Preclinical Pharmacokinetic, Pharmacodynamic, and Safety Profile of OBI-992: A Novel TROP2-Targeted Antibody–Drug Conjugate
Bibliographic record
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).
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".