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.
Highlights
In the United States, nearly 300,000 women are diagnosed with breast cancer each year and it is the second leading cause of cancer-related mortality in women
LIV-1 is frequently expressed in breast, prostate, and melanoma, even in patients previously treated with hormonal therapies (Table 1 and Fig. 1)
antibody–drug conjugate (ADC) directed toward tumor-specific antigens are clinically proven as effective treatments of both solid and liquid tumors
Summary
In the United States, nearly 300,000 women are diagnosed with breast cancer each year and it is the second leading cause of cancer-related mortality in women. Radiation, hormone therapy, and chemotherapy are effective treatments for many, but over 40,000 patients succumb to the disease annually. Hormonal therapies, including tamoxifen and aromatase inhibitors, can be effective in treating tumors that express the hormone receptors ER and PgR. HER2-directed therapies are useful for tumors that express HER2/neu; these tumors are the only class of breast cancer that is currently eligible for immunotherapy. For these patients, unconjugated antibodies (Herceptin, Perjeta) are generally used in combination with chemotherapy. The treatment options for triplenegative breast tumors, those that do not express ER, Seattle Genetics, Inc., Bothell, Washington
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