# Small Molecule PSMA-Targeted Alpha Therapy

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $389,581

## Abstract

Project Summary
Despite the expanding array of new targeted agents to treat castration-resistant prostate cancer (CRPC), the
disease remains incurable with nearly half of men with this form of PC developing bone metastases at two years.
Metastatic bone disease carries a one-year survival rate of ~40%. Targeting the prostate-specific membrane
antigen (PSMA) with small molecules for imaging and radionuclide therapy (RT) of prostate and other cancers
has revitalized the field of nuclear medicine. Novartis has recently acquired [177Lu]R2, developed by us, and
[177Lu]PSMA-617, two PSMA-targeted RT labeled with the β-particle emitter 177Lu that are in multi-center clinical
trials. In Europe, there have been preliminary trials using the α-particle emitting agent [225Ac]PSMA-617 that
have shown substantial treatment effects, even in patients that became resistant to the corresponding 177Lu-
labeled compound. However, these encouraging responses to targeted α-particle RT (TAT) often came at the
expense of immediate ablation of the salivary and lacrimal glands, with long-term toxicities unknown. Accordingly,
despite widespread efforts, translational RT for PC is at a crucial stage, having yet to identify an agent that
provides durable responses without compromising quality of life. The approach that we shall take in this
competing renewal is to extend our basic work focusing on 211At, which emits a single α-particle per decay, to a
low-dose, pharmacokinetic clinical trial. We hypothesize that 211At will provide an intermediate between the
minimally toxic, but less effective 177Lu and the more powerful but potentially damaging 225Ac, which emits a total
of four α-particles per decay that are difficult to control in vivo and promote the aforementioned toxicity. Our goal
is to have an agent with an optimal therapeutic index by combining the high linear energy transfer (LET) tumor
cell kill of 211At with greater control of toxicity through molecular design for salutary pharmacokinetics and dosing
strategies. Preliminary in vivo data with our lead 211At-labeled compound, [211At]VK-02-90-Lu, indicates much
lower off-target toxicity than for a related 225Ac-labeled adduct, confirmed by immunohistochemistry, with similar
survival characteristics. The current program is intended to provide the experimental rationale and data for an
IND-enabling therapeutic study.

## Key facts

- **NIH application ID:** 10092113
- **Project number:** 5R01CA184228-07
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** MARTIN G POMPER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $389,581
- **Award type:** 5
- **Project period:** 2014-05-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092113

## Citation

> US National Institutes of Health, RePORTER application 10092113, Small Molecule PSMA-Targeted Alpha Therapy (5R01CA184228-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10092113. Licensed CC0.

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