Abstract
OBI-992, a novel TROP2-targeted antibody-drug conjugate (ADC), is composed of an anti-TROP2 antibody conjugated to exatecan, a topoisomerase 1 inhibitor, via an enzyme-cleavable hydrophilic linker. The stability, pharmacokinetics, pharmacodynamics, and off-target toxicity of OBI-992 were evaluated and compared with a benchmark ADC, datopotamab deruxtecan (Dato-DXd). OBI-992 exhibited better stability in human and monkey serum than Dato-DXd, which was further supported by in vivo PK study in rats. OBI-992 displayed a favorable pharmacokinetic profile compared with Dato-DXd in non-small cell lung cancer cell line-derived xenograft mouse models (NCI-H1975 and NCI-H1975/C797S), with lower clearance, longer half-lives of ADC in serum, and higher exposure of payload in tumor. The higher level of breast cancer resistance protein expression was detected in NCI-H1975/C797S cells, which may contribute better antitumor activity of OBI-992 compared with Dato-DXd as DXd is a much better substrate to breast cancer resistance protein than exatecan. The levels of the payload of OBI-992 in nontarget organs were lower or comparable with Dato-DXd. In addition, OBI-992 exhibited lower toxicity compared with Dato-DXd in the monocytic cell line THP-1 and differentiated neutrophils. Furthermore, in the Good Laboratory Practice toxicity study with cynomolgus monkeys, the highest nonseverely toxic dose was determined to be ≥60 mg/kg. Major toxicities were target-related skin lesions and reduced reticulocytes, which were reversible during recovery period. These results support further clinical development of OBI-992 for the treatment of TROP2-expressing cancers, which is currently in a phase 1 clinical trial (NCT06480240).