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

A new antibody-drug conjugate (ADC) has been developed to treat acute myeloid leukemia (AML) by specifically targeting CD123-positive cells, which are more prevalent in AML than in normal bone marrow. The ADC is equipped with a humanized anti-CD123 antibody and is conjugated with indolinobenzodiazepine dimers (IGNs), which are highly potent against AML cells. The study compared two types of IGNs: mono-imine IGNs in A-ADC and di-imine IGNs in C-ADC.

In vitro cytotoxicity tests showed that both ADCs were highly effective against AML cells with poor prognostic markers and patient samples, inducing DNA damage, cell cycle arrest, and apoptosis. The C-ADC was twice as potent as the A-ADC. The cytotoxicity was CD123-dependent, as blocking CD123 with another antibody significantly reduced the ADCs' potency.

Toxicity tests on healthy bone marrow cells revealed that neither ADC affected the viability of monocytes, lymphocytes, or multipotential progenitors, which have low CD123 expression. However, myeloid progenitors with high CD123 levels showed apoptotic signals after exposure to C-ADC but not A-ADC. CFU assays indicated that C-ADC was 50 times more toxic to normal myeloid progenitors than A-ADC.

In vivo toxicity testing in mice showed that C-ADC had reduced tolerability and caused delayed toxicity with weight loss 30 days post-administration, unlike A-ADC. Consequently, A-ADC, renamed as IMGN632, was chosen for further research due to its selective toxicity and favorable safety profile.

A comparison with gemtuzumab ozogamicin (GO), an ADC approved for AML treatment, showed that IMGN632 was highly sensitive to all tested AML samples at concentrations that did not affect normal progenitors. GO was only effective against 6 out of 17 AML samples without impacting normal progenitors. IMGN632's higher sensitivity in AML cells is likely due to higher CD123 levels and the lower impact of the mono-imine IGN payload on normal progenitors.

Overall, IMGN632 demonstrated significant activity against AML cells at concentrations that spare normal bone marrow cells, indicating its potential for effective treatment with minimal myelosuppression. The findings, along with strong efficacy in AML xenograft models, support the advancement of IMGN632 into clinical trials.