title: 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.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California. mmattie@agensys.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Mattie
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Arthur
authors.initials: A
authors.lastname: Raitano
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Kendall
authors.initials: K
authors.lastname: Morrison
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Karen
authors.initials: K
authors.lastname: Morrison
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Zili
authors.initials: Z
authors.lastname: An
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Linnette
authors.initials: L
authors.lastname: Capo
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Alla
authors.initials: A
authors.lastname: Verlinsky
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Monica
authors.initials: M
authors.lastname: Leavitt
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Ou
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Rossana
authors.initials: R
authors.lastname: Nadell
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Hector
authors.initials: H
authors.lastname: Aviña
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Claudia
authors.initials: C
authors.lastname: Guevara
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Faisal
authors.initials: F
authors.lastname: Malik
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Ruth
authors.initials: R
authors.lastname: Moser
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Steven
authors.initials: S
authors.lastname: Duniho
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Coleman
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pereira
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Fernando
authors.initials: F
authors.lastname: Doñate
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Ingrid B J
authors.initials: IB
authors.lastname: Joseph
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: Pia
authors.initials: P
authors.lastname: Challita-Eid
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Dennis
authors.initials: D
authors.lastname: Benjamin
authors.affiliation: Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
authors.forename: David R
authors.initials: DR
authors.lastname: Stover
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D020869:Gene Expression Profiling; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D058990:Molecular Targeted Therapy; D009842:Oligopeptides / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C583373:ASG-5ME; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D026901:Membrane Transport Proteins; D009842:Oligopeptides; C583905:SLC44A4 protein, human