The Discovery and Preclinical Development of ASG-5ME, an Antibody-Drug Conjugate Targeting SLC44A4-Positive Epithelial Tumors Including Pancreatic and Prostate Cancer.

Abstract

Here, we report the development of an antibody-drug conjugate, ASG-5ME, which targets the solute carrier receptor SLC44A4. SLC44A4 is a member of a family of putative choline transporters that we show to be markedly upregulated in a variety of epithelial tumors, most notably prostate and pancreatic cancer. SLC44A4 is normally expressed on the apical surface of secretory epithelial cells, but in cancer we show expression is not restricted to the luminal surface in advanced and undifferentiated tumors. ASG-5ME consists of a human IgG2 anti-SLC44A4 antibody conjugated through a cleavable linker to the microtubule-disrupting agent monomethylauristatin E. It has potent antitumor activity in both cell line - and patient-derived xenograft models of pancreatic and prostate cancers. Combination studies with ASG-5ME and nab-paclitaxel demonstrated combination effect in both pancreatic and prostate tumor models. Altogether, the data presented here suggest that ASG-5ME may have the potential to offer a new therapeutic option for the treatment of pancreatic and prostate cancers. Mol Cancer Ther; 15(11); 2679-87. ©2016 AACR.

• Authors: Michael Mattie, Arthur Raitano, Kendall Morrison, Karen Morrison, Zili An, Linnette Capo, Alla Verlinsky, Monica Leavitt, Jimmy Ou, Rossana Nadell, Hector Aviña, Claudia Guevara, Faisal Malik, Ruth Moser, Steven Duniho, Jeffrey Coleman, Ying Li, Daniel S Pereira, Fernando Doñate, Ingrid B J Joseph, Pia Challita-Eid, Dennis Benjamin, David R Stover
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 11 Pg. 2679-2687 (11 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 27550944 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• ASG-5ME
• Antibodies, Monoclonal
• Antineoplastic Agents
• Immunoconjugates
• Membrane Transport Proteins
• Oligopeptides
• SLC44A4 protein, human

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antineoplastic Agents (pharmacology)
• Carcinoma (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Gene Expression Profiling
• Humans
• Immunoconjugates (pharmacology)
• Male
• Membrane Transport Proteins (metabolism)
• Mice
• Molecular Targeted Therapy
• Oligopeptides (pharmacology)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays