OBI-992, a Novel TROP2-Targeted Antibody-Drug Conjugate, Demonstrates Antitumor Activity in Multiple Cancer Models
Wan-Fen Li1, Ming-Feng Chiang1, Hao-Cheng Weng1
1OBI Pharma, Inc., Taipei, Taiwan.
Abstract:
Trophoblast cell surface antigen 2 (TROP2) is highly expressed in multiple cancers relative to normal tissues, supporting its role as a target for cancer therapy. OBI-992 is an antibody-drug conjugate (ADC) derived from a novel TROP2-targeted antibody linked to the topoisomerase 1 (TOP1) inhibitor exatecan via an enzyme-cleavable hydrophilic linker, with a drug-antibody ratio of 4. This study evaluated and compared the antitumor activity of OBI-992 with that of benchmark TROP2-targeted ADCs datopotamab deruxtecan (Dato-DXd) and sacituzumab govitecan (SG) in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. OBI-992 treatment exhibited statistically significant antitumor activity versus controls at doses of 3 and 10 mg/kg in various CDX and PDX models, demonstrating comparable or better antitumor activity with benchmark ADCs. In a large-tumor model, longer survival times were observed in OBI-992-treated mice compared with Dato-DXd-treated mice. OBI-992 treatment induced marked bystander killing of TROP2-negative cells in the presence of nearby TROP2-positive cells in both in vitro and in vivo studies. In lung adenocarcinoma CDX models with overexpression of either P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) to mimic ATP-binding cassette transporter-mediated multidrug resistance, OBI-992 treatment maintained antitumor activity when Dato-DXd treatment became less effective. The combination of OBI-992 at suboptimal doses with either poly (ADP-ribose) polymerase (PARP) inhibitors or an immune check point inhibitor produced synergistic antitumor effects in mouse models. Taken together, these translational results support further development of OBI-992 as a cancer therapy.
Insights
OBI-992, a novel TROP2-targeted antibody-drug conjugate, demonstrates significant antitumor activity and bystander killing effects in preclinical cancer models. It shows comparable or superior efficacy to benchmark ADCs and potential synergistic effects when combined with other therapies.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Trophoblast cell surface antigen 2 (TROP2) is a promising therapeutic target due to its high expression in various cancers.
- Antibody-drug conjugates (ADCs) offer targeted delivery of cytotoxic agents to cancer cells.
Purpose of the Study:
- To evaluate the antitumor activity of OBI-992, a novel TROP2-targeted ADC, against benchmark TROP2-targeted ADCs.
- To assess the efficacy of OBI-992 in preclinical cancer models, including its bystander killing effect and activity in multidrug-resistant models.
Main Methods:
- Comparison of OBI-992 with datopotamab deruxtecan (Dato-DXd) and sacituzumab govitecan (SG) in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models.
- In vitro and in vivo studies to assess bystander killing.
- Evaluation of OBI-992 in models with P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) overexpression.
- Combination studies with PARP inhibitors and immune checkpoint inhibitors.
Main Results:
- OBI-992 demonstrated statistically significant antitumor activity in CDX and PDX models at 3 and 10 mg/kg.
- OBI-992 showed comparable or superior antitumor activity to benchmark ADCs, with longer survival in a large-tumor model.
- Marked bystander killing of TROP2-negative cells was observed.
- OBI-992 maintained antitumor activity in multidrug-resistant models where Dato-DXd was less effective.
- Combination therapy with OBI-992 exhibited synergistic antitumor effects.
Conclusions:
- OBI-992 exhibits potent antitumor activity and a favorable profile in preclinical models.
- Its efficacy in multidrug-resistant models and potential for synergistic combinations support its further development.
- OBI-992 represents a promising therapeutic candidate for TROP2-expressing cancers.
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