# Optimizing the Efficacy and Safety of CD33-Targeted Immunotherapy for Acute Myeloid Leukemia and Other CD33+ Disorders

> **NIH NIH R50** · FRED HUTCHINSON CANCER CENTER · 2024 · $161,878

## Abstract

ABSTRACT
Therapies targeting CD33 have long been pursued to improve outcomes in acute myeloid leukemia (AML).
Longer survival with the CD33 monoclonal antibody (mAb)-drug conjugate gemtuzumab ozogamicin (GO)
validates this approach. However, CD33 is a challenging target: several drugs have failed clinically, and benefit
with GO is restricted to AML patient subsets. As one possible shortcoming, almost all CD33-directed drugs,
including GO, recognize the membrane-distal V-set domain of CD33. As a basis for new therapies, the laboratory
of the Unit Director (Roland B. Walter, MD PhD MS) has raised new, fully human mAbs not only against the V-
set domain but also the membrane-proximal C2-set domain of CD33; the latter show enhanced effector cell
functions and target all naturally occurring CD33 variants (i.e., are “CD33PAN” mAbs). With these mAbs now
available, the Walter Lab will conduct well-controlled mechanistic in vitro and in vivo studies to optimize the
efficacy and safety of CD33-targeted therapy, with the explicit goal of patient application. We will primarily focus
our efforts on radioimmunotherapy (RIT) with the alpha particle emitting radioisotope astatine-211 (211At),
leveraging the exquisite radiosensitivity of AML cells, the high potency and target cell selectivity of 211At, and our
institutional infrastructure and expertise in bringing 211At-based RIT from the bench to the clinic. Because CD33
is also displayed on normal blood cells, CD33-targeted drugs cause significant “on-target, off-AML cell” toxicity,
most notably prolonged, profound myelosuppression. Therefore, in parallel to our work on maximizing the
efficacy of CD33-targeted therapy, we are also developing novel gene editing approaches to protect normal
hematopoietic stem and progenitor cells from these drugs to widen their therapeutic window and make their use
safer. The Research Specialist, George S. Laszlo, PhD, has been a member of the Walter Lab since its inception
in 2010. He has been responsible for the training, guidance, and supervision of all technicians as well as the
development and validation of all experimental methodologies, approaches, assays, and generation of all
tools/reagents that, together, built the foundation for the NCI-supported research program on optimizing CD33-
directed therapy as well as several other NIH-supported research projects that the Walter Lab is involved in. A
total of 22 peer-reviewed joint publications between Drs. Laszlo and Walter (9 with Dr. Laszlo as first author)
document their fruitful work relationship. Over the next 5 years, Dr. Laszlo will be essential for the conduct of our
studies described in this application, with key roles in the generation, production, purification, and
characterization of recombinant mAbs and derived therapeutics, the development of genetically engineered cell
line-based tools for drug testing, and the in vivo assessment of drug efficacies against human AML cells. With
his skills and expertise, Dr. Las...

## Key facts

- **NIH application ID:** 10906142
- **Project number:** 5R50CA274319-02
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** GEORGE S LASZLO
- **Activity code:** R50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $161,878
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906142

## Citation

> US National Institutes of Health, RePORTER application 10906142, Optimizing the Efficacy and Safety of CD33-Targeted Immunotherapy for Acute Myeloid Leukemia and Other CD33+ Disorders (5R50CA274319-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10906142. Licensed CC0.

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