A CD117-Amanitin Antibody Drug Conjugate (ADC) Effectively Depletes Human and Non-Human Primate Hematopoietic Stem and Progenitor Cells (HSPCs): targeted Non-Genotoxic Conditioning for Bone Marrow Transplant

Pearse, Bradley R.; McDonough, Sean M.; Proctor, Jennifer L.; Panwar, Rajiv; Sarma, Ganapathy N.; Kien, Lena; Dushime, Junia; Adams, Hillary L.; Hyzy, Sharon L.; Brooks, Melissa; Palchaudhuri, Rahul; Li, Qing; Sawant, Pranoti; Lamothe, Tahirih L.; Jain, Nidhi; McDonagh, Charlotte F.; Boitano, Anthony E.; Cooke, M.

doi:10.1016/j.bbmt.2018.12.101

Cited by 9 publications

(5 citation statements)

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“…These antibodies use the ribosomal inhibiting toxin amanitin and are effective at prolonging survival in mice bearing AML xenografts. Both the CD45 and CD117 amanitin ADC depleted human and nonhuman primate HSPC to confirm the potential utility in conditioning [103,104]. These results are still preliminary but offer a possible pathway to AML immunotherapy incorporating allo-HSCT that avoids the complexities of CAR T cell generation.…”

Section: Strategies Incorporating Allogeneic Hematopoietic Stem Cell mentioning

confidence: 81%

Is Hematopoietic Stem Cell Transplantation Required to Unleash the Full Potential of Immunotherapy in Acute Myeloid Leukemia?

Abadir

Gasiorowski

Silveira

et al. 2020

JCM

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From monoclonal antibodies (mAbs) to Chimeric Antigen Receptor (CAR) T cells, immunotherapies have enhanced the efficacy of treatments against B cell malignancies. The same has not been true for Acute Myeloid Leukemia (AML). Hematologic toxicity has limited the potential of modern immunotherapies for AML at preclinical and clinical levels. Gemtuzumab Ozogamicin has demonstrated hematologic toxicity, but the challenge of preserving normal hematopoiesis has become more apparent with the development of increasingly potent immunotherapies. To date, no single surface molecule has been identified that is able to differentiate AML from Hematopoietic Stem and Progenitor Cells (HSPC). Attempts have been made to spare hematopoiesis by targeting molecules expressed only on later myeloid progenitors as well as AML or using toxins that selectively kill AML over HSPC. Other strategies include targeting aberrantly expressed lymphoid molecules or only targeting monocyte-associated proteins in AML with monocytic differentiation. Recently, some groups have accepted that stem cell transplantation is required to access potent AML immunotherapy and envision it as a rescue to avoid severe hematologic toxicity. Whether it will ever be possible to differentiate AML from HSPC using surface molecules is unclear. Unless true specific AML surface targets are discovered, stem cell transplantation could be required to harness the true potential of immunotherapy in AML.

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Section: Strategies Incorporating Allogeneic Hematopoietic Stem Cell mentioning

confidence: 81%

Is Hematopoietic Stem Cell Transplantation Required to Unleash the Full Potential of Immunotherapy in Acute Myeloid Leukemia?

Abadir

Gasiorowski

Silveira

et al. 2020

JCM

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“…In particular, promising results have been recently reported with use of antibody-drug conjugate (ADCs) for HSCT in both humanized mouse models and nonhuman primates, as well as for autologous gene therapy, and they are expected to translate soon into clinical trials. 17,28,29 These observations will be instrumental to extend a nongenotoxic regimen to patients undergoing secondary HSC transplant for loss of chimerism or insufficient thymic output.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of anti-CD45–saporin as conditioning agent for RAG deficiency

Castiello

Bosticardo

Sacchetti

et al. 2021

Journal of Allergy and Clinical Immunology

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“…Different variations of antibody-based conditioning are being tested both preclinically and clinically, such as antibody-drug conjugates specifically targeting HSPCs. Antibody-drug conjugates (ADC) such as CD177-ADC [ 35 , 36 , 37 ] or CD45-ADC [ 38 , 39 , 40 , 41 , 42 ] have proven to be a safer conditioning regimen than conventional chemotherapy in preclinical models. In addition, monoclonal antibodies targeting CD117 [ 43 , 44 , 45 , 46 ] have been successfully developed and paved the way for the use of the anti-CD117 antibody in a currently ongoing clinical trial (NCT02963064).…”

Section: Discussionmentioning

confidence: 99%

Combining Mobilizing Agents with Busulfan to Reduce Chemotherapy-Based Conditioning for Hematopoietic Stem Cell Transplantation

García-Pérez

Roon

Schilham

et al. 2021

Cells

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In the context of hematopoietic stem cell (HSC) transplantation, conditioning with myelo- and immune-ablative agents is used to eradicate the patient’s diseased cells, generate space in the marrow and suppress immune reactions prior to the infusion of donor HSCs. While conditioning is required for effective and long-lasting HSC engraftment, currently used regimens are also associated with short and long-term side effects on extramedullary tissues and even mortality. Particularly in patients with severe combined immunodeficiency (SCID), who are generally less than 1-year old at the time of transplantation and often suffer from existing comorbidities. There is a pressing need for development of alternative, less toxic conditioning regimens. Hence, we here aimed to improve efficacy of currently used myeloablative protocols by combining busulfan with stem-cell niche-directed therapeutic agents (G-CSF or plerixafor) that are approved for clinical use in stem cell mobilization. T, B and myeloid cell recovery was analyzed in humanized NSG mice after different conditioning regimens. Increasing levels of human leukocyte chimerism were observed in a busulfan dose-dependent manner, showing comparable immune recovery as with total body irradiation in CD34-transplanted NSG mice. Notably, a better T cell reconstitution compared to TBI was observed after busulfan conditioning not only in NSG mice but also in SCID mouse models. Direct effects of reducing the stem cell compartment in the bone marrow were observed after G-CSF and plerixafor administration, as well as in combination with low doses of busulfan. Unfortunately, these direct effects on the stem population in the bone marrow were not reflected in increased human chimerism or immune recovery after CD34 transplantation in NSG mice. These results indicate moderate potential of reduced conditioning regimens for clinical use relevant for all allogeneic transplants.

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A CD117-Amanitin Antibody Drug Conjugate (ADC) Effectively Depletes Human and Non-Human Primate Hematopoietic Stem and Progenitor Cells (HSPCs): targeted Non-Genotoxic Conditioning for Bone Marrow Transplant

Cited by 9 publications

References 0 publications

Is Hematopoietic Stem Cell Transplantation Required to Unleash the Full Potential of Immunotherapy in Acute Myeloid Leukemia?

Is Hematopoietic Stem Cell Transplantation Required to Unleash the Full Potential of Immunotherapy in Acute Myeloid Leukemia?

Efficacy and safety of anti-CD45–saporin as conditioning agent for RAG deficiency

Combining Mobilizing Agents with Busulfan to Reduce Chemotherapy-Based Conditioning for Hematopoietic Stem Cell Transplantation

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