Selective Elimination of AML Cells with IMGN632: A CD123-Targeted ADC for Bone Marrow Preservation

A new antibody-drug conjugate (ADC) has been developed to target CD123, a protein that is more prevalent in acute myeloid leukemia (AML) cells than in normal bone marrow cells. This ADC is designed to selectively eliminate CD123-positive AML cells while sparing normal cells. The ADC uses a humanized anti-CD123 antibody with two engineered cysteines for the attachment of a payload, which in this case are indolinobenzodiazepine dimers (IGNs). These IGNs are potent against AML cells and can either alkylate or crosslink DNA.

The effectiveness of the ADC was tested on AML cell lines and patient samples, showing high cytotoxicity with IC50 values ranging from 0.4 to 60 pM and killing 90% of AML progenitors at concentrations between 2 to 46 pM. The di-imine IGN ADC was found to be twice as active as the mono-imine IGN ADC. The cytotoxicity was dependent on CD123 expression, as evidenced by a significant reduction in potency when CD123 was masked.

In toxicity studies using healthy donor bone marrow cells, the ADCs did not affect the viability of certain cell types with low CD123 levels but did induce apoptosis in myeloid progenitors with high CD123 levels. Notably, the di-imine IGN ADC was found to be 50-fold more cytotoxic to normal myeloid progenitors than the mono-imine IGN ADC. In animal studies, the di-imine IGN ADC showed reduced tolerability and delayed toxicity.

When compared to an ADC previously approved for AML treatment, IMGN632 (the mono-imine IGN ADC) demonstrated higher sensitivity in AML cells at concentrations that did not affect normal progenitors, highlighting its potential efficacy with limited myelosuppression. The study supports the advancement of IMGN632 into clinical trials due to its potent activity and favorable tolerability profile. Several authors are employed by ImmunoGen, Inc., indicating a potential conflict of interest.