IMGN779 Drug Description

IMGN779 is a CD33-targeting ADC consisting of a humanized anti-CD33 antibody, Z4681A, conjugated to approximately three DGN462 molecules per antibody.  The novel DNA-alkylating agent is conjugated using a cleavable disulfide linker, sulfo-SPDB. [1][2]

IMGN779 demonstrates antibody-driven clearance and release of DGN462 over time.[1]

Acute myeloid leukemia
CD33 is broadly expressed on leukemic blasts of patients with acute myeloid leukemia (AML).  This makes it a promising target for AML therapy. Elevated levels of CD33 are found in cases of AML having molecular markers associated with poor prognosis, including mutations in FMS-like tyrosine kinase 3 (FLT3). Scientists found that the internal tandem duplication mutation (FLT3-ITD) is the most common FLT3 mutation, present in about 20-25% of all AML cases. Patients with FLT3-ITD AML generally have a worse prognosis than patients with wild-type (WT) FLT3, with an increased rate of relapse and a shorter duration of response to induction chemotherapy.[2]

IMGN779 was found to demonstrate targeted activity against AML cell lines in vitro, with IC50 values ranging from 2-3,000 pM. The MV4-11 cell line, which has a FLT3-ITD mutation, was the most sensitive to IMGN779 of the cell lines tested, with an IC50 of 2 pM.[1][2]

Researchers also found IMGN779 to be highly active in vitro against primary patient AML cells isolated from peripheral blood or bone marrow samples. They noted that patient AML cells with a FLT3-ITD mutation were more sensitive to the trial drug compared with FLT3 WT AML samples.[2]

Novel Payload: DGN465
DGN462, the payload in IMGN779, is a member of the novel IGN class of DNA-acting cytotoxic agents that consists of an indolino-benzodiazepine dimer containing a mono-imine moiety. Scientists observed that a DGN462-ADC to a non-relevant target was inactive (T/C = 95%) at the same dose, demonstrating that the activity of IMGN779 was due to its CD33 targeting [2]

Structure

Fig. 1.0: Structure of IMGN779.[1]
Clinical trials
IMGN779 is designed to be stable in the bloodstream. ImmunoGen, Inc. Waltham, MD, has initiated a number of preclinical and clinical trials.

Summary

IMGN779 is composed of:

  • Z4681A antibody (a humanized monoclonal antibody; targets CD33 receptors)
  • Sulfo-SPDB Linker (Charged, disulfide-cleavable)
  • DGN462 cytotoxic agent (DNA-alkylating payload, ~3 DGN462 molecules conjugated per antibody)
  • Symmetrical mass distribution profile, very low unconjugated Ab (D0)

Illustration: Structure of IMGN779 Courtesy: ImmungoGen, Inc.