# Kallikrein-Targeted Alpha-Particle Therapy of Late-Stage Prostate Cancer

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $322,244

## Abstract

PROJECT DESCRIPTION –
This R01 proposal resubmission from The Johns Hopkins University School of Medicine is founded on recent
work spearheaded by Dr. Daniel Thorek in close collaboration with basic science and clinical investigators.
Based upon extensive preliminary and pilot data, the central hypothesis is that a novel targeted
radioimmunotherapy construct, [225Ac]hu11B6, will be an important tool to treat late-stage disseminated and
locally advanced prostate cancer. The monocloncal antibody hu11B6 enables highly specific targeting of
active-hK2, a protease solely expressed in prostate-derived tissues and prostate carcinoma, that is tightly
regulated by the androgen receptor (AR). While treatment is effective if disease is detected early, disseminated
prostate cancer is incurable and claims a staggering 30,000 lives/year in the United States. To address our
hypothesis that targeted alpha-particle radioimmunotherapy with [225Ac]hu11B6 can effectively ablate late-
stage and disseminated disease, we propose three Specific Aims. In Specific Aim 1 (SA1) we establish the
global pharmacokinetic profile and survival benefit of the construct in models of 1) osseous metastases and 2)
novel genetically engineered models of aggressive adenocarcinoma with appropriate non-specific and excess-
blocked controls. Next, in SA2 we profile the microscopic distribution and radiobiological action of
[225Ac]hu11B6 in the advanced tumor setting. This rigorous approach enables us to define biological factors
which influence uptake, and to evaluate treatment response at the scale upon which alpha-particle therapy
exerts its effects. SA3 builds upon our extensive evaluation of the approved alpha-emitting 223Ra in models of
advanced disease to use it in combination with [225Ac]hu11B6. This forms an innovative combination alpha-
particle therapy strategy to enhance the efficacy of each agent by irradiating both the cancer cells and their
surrounding bone metastatic microenvironment, while avoiding overlapping toxicities. The innovation of this
proposal derives from the original design of the [225Ac]hu11B6 construct in addition to its evaluation in
advanced models that reflect fatal late-stage disease biology. There is a clear biological mandate that AR-
amplification is the mechanism by which advanced disease develops to the castrate resistant stage. The
proposed approach is distinguished from contemporary targeted prostate cancer radionuclide therapies (such
as PSMA- or bombesin-targeting therapies) in that it systematically targets a tumor-associated protein whose
expression is exclusively associated with prostate tissue and correlates with AR-activity. These considerations
directly influence the overall impact of this proposal, as we respectfully submit that we have developed a
uniquely potent and specific tool to eradicate disseminated foci of disease for which there is no current
treatment. As indicated by our Preliminary Data, this proposal has the potential to motiv...

## Key facts

- **NIH application ID:** 9960437
- **Project number:** 5R01CA201035-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Daniel Lyndon Jaffe Thorek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $322,244
- **Award type:** 5
- **Project period:** 2016-12-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960437

## Citation

> US National Institutes of Health, RePORTER application 9960437, Kallikrein-Targeted Alpha-Particle Therapy of Late-Stage Prostate Cancer (5R01CA201035-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9960437. Licensed CC0.

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