# Project 4 - Targeting AML using novel bispecific and antibody-drug conjugates.

> **NIH NIH P50** · WASHINGTON UNIVERSITY · 2020 · $324,449

## Abstract

Project Summary
The long-term goal of this project is to develop and translate into early phase clinical trials novel
antibody-based reagents for the treatment of acute myelogenous leukemia (AML). Less than half of AML
patients are cured with current treatment approaches, and relapse and refractory AML patients have a median
overall survival of about 4 months. Allogeneic hematopoietic cell transplant (alloHCT) remains the only curative
therapy for patients with relapsed and refractory AML. However, wider application of alloHCT has been limited
by the morbidity associated with the procedure, which arises from graft-versus-host disease and from the
toxicity of the conditioning regimen, a course of cytotoxic drugs and/or irradiation that is used to enable
engraftment of donor hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. In this proposal,
we will utilize antibody-based immunotherapy approaches to treat AML relapse and allow for alloHCT
without the need for chemotherapy and/or irradiation. In Aim 1, we will conduct a “first-in-human” Phase I
clinical trial of AMV564, a CD33 x CD3 tetravalent bispecific antibody in patients with relapsed or refractory
AML (ClinicalTrials.gov id: NCT03144245). This study is designed in two segments: a Dose Escalation Stage
testing up to 10 doses of AMV564 at 3 patients per dose, followed by an Expansion Stage segment at the
recommended Phase 2 dose of AMV564. We will characterize the immunomodulatory activity and potential
anti-tumor activity of AMV564 by completing correlative studies evaluating (1) serum cytokines, (2) AML and T
cell subset numbers, phenotype and function and (3) the subclonal architecture of AML blasts. In Aim 2, we
will determine if antibody-based drug conjugates can mitigate cytokine release syndrome (CRS) associated
with T cell immunotherapeutics, kill AML blasts and provide conditioning for alloHSCT. T cell engaging
therapies, which include bispecific retargeting reagents like AMV564, have been limited by CRS. We will test if
targeted depletion of macrophage and monocyte populations with toxin-conjugated antibody fragments or
modulation of the IFNγ and IL-6 signaling pathways will prevent CRS mediated by T cell engaging therapies. If
successful, these CRS-mitigating strategies would reduce the main limitation currently facing T cell engaging
therapies. Next, we will test if toxin-conjugated antibody antigen binding fragments (Fabs) or bispecific
antibodies targeting HSPCs/AML (via CD45 or c-Kit) and T lymphocytes/NK cells (via CD2 or CD7) can
simultaneously treat AML and provide conditioning for alloHCT without the need for radiation or chemotherapy.
The potential applications of this more targeted and less toxic conditioning regimen are not limited to alloHCT
alone, but would also provide a platform for autologous gene therapy for inborn errors of metabolism,
hemoglobinopathies, and primary immune deficiencies.

## Key facts

- **NIH application ID:** 9961540
- **Project number:** 5P50CA171963-08
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** John F. Dipersio
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $324,449
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961540

## Citation

> US National Institutes of Health, RePORTER application 9961540, Project 4 - Targeting AML using novel bispecific and antibody-drug conjugates. (5P50CA171963-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9961540. Licensed CC0.

---

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