Multiplex base editing to protect from CD33 directed drugs for immune and gene therapy

Florence Borot (), Olivier Humbert (), Jeffrey T. Ehmsen, Emily Fields, Sajeev Kohli, Stefan Radtke, Kyle Swing, Dnyanada Pande, Mark R. Enstrom, George S. Laszlo, Thiyagaraj Mayuranathan, Abdullah Mahmood Ali, Mitchell J. Weiss, Jonathan S. Yen, Gregory A. Newby, Roland B. Walter, David R. Liu, Siddhartha Mukherjee () and Hans-Peter Kiem ()
Additional contact information
Florence Borot: Columbia University
Olivier Humbert: Fred Hutchinson Cancer Center
Jeffrey T. Ehmsen: Johns Hopkins University School of Medicine
Emily Fields: Fred Hutchinson Cancer Center
Sajeev Kohli: Broad Institute of Harvard and MIT
Stefan Radtke: Fred Hutchinson Cancer Center
Kyle Swing: Fred Hutchinson Cancer Center
Dnyanada Pande: Fred Hutchinson Cancer Center
Mark R. Enstrom: Fred Hutchinson Cancer Center
George S. Laszlo: Fred Hutchinson Cancer Center
Thiyagaraj Mayuranathan: St. Jude Children’s Research Hospital
Abdullah Mahmood Ali: Columbia University
Mitchell J. Weiss: St. Jude Children’s Research Hospital
Jonathan S. Yen: St. Jude Children’s Research Hospital
Gregory A. Newby: Johns Hopkins University School of Medicine
Roland B. Walter: Fred Hutchinson Cancer Center
David R. Liu: Broad Institute of Harvard and MIT
Siddhartha Mukherjee: Columbia University
Hans-Peter Kiem: Fred Hutchinson Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The selection of genetically engineered immune or hematopoietic cells in vivo after gene editing remains a clinical problem and requires a method to spare on-target toxicity to normal cells. Here, we develop a base editing approach exploiting a naturally occurring CD33 single nucleotide polymorphism leading to removal of full-length CD33 surface expression on edited cells. CD33 editing in human and nonhuman primate hematopoietic stem and progenitor cells protects myeloid progeny from CD33-targeted therapeutics without affecting normal hematopoiesis in vivo, thus demonstrating potential for improved immunotherapies with reduced off-leukemia toxicity. For broader application to gene therapies, we demonstrate highly efficient (>70%) multiplexed adenine base editing of the CD33 and gamma globin genes, resulting in long-term persistence of dual gene-edited cells with HbF reactivation in nonhuman primates. Using the CD33 antibody-drug conjugate Gemtuzumab Ozogamicin, we show resistance of engrafted, multiplex edited human cells in vivo, and a 2-fold enrichment for edited cells in vitro. Together, our results highlight the potential of adenine base editors for improved immune and gene therapies.

Date: 2025
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DOI: 10.1038/s41467-025-59713-2

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