Selective hematopoietic stem cell ablation using CD117-antibody-drug-conjugates enables safe and effective transplantation with immunity preservation

Czechowicz, Agnieszka; Palchaudhuri, Rahul; Scheck, Amelia; Hu, Yu; Hoggatt, Jonathan; Sáez, Borja; Pang, Wendy W.; Mansour, Michael K.; Tate, Tiffany; Chan, Yan Yi; Walck, Emily; Wernig, Gerlinde; Shizuru, Judith A.; Winau, Florian; Scadden, David T.; Rossi, Derrick J.

doi:10.1038/s41467-018-08201-x

Cited by 147 publications

(134 citation statements)

References 24 publications

(32 reference statements)

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“…Anti-CD117 ADCs significantly reduce HSPCs in animal models. 42 A major concern targeting CD117 with a potent ADC is its significant expression outside of the hematopoietic system, which raises the possibility of increased toxicity. 43 The even distribution across the major HSPC subtypes would likely make CD300f a more efficient conditioning agent compared with current AML targets being studied, which often have variable HSPC expression.…”

Section: Discussionmentioning

confidence: 99%

Targeting CD300f to enhance hematopoietic stem cell transplantation in acute myeloid leukemia

et al. 2020

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) significantly reduces the rate of relapse in acute myeloid leukemia (AML) but comes at the cost of significant treatment-related mortality. Despite the reduction in relapse overall, it remains common, especially in high-risk groups. The outcomes for patients who relapse after transplant remains very poor. A large proportion of the morbidity that prevents most patients from accessing allo-HSCT is due to toxic nonspecific conditioning agents that are required to remove recipient hematopoietic stem and progenitor cells (HSPCs), allowing for successful donor engraftment. CD300f is expressed evenly across HSPC subtypes. CD300f has transcription and protein expression equivalent to CD33 on AML. We have developed an anti-CD300f antibody that efficiently internalizes into target cells. We have generated a highly potent anti-CD300f antibody-drug conjugate (ADC) with a pyrrolobenzodiazepine warhead that selectively depletes AML cell lines and colony forming units in vitro. The ADC synergizes with fludarabine, making it a natural combination to use in a minimal toxicity conditioning regimen. Our ADC prolongs the survival of mice engrafted with human cell lines and depletes primary human AML engrafted with a single injection. In a humanized mouse model, a single injection of the ADC depletes CD34+ HSPCs and CD34+CD38−CD90+ hematopoietic stem cells. This work establishes an anti-CD300f ADC as an attractive potential therapeutic that, if validated in transplant models using a larger cohort of primary AML samples, will reduce relapse rate and toxicity for patients with AML undergoing allo-HSCT.

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Section: Discussionmentioning

confidence: 99%

Targeting CD300f to enhance hematopoietic stem cell transplantation in acute myeloid leukemia

et al. 2020

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“…By simultaneously targeting the stem cell compartment and malignant cells, the therapeutic goals of HSCT can hypothetically be achieved with toxicities largely confined to the hematopoietic system. Indeed, recent work in murine 17,18,22,23,25,50 , non-human primates 51,52,53 , and early human trials 54 have demonstrated feasibility and limited toxicities of antibody and ADC-based therapies alongside high efficacy in depleting recipient HSCs and/or malignant cells.…”

Section: Discussionmentioning

confidence: 99%

Antibody-drug conjugates targeting CD45 plus Janus kinase inhibitors effectively condition for allogeneic hematopoietic stem cell transplantation

Persaud¹,

Ritchey²,

Choi³

et al. 2020

Preprint

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Despite the curative potential of hematopoietic stem cell transplantation (HSCT), transplant conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADC) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely involved syngeneic HSCT; however, for treatment of acute leukemias or tolerance induction for solid organ transplantation, strategies for allogeneic HSCT (allo-HSCT) are needed. Using murine allo-HSCT models, we show that combining CD45-targeted ADCs with the Janus kinase inhibitor baricitinib enables multilineage alloengraftment with >80-90% donor chimerism. Mechanistically, baricitinib impaired T and NK cell survival, proliferation and effector function, with NK cells being particularly susceptible due to inhibited IL-15 signaling. Unlike irradiated mice, CD45-ADC-conditioned mice did not manifest graft-versus-host alloreactivity when challenged with mismatched T cells. Our studies demonstrate novel allo-HSCT conditioning strategies that exemplify the promise of immunotherapy to improve the safe application of HSCT for treating hematologic diseases.

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“…With more gene therapy products on the horizon (such as hemophilia), the application of in vivo HSC transduction could extrapolate genetic treatments to a larger patient population. Further improvements of in vivo HSC gene therapy with HDAd vectors on the road to clinical application include more effective mobilization protocols (particularly for some patients, such as SCD patients), complete elimination of innate responses upon intravenous injection, more advanced capsid modifications that circumvent pre-existing anti-Ad immunity, improved selection regimens [240,255]…”

Section: Discussionmentioning

confidence: 99%

Adenovirus vectors in hematopoietic stem cell genome editing

Lieber

2019

FEBS Letters

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Genome editing of hematopoietic stem cells (HSCs) represents a therapeutic option for a number of hematological genetic diseases, as HSCs have the potential for self-renewal and differentiation into all blood cell lineages. This review presents advances of genome editing in HSCs utilizing adenovirus vectors as delivery vehicles. We focus on capsid-modified, helper-dependent adenovirus vectors that are devoid of all viral genes and therefore exhibit an improved safety profile. We discuss HSC genome engineering for several inherited disorders and infectious diseases including hemoglobinopathies, Fanconi anemia, hemophilia, and HIV-1 infection by ex vivo and in vivo editing in transgenic mice, nonhuman primates, as well as in human CD34 + cells. Mechanisms of therapeutic gene transfer including episomal expression of designer nucleases and base editors, transposase-mediated random integration, and targeted homology-directed repair triggered integration into selected genomic safe harbor loci are also reviewed.

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Selective hematopoietic stem cell ablation using CD117-antibody-drug-conjugates enables safe and effective transplantation with immunity preservation

Cited by 147 publications

References 24 publications

Targeting CD300f to enhance hematopoietic stem cell transplantation in acute myeloid leukemia

Targeting CD300f to enhance hematopoietic stem cell transplantation in acute myeloid leukemia

Antibody-drug conjugates targeting CD45 plus Janus kinase inhibitors effectively condition for allogeneic hematopoietic stem cell transplantation

Adenovirus vectors in hematopoietic stem cell genome editing

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