Fertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model

Naoya Uchida (), Ulana Stasula, Selami Demirci, Paula Germino-Watnick, Malikiya Hinds, Anh Le, Rebecca Chu, Alexander Berg, Xiong Liu, Ling Su, Xiaolin Wu, Allen E. Krouse, N. Seth Linde, Aylin Bonifacino, So Gun Hong, Cynthia E. Dunbar, Leanne Lanieri, Anjali Bhat, Rahul Palchaudhuri, Bindu Bennet, Megan Hoban, Kirk Bertelsen, Lisa M. Olson, Robert E. Donahue and John F. Tisdale
Additional contact information
Naoya Uchida: National Institutes of Health (NIH), Bethesda
Ulana Stasula: National Institutes of Health (NIH), Bethesda
Selami Demirci: National Institutes of Health (NIH), Bethesda
Paula Germino-Watnick: National Institutes of Health (NIH), Bethesda
Malikiya Hinds: National Institutes of Health (NIH), Bethesda
Anh Le: National Institutes of Health (NIH), Bethesda
Rebecca Chu: National Institutes of Health (NIH), Bethesda
Alexander Berg: National Institutes of Health (NIH), Bethesda
Xiong Liu: National Institutes of Health (NIH), Bethesda
Ling Su: Frederick National Laboratory for Cancer Research
Xiaolin Wu: Frederick National Laboratory for Cancer Research
Allen E. Krouse: NHLBI, NIH
N. Seth Linde: NHLBI, NIH
Aylin Bonifacino: NHLBI, NIH
So Gun Hong: NHLBI, NIH
Cynthia E. Dunbar: NHLBI, NIH
Leanne Lanieri: Magenta Therapeutics
Anjali Bhat: Magenta Therapeutics
Rahul Palchaudhuri: Magenta Therapeutics
Bindu Bennet: Magenta Therapeutics
Megan Hoban: Magenta Therapeutics
Kirk Bertelsen: Magenta Therapeutics
Lisa M. Olson: Magenta Therapeutics
Robert E. Donahue: National Institutes of Health (NIH), Bethesda
John F. Tisdale: National Institutes of Health (NIH), Bethesda

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Hematopoietic stem cell (HSC) gene therapy has curative potential; however, its use is limited by the morbidity and mortality associated with current chemotherapy-based conditioning. Targeted conditioning using antibody-drug conjugates (ADC) holds promise for reduced toxicity in HSC gene therapy. Here we test the ability of an antibody-drug conjugate targeting CD117 (CD117-ADC) to enable engraftment in a non-human primate lentiviral gene therapy model of hemoglobinopathies. Following single-dose CD117-ADC, a >99% depletion of bone marrow CD34 + CD90 + CD45RA- cells without lymphocyte reduction is observed, which results are not inferior to multi-day myeloablative busulfan conditioning. CD117-ADC, similarly to busulfan, allows efficient engraftment, gene marking, and vector-derived fetal hemoglobin induction. Importantly, ADC treatment is associated with minimal toxicity, and CD117-ADC-conditioned animals maintain fertility. In contrast, busulfan treatment commonly causes severe toxicities and infertility in humans. Thus, the myeloablative capacity of single-dose CD117-ADC is sufficient for efficient engraftment of gene-modified HSCs while preserving fertility and reducing adverse effects related to toxicity in non-human primates. This targeted conditioning approach thus provides the proof-of-principle to improve risk-benefit ratio in a variety of HSC-based gene therapy products in humans.

Date: 2023
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DOI: 10.1038/s41467-023-41153-5

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