Preclinical data from SGN-CD33A (Seattle Genetics, Inc), a novel CD33-directed antibody-drug conjugate (ADC) in development for the treatment of acute myeloid leukemia (AML) presented at the 54th American Society of Hematology (ASH) Annual Meeting and Exposition being held December 8-11, 2012 in Atlanta, GA shows that the trial drug induced CD33-specific activity at low doses in a broad panel of AML cell lines and primary AML patient samples, including those resistant to multiple other anti-leukemic agents. Other key findings confirm that SGN-CD33A yielded anti-tumor activity, durable remissions and improved survival in multiple preclinical AML models. The data support a planned 2013 phase I clinical trial of SGN-CD33A for AML.
The CD33 antibody is attached to a highly potent cytotoxic agent called a pyrrolobenzodiazepine (PBD) dimer via a proprietary site-specific conjugate technology to a monoclonal antibody with engineered cysteines (EC-mAb). The pyrrolobenzodiazepines drived from naturally occurring antitumor antibiotics discovered in the 1960s. Many potent PBDs contain a C2-endo-exo unsaturated motif associated with the pyrrolo C-ring. Researchers explain that it is this ability to form covalent DNA adducts that is linked to the anti-tumor and cytotoxic activity of PBDs. Genetics expects to advance SGN-CD33A into a phase I clinical trial in 2013.
“Our SGN-CD33A program showcases our next generation ADC technology, including our latest highly potent cell-killing agent and our new engineered antibody technology,” said Jonathan Drachman, M.D., Senior Vice President, Research and Translational Medicine at Seattle Genetics. “Of approximately 30 ADCs in development, more than 50% utilize Seattle Genetics’ technology. Through our continued innovation we are leading the development of novel ADCs, and believe that ADCs can transform the way cancer is treated.”
ADCs are monoclonal antibodies that are designed to selectively deliver cytotoxic agents to tumor cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.
PBDs are a class of DNA-crosslinking agents that are significantly more potent than systemic chemotherapeutic drugs. Seattle Genetics has been working with PBDs since 2008 under an exclusive licensing arrangement with Spirogen Ltd. This company has developed highly potent PBD “warheads” based which are joined to antibodies by linkers which are stable in the blood stream but release the PBD once it is safely inside the targeted cancer cells. Over the past four years, Seattle Genetics has selected and optimized specific PBD molecules combined with novel linkers for use in ADCs, and has conducted process development and scale-up activities to create robust synthetic GMP manufacturing processes for these PBD drug-linkers.