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    ascheck@stanford.edu
    University - Staff Department: Medicine - Med/Blood and Marrow Transplantation Position: Manager, Clinical Data Management

All Publications

  • Nongenotoxic antibody-drug conjugate conditioning enables safe and effective platelet gene therapy of hemophilia A mice. Blood advances Gao, C., Schroeder, J. A., Xue, F., Jing, W., Cai, Y., Scheck, A., Subramaniam, S., Rao, S., Weiler, H., Czechowicz, A., Shi, Q. 2019; 3 (18): 2700–2711

    Abstract

    Gene therapy offers the potential to cure hemophilia A (HA). We have shown that hematopoietic stem cell (HSC)-based platelet-specific factor VIII (FVIII) (2bF8) gene therapy can produce therapeutic protein and induce antigen-specific immune tolerance in HA mice, even in the presence of inhibitory antibodies. For HSC-based gene therapy, traditional preconditioning using cytotoxic chemotherapy or total body irradiation (TBI) has been required. The potential toxicity associated with TBI or chemotherapy is a deterrent that may prevent patients with HA, a nonmalignant disease, from agreeing to such a protocol. Here, we describe targeted nongenotoxic preconditioning for 2bF8 gene therapy utilizing a hematopoietic cell-specific antibody-drug conjugate (ADC), which consists of saporin conjugated to CD45.2- and CD117-targeting antibodies. We found that a combination of CD45.2- and CD117-targeting ADC preconditioning was effective for engrafting 2bF8-transduced HSCs and was favorable for platelet lineage reconstitution. Two thirds of HA mice that received 2bF8 lentivirus-transduced HSCs under (CD45.2+CD117)-targeting ADC conditioning maintained sustained therapeutic levels of platelet FVIII expression. When CD8-targeting ADC was supplemented, chimerism and platelet FVIII expression were significantly increased, with long-term sustained platelet FVIII expression in all primary and secondary recipients. Importantly, immune tolerance was induced and hemostasis was restored in a tail-bleeding test, and joint bleeding also was effectively prevented in a needle-induced knee joint injury model in HA mice after 2bF8 gene therapy. In summary, we show for the first time efficient engraftment of gene-modified HSCs without genotoxic conditioning. The combined cocktail ADC-mediated hematopoietic cell-targeted nongenotoxic preconditioning that we developed is highly effective and favorable for platelet-specific gene therapy in HA mice.

    View details for DOI 10.1182/bloodadvances.2019000516

    View details for PubMedID 31515232

  • Selective hematopoietic stem cell ablation using CD117-antibody-drug-conjugates enables safe and effective transplantation with immunity preservation NATURE COMMUNICATIONS Czechowicz, A., Palchaudhuri, R., Scheck, A., Hu, Y., Hoggatt, J., Saez, B., Pang, W. W., Mansour, M. K., Tate, T. A., Chan, Y., Walck, E., Wernig, G., Shizuru, J. A., Winau, F., Scadden, D. T., Rossi, D. J. 2019; 10

    View details for DOI 10.1038/s41467-018-08201-x

    View details for Web of Science ID 000457862200002

  • Hematopoietic chimerism and donor-specific skin allograft tolerance after non-genotoxic CD117 antibody-drug-conjugate conditioning in MHC-mismatched allotransplantation NATURE COMMUNICATIONS Li, Z., Czechowicz, A., Scheck, A., Rossi, D. J., Murphy, P. M. 2019; 10

    View details for DOI 10.1038/s41467-018-08202-w

    View details for Web of Science ID 000457862200001

  • Irradiation- and busulfan-free stem cell transplantation in Fanconi anemia using an anti-CD117 antibody: a phase 1b trial. Nature medicine Agarwal, R., Bertaina, A., Soco, C., Long-Boyle, J. R., Saini, G., Kunte, N., Hiroshima, L., Chan, Y. Y., Willner, H., Krampf, M. R., Nofal, R., Barbarito, G., Sen, S., Van Hentenryck, M., Walck, E., Scheck, A., Perriman, R. J., Bouge, A., Istomina, E., Din, H. N., Klinger, E. F., Cheng, J. C., Wlodarski, M. W., Boelens, J. J., Shizuru, J. A., Pang, W. W., Weinberg, K., Parkman, R., Roncarolo, M. G., Porteus, M., Czechowicz, A. 2025

    Abstract

    Current hematopoietic stem cell transplantation (HSCT) conditioning strategies cause widespread tissue damage and systemic toxicities, especially in patients with DNA-repair deficiencies such as Fanconi anemia (FA). We have developed an alternative conditioning approach that incorporates the anti-CD117 antibody, briquilimab, which targets host hematopoietic stem and progenitor cells in place of genotoxic irradiation- and busulfan-based chemotherapy. Here we report a phase 1b clinical trial in patients with FA and bone marrow failure, evaluating safety and efficacy of briquilimab-based conditioning in combination with rabbit anti-thymocyte globulin, cyclophosphamide, fludarabine and rituximab immunosuppression and T cell receptor (TCR)αβ+ T cell-depleted and CD19+ B cell-depleted haploidentical HSCT. Primary endpoints of the trial included safety and engraftment, and secondary endpoints included pharmacokinetic measures and hematological and immunological recovery. All three patients have each undergone 2 years of follow-up to complete the phase 1b analysis. No treatment-emergent adverse events or acute graft-versus-host disease was observed. Patients experienced minimal toxicities, with typical mucositis and no veno-occlusive disease. Median neutrophil engraftment was 11 days (range 11-13 days) with robust donor chimerism up to 2 years post-HSCT (99-100%), meeting the primary endpoints of the study. Briquilimab cleared in each patient before HSCT without the need for adjustment. Red blood cell, platelet and lymphocyte recovery was comparable to previous reports with TCRαβ+ T cell-depleted and CD19+ B cell-depleted grafts. All patients are alive and well with resolution of earlier chromosomal breakage abnormalities in peripheral blood lymphocytes post treatment. These data demonstrate the broad potential of this protocol in maintaining HSCT efficacy while reducing toxicity. The phase 2 trial is ongoing (ClinicalTrials.gov identifier: NCT04784052 ).

    View details for DOI 10.1038/s41591-025-03817-1

    View details for PubMedID 40696207

    View details for PubMedCentralID 6509544

  • Radiation and Busulfan-Free Hematopoietic Stem Cell Transplantation Using Briquilimab (JSP191) Anti-CD117 Antibody-Conditioning, Transient Immunosuppression and TCR α β + T-Cell/CD19+B-Cell Depleted Haploidentical Grafts in Patients with Fanconi Anemia Agarwal, R., Bertaina, A., Soco, C., Saini, G., Kunte, N., Hiroshima, L., Chan, Y., Willner, H., Krampf, M. L., Nofal, R., Barbarito, G., Sen, S., Felber, M., Van Hentenryck, M., Walck, E., Scheck, A., Thongthip, S., Logan, A. C., Dougall, K., Bouge, A., Boelens, J., Long-Boyle, J. R., Weissman, I. L., Shizuru, J., Pang, W. W., Weinberg, K. I., Parkman, R., Roncarolo, M., Porteus, M., Czechowicz, A. AMER SOC HEMATOLOGY. 2023

    View details for DOI 10.1182/blood-2023-178400

    View details for Web of Science ID 001159306700230

  • Selective hematopoietic stem cell ablation using CD117-antibody-drug-conjugates enables safe and effective transplantation with immunity preservation. Nature communications Czechowicz, A., Palchaudhuri, R., Scheck, A., Hu, Y., Hoggatt, J., Saez, B., Pang, W. W., Mansour, M. K., Tate, T. A., Chan, Y. Y., Walck, E., Wernig, G., Shizuru, J. A., Winau, F., Scadden, D. T., Rossi, D. J. 2019; 10 (1): 617

    Abstract

    Hematopoietic stem cell transplantation (HSCT) is a curative therapy for blood and immune diseases with potential for many settings beyond current standard-of-care. Broad HSCT application is currently precluded largely due to morbidity and mortality associated with genotoxic irradiation or chemotherapy conditioning. Here we show that a single dose of a CD117-antibody-drug-conjugate (CD117-ADC) to saporin leads to>99% depletion of host HSCs, enabling rapid and efficient donor hematopoietic cell engraftment. Importantly, CD117-ADC selectively targets hematopoietic stem cells yet does not cause clinically significant side-effects. Blood counts and immune cell function are preserved following CD117-ADC treatment, with effective responses by recipients to both viral and fungal challenges. These results suggest that CD117-ADC-mediated HSCT pre-treatment could serve as a non-myeloablative conditioning strategy for the treatment of a wide range of non-malignant and malignant diseases, and might be especially suited to gene therapy and gene editing settings in which preservation of immunity is desired.

    View details for PubMedID 30728354

  • Selective HSC-Ablation using Anti-CD117 Antibody Drug Conjugate Enables Safe and Effective Murine and Human Hematopoietic Stem Cell Transplantation Czechowicz, A., Palchaudhuri, R., Scheck, A., Hu, Y., Hoggatt, J., Saez, B., Mansour, M. K., Winau, F., Scadden, D. T., Rossi, D. J. NATURE PUBLISHING GROUP. 2018: 83-84

    View details for Web of Science ID 000487702801005

  • Selective HSC-Ablation Using CD117 Antibody-Drug-Conjugates Enables Safe and Effective Murine and Human Hematopoietic Stem Cell Transplantation Czechowicz, A., Palchaudhuri, R., Scheck, A., Hu, Y., Hoggatt, J., Saez, B., Pang, W. W., Mansour, M. K., Shizuru, J. A., Winau, F., Scadden, D. T., Rossi, D. J. CELL PRESS. 2018: 23–24

    View details for Web of Science ID 000435342200045

  • Immune Sparing Conditioning for BMT/HSCT Using Anti-Ckit Immunotoxins Czechowicz, A., Palchaudhuri, R., Scheck, A., Hu, Y., Winau, F., Hoggatt, J., Saez, B., Mansour, M. K., Sykes, D., Scadden, D., Rossi, D. ELSEVIER SCIENCE INC. 2018: S60–S61

    View details for Web of Science ID 000425476000058

  • Completely Non-Myeloablative/Non-Lymphoablative Conditioning for BMT/HSCT Using Anti-Ckit Immunotoxins Czechowicz, A., Palchaudhuri, R., Scheck, A., Hoggatt, J., Saez, B., Scadden, D. T., Rossi, D. J. AMER SOC HEMATOLOGY. 2016

    View details for Web of Science ID 000394446806031