title: RN927C, a Site-Specific Trop-2 Antibody-Drug Conjugate (ADC) with Enhanced Stability, Is Highly Efficacious in Preclinical Solid Tumor Models.
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 IC50generally 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.
authors: Oncology-Rinat R&D, Pfizer Inc., South San Francisco, California.
authors: Pavel
authors: P
authors: Strop
authors: Oncology-Rinat R&D, Pfizer Inc., South San Francisco, California.
authors: Thomas-Toan
authors: TT
authors: Tran
authors: Oncology-Rinat R&D, Pfizer Inc., South San Francisco, California.
authors: Magdalena
authors: M
authors: Dorywalska
authors: Oncology-Rinat R&D, Pfizer Inc., South San Francisco, California.
authors: Kathy
authors: K
authors: Delaria
authors: Worldwide Medicinal Chemistry, Pfizer Inc., Groton, Connecticut.
authors: Russell
authors: R
authors: Dushin
authors: Oncology-Rinat R&D, Pfizer Inc., South San Francisco, California.
authors: Oi Kwan
authors: OK
authors: Wong
authors: Oncology-Rinat R&D, Pfizer Inc., South San Francisco, California.
authors: Wei-Hsien
authors: WH
authors: Ho
authors: Worldwide Medicinal Chemistry, Pfizer Inc., Groton, Connecticut.
authors: Dahui
authors: D
authors: Zhou
authors: Pharmacokinetics, Dynamics & Metabolism, Pfizer Inc., San Diego, California.
authors: Aidong
authors: A
authors: Wu
authors: Pharmacokinetics, Dynamics & Metabolism, Pfizer Inc., San Diego, California.
authors: Eugenia
authors: E
authors: Kraynov
authors: Drug Safety R&D, Pfizer Inc., San Diego, California.
authors: Laura
authors: L
authors: Aschenbrenner
authors: Drug Safety R&D, Pfizer Inc., San Diego, California.
authors: Bora
authors: B
authors: Han
authors: Worldwide Medicinal Chemistry, Pfizer Inc., Groton, Connecticut.
authors: Christopher J
authors: CJ
authors: O'Donnell
authors: Oncology-Rinat R&D, Pfizer Inc., South San Francisco, California.
authors: Jaume
authors: J
authors: Pons
authors: Oncology-Rinat R&D, Pfizer Inc., South San Francisco, California.
authors: Arvind
authors: A
authors: Rajpal
authors: Oncology-Rinat R&D, Pfizer Inc., South San Francisco, California.
authors: Dave L
authors: DL
authors: Shelton
authors: Oncology-Rinat R&D, Pfizer Inc., South San Francisco, California. Shu-Hui.Liu@pfizer.com.
authors: Shu-Hui
authors: SH
authors: Liu
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004355:Drug Stability; D005260:Female; D015870:Gene Expression; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology*; D008247:Lysosomes; D051379:Mice; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D018796:Immunoconjugates; C499380:TACSTD2 protein, human