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Preclinical Efficacy of Anti-RON Antibody–Drug Conjugate Zt/g4-MMAE for Targeted Therapy of Pancreatic Cancer Overexpressing RON Receptor Tyrosine Kinase
- Source :
- Molecular Pharmaceutics. 15:3260-3271
- Publication Year :
- 2018
- Publisher :
- American Chemical Society (ACS), 2018.
-
Abstract
- Aberrant expression of the RON receptor tyrosine kinase, a cell surface protein, is a pathogenic feature in pancreatic cancer, which renders it a drug target for targeted therapy. Nevertheless, development of therapeutics targeting RON for pancreatic cancer therapy is hampered due to the lack of full addiction by pancreatic cancer cells to RON signaling for growth and survival. Here we describe a novel strategy using anti-RON antibody-directed drug delivery in the form of an antibody-drug conjugate for inhibition and/or eradication of pancreatic cancers. Monoclonal antibody Zt/g4 specific to the RON Sema domain was selected as the drug carrier based on its ability to induce robust RON internalization. Conjugation of Zt/g4 with monomethyl auristatin E, designated as Zt/g4-MMAE, was achieved through a protease-sensitive dipeptide linker to reach a drug to antibody ratio of 3.29:1. Zt/g4-MMAE was stable in human plasma with a dissociation rate less than 4% within a 10 day period. In vitro, Zt/g4-MMAE rapidly induced RON internalization, resulting in cell cycle arrest followed by massive cell death. The maximal effect was seen in pancreatic cancer cells with more than 10 000 receptor molecules per cell. Zt/g4-MMAE also synergized in vitro with chemotherapeutics including gemcitabine, 5-fluorouracil, and oxaliplatin to further reduce PDAC cell viability. In vivo, Zt/g4-MMAE exerts a long-lasting activity, which not only inhibited but also eradicated pancreatic xenograft tumors. These finding indicate that Zt/g4-directed drug delivery is highly effective for eradicating pancreatic tumors. Thus, Zt/g4-MMAE is a novel biotherapeutic with potential for therapy of RON-expressing pancreatic malignancies.
- Subjects :
- 0301 basic medicine
Antibody-drug conjugate
Immunoconjugates
Cell Survival
Sema domain
medicine.medical_treatment
Mice, Nude
Pharmaceutical Science
Deoxycytidine
Receptor tyrosine kinase
Targeted therapy
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cell Line, Tumor
Pancreatic cancer
Antineoplastic Combined Chemotherapy Protocols
Drug Discovery
medicine
Animals
Humans
Drug Carriers
biology
business.industry
Antibodies, Monoclonal
Receptor Protein-Tyrosine Kinases
Drug Synergism
medicine.disease
Xenograft Model Antitumor Assays
Gemcitabine
Oxaliplatin
Pancreatic Neoplasms
030104 developmental biology
Monomethyl auristatin E
chemistry
030220 oncology & carcinogenesis
Drug delivery
Cancer research
biology.protein
Molecular Medicine
Female
Fluorouracil
Drug carrier
business
Oligopeptides
Subjects
Details
- ISSN :
- 15438392 and 15438384
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- Molecular Pharmaceutics
- Accession number :
- edsair.doi.dedup.....339be89c1a9247902d6f2af1599d7362