Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients

Frankel, Arthur E.; Woo, Jeong Soo; Ahn, Chul; Pemmaraju, Naveen; Medeiros, Bruno C.; Carraway, Hetty E.; Frankfurt, Olga; Forman, Stephen J.; Yang, Xinyun; Konopleva, Marina; Garnache‐Ottou, Francine; Angelot‐Delettre, Fanny; Brooks, Chris; Szarek, Michael; Rowinsky, Eric K.

doi:10.1182/blood-2014-04-566737

Cited by 210 publications

(165 citation statements)

References 48 publications

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“…These data showed that a single cycle of SL-401 induced major responses in 78% of the patients. 24 The way to use SL-401 in BPDCN patients must, howe ver, be discussed in the light of data from literature obtained in such patients. SL-401 can be used to consolidate the effects of first-line chemotherapy, reducing the number of relapses, which always occur after chemothe rapy treatment.…”

Section: Discussionmentioning

confidence: 99%

In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent

Angelot‐Delettre¹,

Roggy²,

Frankel³

et al. 2014

Haematologica

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ABSTRACTlabile group of amino acids to a diphtheria toxin (DT) payload that has been truncated at its receptor binding region. 20 Since IL-3, the natural ligand for IL-3R, binds with very high specificity and avidity, 21 SL-401 is able to transport DT efficiently and preferentially to cells that overexpress IL-3R, leading to internalization followed by receptor-mediated endocytosis and localization of SL-401 to early endosomes. After cleavage of the SL-401 DT constituent in the acidic medium of endosomes, DT translocates into the cytosol and binds to ADP-ribosylated elongation factor 2, leading to blockade of protein synthesis and cell death. 22 Given the ubiquitous and high expression of IL-3R by BPDCN and the lack of therapies available to treat BPDCN, SL-401 is a potential therapeutic for BPDCN. The present study evaluated the cytotoxicity of SL-401 against patient-derived BPDCN cell lines (CAL-1 and GEN2.2) and primary BPDCN cells isolated directly from 12 patients. The investigations were performed in vitro, as well as in vivo in a murine model of BPDCN. The aim of the study was to provide further support for the use of SL-401 in patients suffering from BPDCN. Methods Patients' cells and cell linesPeripheral blood or bone marrow cells were obtained for diagnostic purposes from 12 BPDCN patients (Table 1) from our national network that collects data and cells from cases diagnosed in France since (authorization number #DC-2008. BPDCN was diagnosed from the results of histopathology and immunostaining of cutaneous lesions, blood or bone marrow. 2,8 Two established cell lines derived from BPDCN patients were used (GEN 2.2, patent #0215927, Dr. Plumas, EFS Rhone-Alpes, Grenoble, France and CAL-1, Dr. Maeda, Nagasaki University, Japan) as well as TF/H-Ras (Prof. Frankel) and CD123 neg (MFI<800) Daudi cell lines (ACC78, DSMZ Braunschweig, Germany) as positive and negative controls, respectively. Other lymphoid and myeloid leukemic cells used to compare sensitivity to SL-401 are described in the Online Supplementary Appendix. Drug and cultureThe SL-401 drug (Stemline Therapeutics, New York, NY, USA) was stored at -80°C and tested at eight concentrations ranging from 365 pM to 0.08 fM (21 ng/mL to 0.4 ng/mL) in order to cover (including myeloperoxidase, CD13, CD33, CD117, CD15, CD65, CD14, CD64); T : T lymphoid markers (including membrane CD3, intracytoplasmic CD3, CD7, CD5, CD2, CD8) Cytotoxicity evaluation by flow cytometryFlow cytometry was performed using a CANTO II cytometer (BD Biosciences, San Jose, CA, USA) and DIVA 6.2 software (BD Biosciences). The cytotoxic effects of SL-401 and the various drugs were evaluated using annexin-V and 7-amino actinomycin D (AV/7AAD) and a panel of different monoclonal antibodies to gate the blastic population described in the Online Supplementary Appendix. In the mouse model, anti-mouse and anti-human CD45 plus anti-human CD123, CD4, CD56, CD304 were used to identify BPDCN human cells (Online Supplementary Appendix). A defined number of calibrated 3-mm latex beads (Flowco...

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Section: Discussionmentioning

confidence: 99%

In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent

Angelot‐Delettre¹,

Roggy²,

Frankel³

et al. 2014

Haematologica

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“…Due to the rarity of the disease, prospective clinical trials to define the role of autologous and allogeneic HCT in BPDCN may not be feasible. A better understanding of the pathophysiology and novel therapeutic agents for BPDCN are urgently needed [15].…”

Section: Discussionmentioning

confidence: 99%

Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: 10‐Color flow cytometry diagnosis and HyperCVAD therapy

Deotare

Yee

et al. 2016

American J Hematol

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Few studies describe the comprehensive immunophenotypic pattern of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in the bone marrow and its treatment. This retrospective analysis evaluates the diagnostic flow cytometry (FCM) pattern and outcome of nine patients diagnosed with BPDCN. A four‐tube 10‐color FCM panel used for diagnosis of acute leukemia (AL), showed cells in the blast gate (CD45dim/low SSC) and were positive for CD4(bright), CD33(dim), CD56(heterogenous), CD123(bright), CD36, CD38, HLA‐DR, CD71. Seven patients received front‐line induction therapy with HyperCVAD with an overall response rate of 86%. Five of six responders underwent planned allogeneic hematopoietic cell transplantation (allo‐HCT). For a median follow up of 13.3 months, the 1‐year disease free survival and overall survival were 56 and 67%, respectively. An accurate diagnosis of BPDCN can be made by 10‐color FCM using a four‐tube AL panel demonstrating a characteristic pattern of antigen expression. Front‐line induction chemotherapy with HyperCVAD can yield high remission rates, but allo‐HCT is required for long‐term durable remissions. Am. J. Hematol. 91:283–286, 2016. © 2015 Wiley Periodicals, Inc.

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“…Examples include unconjugated monoclonal antibodies, T-cell engaging bispecific antibodies, immunotoxins, and chimeric antigen receptor (CAR)-modified T cells (36)(37)(38)(39)(40)(41). Although each of the modality has its own advantages, our study shows that SGN-CD123A is highly active against AML models regardless of cytogenetic profiles and MDR status, and can be effectively combined with quizartinib.…”

Section: Mdr Proteins (30mentioning

confidence: 94%

Characterization of SGN-CD123A, A Potent CD123-Directed Antibody–Drug Conjugate for Acute Myeloid Leukemia

Sutherland

et al. 2018

Molecular Cancer Therapeutics

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Treatment choices for acute myelogenous leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. IL3 receptor alpha (IL3Ra, or CD123) is expressed on the majority of AML blasts, and there is evidence that its expression is increased on leukemic relative to normal hematopoietic stem cells, which makes it an attractive target for antibody-based therapy. Here, we report the generation and preclinical characterization of SGN-CD123A, an antibody-drug conjugate using the pyrrolobenzodiazepine dimer (PBD) linker and a humanized CD123 antibody with engineered cysteines for site-specific conjugation. Mechanistically, SGN-CD123A induces activation of DNA damage response pathways, cell-cycle changes, and apoptosis in AML cells. In vitro, SGN-CD123A-mediated potent cytotoxicity of 11/12 CD123 þ AML cell lines and 20/23 primary samples from AML patients, including those with unfavorable cytogenetic profiles or FLT3 mutations. In vivo, SGN-CD123A treatment led to AML eradication in a disseminated disease model, remission in a subcutaneous xenograft model, and significant growth delay in a multidrug resistance xenograft model. Moreover, SGN-CD123A also resulted in durable complete remission of a patient-derived xenograft AML model. When combined with a FLT3 inhibitor quizartinib, SGN-CD123A enhanced the activity of quizartinib against two FLT3-mutated xenograft models. Overall, these data demonstrate that SGN-CD123A is a potent antileukemic agent, supporting an ongoing trial to evaluate its safety and efficacy in AML patients (NCT02848248). Mol Cancer Ther; 17(2); 554-64. Ó2017 AACR.

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Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients

Cited by 210 publications

References 48 publications

In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent

In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent

Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: 10‐Color flow cytometry diagnosis and HyperCVAD therapy

Characterization of SGN-CD123A, A Potent CD123-Directed Antibody–Drug Conjugate for Acute Myeloid Leukemia

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