# Development of 211Astatine-Conjugated Anti-CD45 Antibody-Based Conditioning for Hematopoietic Stem Cell Gene Therapy and Editing

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $1

## Abstract

ABSTRACT
The inherited disorders of hemoglobin (Hb) are the most common monogenic diseases worldwide and, even in
developed countries, associated with substantial morbidity and shortened life expectancy. Allogeneic
hematopoietic cell transplantation (HCT) is clinically pursued as a means to treat the underlying cause of these
disorders – the genetic defect in the patients’ hematopoietic stem and progenitor cells (HSPCs). However, this
approach is limited by the availability of HLA-matched donors in the majority of patients and associated
immunological complications. Use of autologous HSPCs either transduced with a functional b-hemoglobin gene
or modified with recently-developed genome-editing technologies would overcome the current limitations of
allogeneic HCT. In particular, the recapitulation of naturally-occurring hereditary persistence of fetal hemoglobin
(HPFH) mutations in HSPCs using gene editing can, in principle, reverse the clinical phenotype of these
disorders. However, just like with allogeneic HCT, there is still need for conditioning to facilitate engraftment of
these cells. To date, this is accomplished with g-beam total body irradiation (TBI) or alkylating agents such as
busulfan which carry the risk of significant toxicities including infertility, growth retardation, and – as has already
been reported – secondary malignancies. Thus, a critical remaining factor for next-generation transplant
approaches and gene therapy/editing will be the development of nongenotoxic conditioning regimens that have
minimal toxicity and allow robust engraftment of allogeneic or modified autologous HSPCs. One promising
strategy is the use of radioimmunotherapy (RIT) with a-emitting radionuclides conjugated to antibodies targeting
CD45, an antigen expressed on almost all hematopoietic cells except platelets and erythrocytes and some of
their progenitors. Compared to b-emitters, a-emitters deliver a higher amount of energy over just a few cell
diameters for potent, precise, and efficiently targeted cell kill and minimized toxicity to non-targeted surrounding
cells. With a half-life of 7.2 hours, astatine-211 (211At) is ideal for patient application. Based on our previous
studies in dogs demonstrating that 211At-anti-CD45 RIT can replace g-beam TBI as conditioning before allogeneic
HCT, we are currently using 211At-anti-CD45 RIT in patients with active hematologic malignancies. We now plan
to develop 211At-anti-CD45 RIT as conditioning before autologous transplantation of gene-modified HSPCs for
people with hemoglobinopathies, exploiting Fc engineering of antibodies to further minimize non-specific
toxicities associated with RIT. We hypothesize that optimized 211At-anti-CD45 RIT will enable engraftment of
autologous HSPCs edited with CRISPR/Cas9 at the g-globin gene locus to reproduce HPFH mutations and have
significantly less off-target toxicities and better tolerability than the standard conditioning with high-dose g-beam
TBI. As we are interested in...

## Key facts

- **NIH application ID:** 10159976
- **Project number:** 5R01HL151765-02
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** HANS-PETER KIEM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2020-05-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159976

## Citation

> US National Institutes of Health, RePORTER application 10159976, Development of 211Astatine-Conjugated Anti-CD45 Antibody-Based Conditioning for Hematopoietic Stem Cell Gene Therapy and Editing (5R01HL151765-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10159976. Licensed CC0.

---

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