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

Castiello, Maria Carmina; Bosticardo, Marita; Sacchetti, Nicolò; Calzoni, Enrica; Fontana, Elena; Yamazaki, Yasuhiro; Drăghici, Elena; Corsino, Cristina; Bortolomai, Ileana; Sereni, Lucia Piceni; Yu, Hsin-Hui; Uva, Paolo; Palchaudhuri, Rahul; Scadden, David T.; Villa, Anna; Notarangelo, Luigi D.

doi:10.1016/j.jaci.2020.04.033

Cited by 32 publications

(31 citation statements)

References 38 publications

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“…In line with this, the possible use of targeted biologic agents for stem cell depletion (e.g. monoclonal antibodies such as anti-CD117 or anti-CD45) is very promising (55)(56)(57).…”

Section: Hematopoietic Stem Cell Transplantationmentioning

confidence: 93%

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Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease

et al. 2020

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X-linked severe immunodeficiency disease (SCID-X1) is an inherited, rare, and life-threating disease. The genetic origin is a defect in the interleukin 2 receptor γ chain (IL2RG) gene and patients are classically characterized by absence of T and NK cells, as well as presence of partially-functional B cells. Without any treatment the disease is usually lethal during the first year of life. The treatment of choice for these patients is hematopoietic stem cell transplantation, with an excellent survival rate (>90%) if an HLA-matched sibling donor is available. However, when alternative donors are used, the success and survival rates are often lower. Gene therapy has been developed as an alternative treatment initially using γ-retroviral vectors to correct the defective γ chain in the absence of pre-conditioning treatment. The results were highly promising in SCID-X1 infants, showing long-term T-cell recovery and clinical benefit, although NK and B cell recovery was less robust. However, some infants developed T-cell acute lymphoblastic leukemia after the gene therapy, due to vector-mediated insertional mutagenesis. Consequently, considerable efforts have been made to develop safer vectors. The most recent clinical trials using lentiviral vectors together with a low-dose pre-conditioning regimen have demonstrated excellent sustained T cell recovery, but also B and NK cells, in both children and adults. This review provides an overview about the different gene therapy approaches used over the last 20 years to treat SCID-X1 patients, particularly focusing on lymphoid immune reconstitution, as well as the developments that have improved the process and outcomes.

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“…In line with this, the possible use of targeted biologic agents for stem cell depletion (e.g. monoclonal antibodies such as anti-CD117 or anti-CD45) is very promising (55)(56)(57).…”

Section: Hematopoietic Stem Cell Transplantationmentioning

confidence: 93%

“…Furthermore, the application of conditioning treatment based on biologic agents for stem cell depletion (e.g. monoclonal antibodies), with the objective to avoid the toxic effects of classical treatments, is very promising (55)(56)(57).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease

et al. 2020

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“…To this end, the efficacy of this compound was tested in null and hypomorhic Rag1 models, achieving multilineage engraftment and robust immune reconstitution while preserving thymic epithelial cell homeostasis. A synergistic effect on myeloid chimerism and immune recovery was achieved when CD45-SAP was combined with low-dose of irradiation (61). However, mild transient hepatotoxicity secondary to CD45-SAP (60,61) or upon single saporin injection (62) or radiolabeled anti-CD45 antibody (63)(64)(65) have been observed posing clinical concerns.…”

Section: Approaching Non-genotoxic Conditioning For Rag Deficienciesmentioning

confidence: 99%

“…A synergistic effect on myeloid chimerism and immune recovery was achieved when CD45-SAP was combined with low-dose of irradiation (61). However, mild transient hepatotoxicity secondary to CD45-SAP (60,61) or upon single saporin injection (62) or radiolabeled anti-CD45 antibody (63)(64)(65) have been observed posing clinical concerns. Overall, while these preclinical models indicate ADCs as safer conditional regimens than conventional chemotherapy, further investigation is needed before moving to the clinical setting.…”

Section: Approaching Non-genotoxic Conditioning For Rag Deficienciesmentioning

confidence: 99%

Innovative Cell-Based Therapies and Conditioning to Cure RAG Deficiency

2020

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Genetic defects in recombination activating genes (RAG) 1 and 2 cause a broad spectrum of severe immune defects ranging from early severe and repeated infections to inflammation and autoimmune manifestations. A correlation between in vitro recombination activity and immune phenotype has been described. Hematopoietic cell transplantation is the treatment of care; however, the availability of next generation sequencing and whole genome sequencing has allowed the identification of novel genetic RAG variants in immunodeficient patients at various ages, raising therapeutic questions. This review addresses the recent advances of novel therapeutic approaches for RAG deficiency. As conventional myeloablative conditioning regimens are associated with acute toxicities and transplanted-related mortality, innovative minimal conditioning regimens based on the use of monoclonal antibodies are now emerging and show promising results. To overcome shortage of compatible donors, gene therapy has been developed in various RAG preclinical models. Overall, the transplantation of autologous gene corrected hematopoietic precursors and the use of non-genotoxic conditioning will open a new era, offering a cure to an increasing number of RAG patients regardless of donor availability and severity of clinical conditions.

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“…In mouse models, CD45-SAP and cKit-SAP were well-tolerated and effectively permitted syngeneic HSCT with high-level donor chimerism. Moreover, these conditioning regimens were used therapeutically in mouse models of sickle cell disease 17 , hemophilia 19 , Fanconi anemia 20 , and recombinase-activating gene (RAG) deficiency 21 .…”

Section: Introductionmentioning

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

Cited by 32 publications

References 38 publications

Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease

Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease

Innovative Cell-Based Therapies and Conditioning to Cure RAG Deficiency

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

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