Results from a preclinical trial shows that IMGN779, a novel, DNA-alkylating, anticancer therapeutics based on ImmunoGen, Inc, antibody-drug conjugates (ADC) technology, shows potent activity against CD33-expressing acute myeloid leukemia cells, including leukemic stem cells, while sparing normal cells. The data was presented at the 19th Congress of the European Hematology Association (EHA) meeting in Milan, Italy (EHA Abstract# P802). Based on these really results, researchers are hopeful that IMGN779 may become a treatment for acute myeloid leukemia or AML.
Acute myeloid leukemia or AML is a hematologic malignancy that starts in the bone marrow where different types of new blood cells are made. In the US in 2014, more than 18,000 adults will be newly diagnosed with AML and more than 10,000 will die from the disease.
“Despite good initial responses to existing therapies, many AML patients relapse, driving the need for new treatment options,” commented Charles Morris, MD, ImmunoGen’s Executive Vice President and Chief Development Officer. “We believe the unique profile of IMGN779 will enable the achievement of desired activity with a better tolerability profile than other agents currently used to treat this disease.”
IMGN779 is an ADC designed to selectively target and kill AML cells, including leukemic stem cells, while sparing normal cells. IMGN779 utilizes the highly potent, DNA-alkylating, payload DGN462, which is conjugated via cleavable disulfide linker to the CD33-targeting antibody, Z4681A.
In preclinical findings presented at EHA meeting in Milan, IMGN779 demonstrated potent, targeted activity against primary AML patient cells in vitro. IMGN779 can selectively kill leukemic cells or blasts cells while sparing normal hematopoietic or blood stem cells. The researchers showed that the drug was highly active against human AML xenografts in vivo, demonstrating potent and targeted activity. IMGN779 was well tolerated without delayed toxicity in animal models.
IMGN779 is on track to become the Company’s next wholly owned clinical-stage compound. ImmunoGen is preparing to submit the IMGN779 IND in mid-2015.
DNA-acting Payload Agents
Created by ImmunoGen’s scientists, the IGN family of DNA-acting payload agents, including DGN462, are designed to effectively alkylate DNA, while avoiding the delayed toxicity that can develop with agents that cross-link DNA in addition to alkylating it. The company developed its IGN family of DNA-acting payload agents to complement its successful family of tubulin-acting agents, including DM1 and DM4, as some cancers respond more to DNA-acting agents than to tubulin-acting agents. ImmunoGen scientists began by developing DNA-acting agents with both DNA-crosslinking and -alkylating properties. However, the researchers noted that these agents were associated with significant delayed toxicity. To achieve the dual objective of efficacy and tolerability with this platform, ImmunoGen developed more advanced IGN agents which are DNA-alkylators only. These IGN payload agents retain high potency, but avoid delayed toxicity.
“Our technologies and approaches are designed to achieve effective, well-tolerated and producible ADC products,” commented John Lambert, PhD, ImmunoGen EVP and Chief Scientific Officer. “While there can be a tendency in this field to want to focus on one element of an ADC — the linker, payload or manufacturing approach — experience shows that ADCs are best thought of as integrated systems.”