CLT030, a leukemic stem cell–targeting CLL1 antibody-drug conjugate for treatment of acute myeloid leukemia

Abstract

The current standard of care for acute myeloid leukemia (AML) is largely ineffective with very high relapse rates and low survival rates, mostly due to the inability to eliminate a rare population of leukemic stem cells (LSCs) that initiate tumor growth and are resistant to standard chemotherapy. RNA-sequencing analysis on isolated LSCs confirmed C-type lectin domain family 12 member A (CLL1, also known as CLEC12A) to be highly expressed on LSCs but not on normal hematopoietic stem cells (HSCs) or other healthy organ tissues. Expression of CLL1 was consistent across different types of AML. We developed CLT030 (CLL1-ADC), an antibody-drug conjugate (ADC) based on a humanized anti-CLL1 antibody with 2 engineered cysteine residues linked covalently via a cleavable linker to a highly potent DNA-binding payload, thus resulting in a site-specific and homogenous ADC product. The ADC is designed to be stable in the bloodstream and to release its DNA-binding payload only after the ADC binds to CLL1-expressing tumor cells, is internalized, and the linker is cleaved in the lysosomal compartment. CLL1-ADC inhibits in vitro LSC colony formation and demonstrates robust in vivo efficacy in AML cell tumor models and tumor growth inhibition in the AML patient-derived xenograft model. CLL1-ADC demonstrated a reduced effect on differentiation of healthy normal human CD34 cells to various lineages as observed in an in vitro colony formation assay and in an in vivo xenotransplantation model as compared with CD33-ADC. These results demonstrate that CLL1-ADC could be an effective ADC therapeutic for the treatment of AML.

Revisiting CLEC12A as leukaemic stem cell marker in AML: highlighting the necessity of precision diagnostics in patients eligible for targeted therapy

“…In addition, we have recently shown the relevance of the marker in myelodysplastic syndrome (MDS) and pointed out important differences in the applicability of the marker in these biologically different disease entities (Toft-Petersen et al, 2016). Given this, the CLEC12A receptor is an attractive treatment target in AML, and current developments in this regard include both CLEC12A-CD3 bispecific antibodies (Lu et al, 2014;Leong et al, 2017) and chimeric antigen receptor (CAR)-engineered T-cells (CAR-T-cells) directed against CLEC12A (Laborda et al, 2017;Tashiro et al, 2017;Wang et al, 2018) and, most recently, the development of a novel antibody-drug conjugate (Jiang et al, 2018).…”

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

“…This finding confirms the potential for neutropenia, but the recovery suggests a potential to spare HSC. An ADC targeting CLL-1 was effective against in AML cell lines in vitro and in vivo [61]. The ADC significantly reduces granulocytic Colony Forming Units (CFU) while sparing erythroid CFUs.…”

Gemtuzumab ozogamicin and novel antibody-drug conjugates in clinical trials for acute myeloid leukemia

“…In a study of cynomolgus monkey model, neutropenia was the major DLT. No obvious off-target toxicity was observed at the dose that can deplete neutrophils and monocytes [102]. CLT030 is an ADC with a humanized anti-CLL1 mAb site-specifically conjugated to two molecules of isoquinolidinobenzodiazepine (IQB), a novel DNA cross-linker, through a cleavable dipeptide linker.…”