ATL-024, a novel topoisomerase I-based ADC targeting the tumor-specific glycopepitope CA242 (CanAg), demonstrates potent activity in colorectal and pancreatic cancer models, and excellent safety profile

CA242 (also known as CanAg) is a tumor-associated carbohydrate antigen that is aberrantly expressed by gastrointestinal solid tumors but is virtually absent from normal tissue. In particular, this glycopepitope is highly expressed in colorectal, pancreatic and gastric tumors (high prevalence and elevated number of copies per tumor cell). Previous clinical trials in the early 2000s showed that CA242 can be safely targeted with an antibody-drug conjugate (ADC), as no significant CA242-related off-tumor toxicities were reported. The modest clinical benefit seen with microtubule inhibitor payloads indicates that alternative payloads, such as topoisomerase-I inhibitors, may enhance therapeutic outcomes in CA242-positive tumors.To exploit CA242 differential expression, we developed a novel CA242-targeting ADC called ATL-024, which is comprised of an anti-CA242 humanized Fc-silenced monoclonal antibody conjugated to the topoisomerase I inhibitor exatecan via a dipeptide cleavable linker. This ADC is a homogeneous construct with a drug-to-antibody ratio (DAR) of 4.ATL-024 demonstrated potent antitumor efficacy in multiple colorectal and pancreatic cancer PDX models showing homogeneous or heterogeneous CA242 expression patterns (as determined by IHC), being effective at doses as low as 3-6mg/kg. Compared to previous cantuzumab-DM4 based ADC (microtubule inhibitor payload), ATL-024 exhibits significantly stronger in vivo anti-tumor activity in colorectal PDX models.In a pilot toxicology study in cynomolgus monkeys, ATL-024 was well tolerated up to 80 mg/kg (Q3W), which was established as the highest non-severely toxic dose (HNSTD). At this dose, findings were limited to mild and reversible hematologic changes in one animal, with normal clinical chemistry parameters, no severe clinical signs and no observed organ toxicities. Pharmacokinetic profiling showed linear dose-dependent exposure and is consistent with systemic stability of the conjugate.Overall, the preclinical characterization of ATL-024 shows a very favorable therapeutic index and support human clinical evaluation for patients with CA242-expressing gastrointestinal tumors such as colorectal or pancreatic tumors. ATL-024 is currently undergoing IND-enabling development.