title: SGN-LIV1A: a novel antibody-drug conjugate targeting LIV-1 for the treatment of metastatic breast cancer.
abstract: In this article, we describe a novel antibody-drug conjugate (ADC; SGN-LIV1A), targeting the zinc transporter LIV-1 (SLC39A6) for the treatment of metastatic breast cancer. LIV-1 was previously known to be expressed by estrogen receptor-positive breast cancers. In this study, we show that LIV-1 expression is maintained after hormonal therapy in primary and metastatic sites and is also upregulated in triple-negative breast cancers. In addition to breast cancer, other indications showing LIV-1 expression include melanoma, prostate, ovarian, and uterine cancer. SGN-LIV1A consists of a humanized antibody conjugated through a proteolytically cleavable linker to monomethyl auristatin E, a potent microtubule-disrupting agent. When bound to surface-expressed LIV-1 on immortalized cell lines, this ADC is internalized and traffics to the lysozome. SGN-LIV1A displays specific in vitro cytotoxic activity against LIV-1-expressing cancer cells. In vitro results are recapitulated in vivo where antitumor activity is demonstrated in tumor models of breast and cervical cancer lineages. These results support the clinical evaluation of SGN-LIV1A as a novel therapeutic agent for patients with LIV-1-expressing cancer.
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington. dsussman@seagen.com.
authors.forename: Django
authors.initials: D
authors.lastname: Sussman
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Leia M
authors.initials: LM
authors.lastname: Smith
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Martha E
authors.initials: ME
authors.lastname: Anderson
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Steve
authors.initials: S
authors.lastname: Duniho
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Joshua H
authors.initials: JH
authors.lastname: Hunter
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Heather
authors.initials: H
authors.lastname: Kostner
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Jamie B
authors.initials: JB
authors.lastname: Miyamoto
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Albina
authors.initials: A
authors.lastname: Nesterova
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Lori
authors.initials: L
authors.lastname: Westendorf
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Van Epps
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Nancy
authors.initials: N
authors.lastname: Whiting
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Benjamin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology; D000915:Antibody Affinity; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000494:pharmacology*; D016130:Immunophenotyping; D008247:Lysosomes / Q000378:metabolism; D061986:MCF-7 Cells; D008870:Microtubules / Q000378:metabolism; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D027682:Cation Transport Proteins; D018796:Immunoconjugates; D009363:Neoplasm Proteins; C000600157:SGN-LIV1A; C418627:SLC39A6 protein, human