Preclinical evaluation of a novel antibody-drug conjugate OBI-992 for Cancer therapy
Ting-Yu Chang1, Chun-Jung Lin1, Shih-Ni Wen1
1OBI Pharma, Inc., 6F, No. 508, Section 7 Zhongxiao East Road, Nangang District, Taipei, Taiwan.
Abstract:
Trophoblast cell surface antigen 2 (TROP2), a transmembrane glycoprotein highly expressed in a variety of epithelial cancers, has been considered as a primary therapeutic target for the development of antibody-drug conjugates (ADCs). OBI-992, an investigational TROP2-targeted ADC, is composed of a novel TROP2 antibody (R4702) conjugated to the topoisomerase I (TOP1) inhibitor exatecan through a hydrophilic enzyme-cleavable linker. This study aimed to characterize R4702 and OBI-992 in vitro. TROP2-targeted antibodies sacituzumab and datopotamab were employed as the comparators for R4702. ADCs sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) were used as benchmarks for OBI-992. Results revealed that R4702 binds to an epitope that is distinct from sacituzumab and datopotamab. The cytotoxicity of the OBI-992, SG, and Dato-DXd against different cancer cells is comparable despite they have different internalization profile. Upregulation of breast cancer resistance protein (BCRP) was observed in SG-resistant and Dato-DXd-resistant cells, but not in OBI-992-resistant cells. In addition, significant downregulation of TROP2 expression was detected with Dato-DXd-resistant cells and only slightly downregulation with SG- and OBI-992-resistant cells was observed. Moreover, substantial enhancement of cytotoxicity and DNA damage was found in the combination of OBI-992 with a poly (ADP-ribose) polymerase (PARP) inhibitor (talazoparib). Taken together, the findings in this study support further clinical development of OBI-992.
Insights
OBI-992, a novel TROP2 antibody-drug conjugate (ADC), shows comparable efficacy to existing ADCs and unique resistance profiles. Combination therapy with OBI-992 and a PARP inhibitor enhances anti-cancer activity, supporting further clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Trophoblast cell surface antigen 2 (TROP2) is a therapeutic target for antibody-drug conjugates (ADCs) in epithelial cancers.
- OBI-992 is an investigational ADC targeting TROP2, comprising a novel antibody (R4702) and a topoisomerase I inhibitor (exatecan).
Purpose of the Study:
- To characterize the novel TROP2 antibody R4702 and the ADC OBI-992 in vitro.
- To compare OBI-992 with existing TROP2-targeted antibodies and ADCs.
Main Methods:
- In vitro characterization of R4702 binding epitope compared to sacituzumab and datopotamab.
- Assessment of OBI-992, sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd) cytotoxicity and internalization.
- Evaluation of resistance mechanisms, including breast cancer resistance protein (BCRP) and TROP2 expression changes.
- Assessment of OBI-992 combination therapy with a PARP inhibitor (talazoparib).
Main Results:
- R4702 binds to a distinct epitope compared to comparators.
- OBI-992, SG, and Dato-DXd exhibit comparable cytotoxicity despite different internalization profiles.
- OBI-992-resistant cells did not show BCRP upregulation, unlike SG- and Dato-DXd-resistant cells.
- TROP2 downregulation was minimal in OBI-992-resistant cells compared to Dato-DXd-resistant cells.
- Combination of OBI-992 with talazoparib significantly enhanced cytotoxicity and DNA damage.
Conclusions:
- OBI-992 demonstrates a promising in vitro profile, including a distinct resistance mechanism.
- The combination of OBI-992 with a PARP inhibitor warrants further investigation.
- Findings support the continued clinical development of OBI-992 for cancer therapy.
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