **Project number:** 5R01CA240703-02
- **Recipient organization:** PROTEOGENOMICS RESEARCH INSTIT/SYS/ MED
- **Principal Investigator:** Bogdan Olenyuk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $735,974
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9954072

## Citation

> US National Institutes of Health, RePORTER application 9954072, Endothelial Cell-Targeted Amatoxin Conjugates for Effective Therapy of Breast Cancer (5R01CA240703-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9954072. Licensed CC0.

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