A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia

He, Simon; Busfield, Samantha J.; Ritchie, David; Hertzberg, Mark; Durrant, Simon; Lewis, Ian D.; Marlton, Paula; McLachlan, Andrew J.; Kerridge, Ian; Bradstock, Kenneth F.; Kennedy, Glen; Boyd, Andrew W.; Yeadon, Trina; Lopez, Angel F.; Ramshaw, Hayley S.; Iland, Harry; Bamford, Simone; Barnden, Megan; DeWitte, Mark; Basser, Russell L.; Roberts, Andrew W.

doi:10.3109/10428194.2014.956316

Cited by 114 publications

(86 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, apart from CD123, which showed limited efficacy in early clinical trials (28), to our knowledge, none has progressed to clinical evaluation in AML. IL1RAP is expressed on candidate AML stem cells, but not on corresponding normal cells (9).…”

Section: Discussionmentioning

confidence: 99%

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Ågerstam

Karlsson

Hansen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is associated with a poor survival rate, and there is an urgent need for novel and more efficient therapies, ideally targeting AML stem cells that are essential for maintaining the disease. The interleukin 1 receptor accessory protein (IL1RAP; IL1R3) is expressed on candidate leukemic stem cells in the majority of AML patients, but not on normal hematopoietic stem cells. We show here that monoclonal antibodies targeting IL1RAP have strong antileukemic effects in xenograft models of human AML. We demonstrate that effector-cell-mediated killing is essential for the observed therapeutic effects and that natural killer cells constitute a critical human effector cell type. Because IL-1 signaling is important for the growth of AML cells, we generated an IL1RAP-targeting antibody capable of blocking IL-1 signaling and show that this antibody suppresses the proliferation of primary human AML cells. Hence, IL1RAP can be efficiently targeted with an anti-IL1RAP antibody capable of both achieving antibody-dependent cellular cytotoxicity and blocking of IL-1 signaling as modes of action. Collectively, these results provide important evidence in support of IL1RAP as a target for antibody-based treatment of AML.A cute myeloid leukemia (AML) is a genetically heterogeneous disease characterized by clonal expansion of leukemic cells. Despite an increased understanding of the underlying disease biology in AML, the standard treatment with cytotoxic chemotherapy has remained largely unchanged over the last decades and the overall 5-y survival remains poor, being <30% (1, 2). Hence, there is a pressing need for novel therapies with increased efficacy and decreased toxicity, ideally targeting the AML stem cells because these cells are believed to be critical in the pathogenesis of AML, and their inadequate eradication by standard therapy is thought to contribute to the high incidence of relapse (3, 4). Although therapeutic antibodies directed at cell-surface molecules have proven effective for the treatment of malignant disorders such as lymphomas and acute lymphoblastic leukemia, as well as solid tumors (5, 6), no antibody-based therapy is currently approved for AML.The interleukin 1 receptor accessory protein (IL1RAP), also called IL1R3, is a coreceptor of type 1 interleukin 1 receptor (IL1R1) and is indispensable for transmission of IL-1 signaling (7). We have previously reported that IL1RAP is a biomarker for putative chronic myeloid leukemia stem cells (8). In a recent study, we showed that IL1RAP is expressed on the cell surface in ∼80% of AML patients and that candidate CD34 + CD38 − AML stem cells can be selectively killed in vitro by antibody-dependent cellular cytotoxicity (ADCC) (9). Furthermore, IL1RAP is upregulated on immature cells in high-risk AML with chromosome 7 aberrations, and increased IL1RAP expression correlates with poor prognosis (10). These findings could suggest IL1RAP as a novel and specific target for an antibody-based therapy in AML; however, in vivo evidences for therapeuti...

show abstract

Section: Discussionmentioning

confidence: 99%

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Ågerstam

Karlsson

Hansen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Toxicological studies in non-human primates have shown no significant effects on the main hematological parameters [57]. A phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of CSL360 was carried out in 40 relapsed, refractory or high-risk AML: only 2 patients responded to this treatment, thus indicating that CD123 blockade achieved using this antibody is insufficient, when used alone, as a therapeutic strategy [91]. Another phase 1 study, using the CSL362 monoclonal antibody was carried out in AML patients in complete remission at high risk for early relapse.…”

Section: Cd123 (Il3rα)mentioning

confidence: 98%

Targeting LSCs through membrane antigens selectively or preferentially expressed on these cells

Pelosi

Castelli

Testa

2015

Blood Cells, Molecules, and Diseases

View full text Add to dashboard Cite

“…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: 95%

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

Sutherland

et al. 2018

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

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.

show abstract

A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia

Cited by 114 publications

References 39 publications

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Targeting LSCs through membrane antigens selectively or preferentially expressed on these cells

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

Contact Info

Product

Resources

About