Preclinical pharmacokinetic, pharmacodynamic, and safety profile of OBI-992: a novel TROP2-targeted antibody–drug conjugate

Abstract OBI-992, a novel TROP2-targeted ADC, is composed of an anti-TROP2 antibody conjugated to exatecan, a topoisomerase 1 (TOP1) 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 PK profile compared to Dato-DXd in non-small cell lung cancer (NSCLC) cell line-derived xenograft (CDX) 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 (BCRP) expression was detected in NCI-H1975/C797S cells, which may contribute better antitumor activity of OBI-992 to compared with Dato-DXd as DXd is much better substrate to BCRP than exatecan. The levels of the payload of OBI-992 in non-target organs were lower or comparable to Dato-DXd. In addition, OBI-992 exhibited lower toxicity compared to Dato-DXd in the monocytic cell line THP-1 and differentiated neutrophils. Furthermore, in the Good Laboratory Practice (GLP) toxicity study with cynomolgus monkeys, the highest non-severely toxic dose (HNSTD) 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 it is currently in Phase 1 clinical trial (NCT06480240).