# Novel Approaches to CD33-Directed Radioimmunotherapy

> **NIH NIH R37** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $686,273

## Abstract

Antigen-specific immunotherapies have long been pursued for acute myeloid leukemia (AML). So far most
exploited are antibodies targeting the membrane-distal V-set domain of CD33, a glycoprotein displayed on the
cell surface of leukemic blasts in almost all cases and possibly leukemia stem cells in some. Improved survival
of some patients with gemtuzumab ozogamicin validates this approach but many patients with CD33+ AML do
not benefit from this antibody-drug conjugate, prompting interest in developing improved CD33-directed
therapeutics. Because AML cells are exquisitely radiosensitive across the entire genetic disease spectrum, a-
emitting radionuclides are ideal to arm anti-CD33 antibodies. Unlike b-emitters, they deliver a very high amount
of radiation over just a few cell diameters, thereby enabling precise and efficient target cell kill (as few as 10 a-
particle hits are sufficient to kill a malignant hematopoietic cell). Early clinical trials with an anti-CD33 antibody
labeled with actinium-225 (225Ac-lintuzumab) have been conducted. Besides high cost, however, important
shortcomings include the long half-life of 225Ac, leading to freely circulating radionuclide if not retained effectively
in target cells, and the release of daughter radionuclides after decay of 225Ac with risk of associated toxicity to
healthy tissues. We hypothesize that labeling with astatine-211 (211At), an a-emitter we have focused on because
of its shorter half-life and because it decays without production of any long-lived or potentially dangerous
daughter isotopes, will provide a novel, superior form of CD33-directed radioimmunotherapy (RIT). Using
humanized mice, we have recently generated a panel of fully human antibodies recognizing either the V-set
domain or, as the first group, the membrane-proximal C2-set domain of human CD33. Since the V-set but not
C2-set domain is missing in some CD33 variants, C2-set domain-directed antibodies can recognize all naturally-
occurring variants of CD33 (i.e. are “CD33PAN antibodies”). With these antibodies available, we now plan to
optimize CD33-directed RIT for application in AML patients, focusing on 211At. To accomplish this task, we have
assembled a multidisciplinary team of investigators with complementary expertise in developing
radioimmunoconjugates and other antibody-based therapeutics for AML. Envisioning broad use, we will study
211At-CD33 RIT as “stand-alone” therapy and as augmentation of HCT conditioning, focusing on MHC-
haploidentical in vivo models AML. Since many HCT candidates do not have an HLA-matched donor, facilitation
of alternative donor HCT remains a critical unmet need, particularly for the extension of this lifesaving option to
patients from ethnic minority groups. We expect results from our studies will be readily translatable into the clinic
and are anticipated to have an important positive impact as they will provide the groundwork for a new treatment
option for patients with AML and other CD33+ n...

## Key facts

- **NIH application ID:** 9913021
- **Project number:** 1R37CA240832-01A1
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Roland Bruno Walter
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $686,273
- **Award type:** 1
- **Project period:** 2019-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913021

## Citation

> US National Institutes of Health, RePORTER application 9913021, Novel Approaches to CD33-Directed Radioimmunotherapy (1R37CA240832-01A1). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/9913021. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*