RN927C, a Site-Specific Trop-2 Antibody-Drug Conjugate (ADC) with Enhanced Stability, Is Highly Efficacious in
Pavel Strop1, Thomas-Toan Tran1, Magdalena Dorywalska1
1Oncology-Rinat R&D, Pfizer Inc., South San Francisco, California.
Abstract:
Trop-2, also known as TACSTD2, EGP-1, GA733-1, and M1S1, is frequently expressed on a variety of human carcinomas, and its expression is often associated with poor prognosis of the diseases. However, it is also present on the epithelium of several normal tissues. A comprehensively designed Trop-2-targeting antibody-drug conjugate (ADC), balancing both efficacy and toxicity, is therefore necessary to achieve clinical utility. To this end, we developed a cleavable Trop-2 ADC (RN927C) using a site-specific transglutaminase-mediated conjugation method and a proprietary microtubule inhibitor (MTI) linker-payload, PF-06380101. Robust in vitro cytotoxicity of RN927C was observed on a panel of Trop-2-expressing tumor cell lines, with IC50 generally in the subnanomolar range. As expected for an MTI-containing ADC, RN927C readily induced mitotic arrest of treated cells in vitro and in vivo, followed by subsequent cell death. The in vivo efficacy of RN927C was tested in multiple cell line and patient-derived xenograft tumor models, including pancreatic, lung, ovarian, and triple-negative breast tumor types. Single-dose administration of RN927C at 0.75 to 3 mg/kg was generally sufficient to induce sustained regression of Trop-2-expressing tumors and showed superior efficacy over standard treatment with paclitaxel or gemcitabine. Administration of RN927C in nonhuman primate toxicity studies resulted in target-mediated effects in skin and oral mucosa, consistent with Trop-2 expression in these epithelial tissues with minimal, non-dose limiting off-target toxicities. On the basis of the combined efficacy and safety results, RN927C is postulated to have a favorable therapeutic index for treatment of solid tumors. Mol Cancer Ther; 15(11); 2698-708. ©2016 AACR.
Insights
A novel Trop-2 antibody-drug conjugate (ADC), RN927C, demonstrated potent anti-tumor activity and a favorable safety profile in preclinical models. This targeted therapy shows promise for treating various solid tumors with improved efficacy over existing treatments.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Trop-2 (TACSTD2) is a transmembrane protein frequently overexpressed in various carcinomas, correlating with poor prognosis.
- Targeting Trop-2 offers a potential therapeutic strategy for cancer, but requires careful balancing of efficacy and toxicity.
- Existing treatments for Trop-2-expressing tumors often have limitations, necessitating novel therapeutic approaches.
Purpose of the Study:
- To develop and characterize a novel, cleavable Trop-2 antibody-drug conjugate (ADC) with optimized efficacy and safety.
- To evaluate the in vitro and in vivo anti-tumor activity of the developed ADC, RN927C.
- To assess the safety and therapeutic index of RN927C in preclinical models.
Main Methods:
- Development of RN927C using site-specific transglutaminase conjugation and a proprietary microtubule inhibitor (MTI) linker-payload (PF-06380101).
- In vitro cytotoxicity assays on Trop-2-expressing tumor cell lines.
- In vivo efficacy studies in cell line and patient-derived xenograft models (pancreatic, lung, ovarian, triple-negative breast cancer).
- Toxicity assessment in nonhuman primates.
Main Results:
- RN927C exhibited potent subnanomolar in vitro cytotoxicity against Trop-2-expressing tumor cells.
- The ADC induced mitotic arrest and cell death in vitro and in vivo.
- Single-dose RN927C demonstrated significant tumor regression in multiple xenograft models, outperforming paclitaxel and gemcitabine.
- Toxicity studies revealed target-mediated effects in skin and oral mucosa with minimal off-target toxicities.
Conclusions:
- RN927C, a cleavable Trop-2 ADC, displays robust anti-tumor efficacy across various solid tumor types.
- The ADC exhibits a favorable therapeutic index, with manageable toxicities consistent with Trop-2 expression.
- RN927C represents a promising targeted therapy candidate for the treatment of solid tumors expressing Trop-2.
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