# Development of caveolae-targeted antibody-drug conjugates

> **NIH NIH P01** · PROTEOGENOMICS RESEARCH INSTIT/SYS/ MED · 2022 · $254,425

## Abstract

PROJECT 2 SUMMARY
The overall objective of the Project 2 is to utilize a newly discovered, active transendothelial transport pathway,
the caveolae pumping system, in order to provide an effective solution to the delivery and toxicity problem of
chemotherapeutics in metastatic breast cancer treatment. In order to address these problems and significantly
improve therapeutic outcome we propose to develop novel antibody-drug conjugates (ADCs) that exploit our
newly discovered endothelial cell (EC) caveolae targeting system in order to sidestep passive delivery problem
of modern chemotherapeutics. We have established that EC caveolae in preclinical models can rapidly and
specifically pump anti-Annexin A1 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 for
greatly enhanced efficacy in tumor destruction in breast cancer. Our main hypothesis is that
immunoconjugates that fully utilize the advantages of the EC caveolae-pumping system will dramatically
increase delivery of chemotherapeutic drugs into tumors, thereby requiring much lower dosages and
dramatically enhancing efficacy of treatment. This hypothesis will be tested by the following specific aims: In
Aim 1, we will design and synthesize Pt(II)-carboxymethyl dextran (CMD) ADCs and optimize carboxylate
derivatization of CMD, conjugation chemistry, and Pt(II) loading in order to maximize binding affinity toward
human Annexin A1 protein. We will test and optimize physicochemical properties, stability on storage, in
human plasma, and Pt(II) release kinetics in the tumor interstitium. In Aim 2 we will assess therapeutic efficacy
of the ADCs in metastatic cancer models. The efficacy of our targeted delivery system will be examined in
MDA-231-LM2-4, and rat tumor models with 13762 breast cancer cells metastasized to lung using whole-body
animal imaging with X-ray/CT. In Aim 3 we will examine the therapeutic efficacy of the ADCs in tumors with
human blood vessels using intravital microscopy (IVM). We will monitor tumor size in response to therapy in
human-on-human IVM model using BT-474 tumor spheroids, and in patient-derived xenografts (PDX) IVM
model. In this Aim we will also translate our select preclinical candidate for clinical testing, where successful
targeted therapeutic will be selected as clinical candidates for cGMP production (Core B) for subsequent
testing in a Phase 1 safety trial in Project 3. Antibodies for conjugation to form ADCs will be provided by Core
B. Core B will also provide quality control analysis of ADCs and confirmation of antibody binding affinity
following conjugation. Tumor targeting, delivery and accumulation of these novel therapies will be assessed in
rodents using multi-modality imaging services provided by Core C, which includes X-ray/CT, SPECT-CT, IVM,
and histology. Core E will handle the biostatistical analysis of data generated during the co...

## Key facts

- **NIH application ID:** 10449306
- **Project number:** 5P01CA221775-04
- **Recipient organization:** PROTEOGENOMICS RESEARCH INSTIT/SYS/ MED
- **Principal Investigator:** Bogdan Olenyuk
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $254,425
- **Award type:** 5
- **Project period:** 2019-07-08 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449306

## Citation

> US National Institutes of Health, RePORTER application 10449306, Development of caveolae-targeted antibody-drug conjugates (5P01CA221775-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10449306. Licensed CC0.

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