Earlier today, Seattle Genetics announced that it has signed a clinical collaboration agreement with Genentech, a member of the Roche Group, for the evaluation of its investigational antibody-drug conjugate (ADC) SGN-LIV1A in combination with atezolizumab (Tecentriq?) in patients with metastatic triple-negative breast cancer (mTNBC).
Antibody-drug conjugates, also known as ADCs, are novel drugs consisting of three components.? They link potent cytotoxic anticancer agent via a biodegradable linker to an antibody. The antibody binds to specific markers (antigens or receptors) at the surface of the cancer cell. The whole antibody-drug conjugate is then internalized within the cancer cell, where the linker is degraded and the active drug released.
ADCs make use of antibodies that are specific to cell surface proteins and are able to offer various advantages over current chemotherapeutics, including improved target specificity and potency. While this approach is successful in hematological malignancies, it has some limitations in the treatment of solid tumors.
The focused delivery of the cytotoxic agent to the tumor cell is designed to maximize the anti-tumor effect of ADCs, while minimizing its normal tissue exposure, potentially leading to an improved therapeutic index. 
SGN-LIV1A is a novel investigational ADC targeted to LIV-1 protein utilizing Seattle Genetics? proprietary ADC technology. The zinc transporter LIV-1 (SLC39A6) was previously known to be expressed by estrogen receptor?positive breast cancers. However, a number of studies have shown 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, LIV-1 has also been detected in a number of other cancers, including melanoma, prostate, ovarian, and cervical cancer. 
The LIV-1 subfamily of ZIP zinc transporters consists of nine human sequences that share considerable homology across transmembrane domains. Many of these sequences have been shown to transport zinc and/or other ions across cell membranes.
Seattle Genetics’ investigational drug SGN-LIV1A consists of a LIV-1-targeted monoclonal antibody linked to a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE) by a protease-cleavable linker. The agent is using the same technology as brentuximab vedotin (Adcetris?; Seattle Genetics). It is designed to bind to LIV-1 on cancer cells and release the cell-killing agent into target cells upon internalization. SGN-LIV1A may also cause antitumor activity through other mechanisms, including activation of an immune response.
The investigational drug will be to be studies in combination with atezolizumab (Tecentriq?; Genentech/Roche) as part of an initiative for the development of novel cancer immunotherapy combinations.
Atezolizumab (also known as MPDL3280A) is a monoclonal antibody designed to interfere with a protein called PD-L1. By targeting PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, the drug prevents PD-L1 from binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PD-L1, atezolizumab may enable the activation of T cells.
Furthermore, as a biomarker, PD-L1 a is to identify those patients most likely to benefit when treated with atezolizumab and determine which patients may benefit most from a combination of atezolizumab and another medicine, including SGN-LIV1A.
SGN-LIV1A, one of four clinical-stage treatments under development by Seattle Genetics for solid tumors, consists of a LIV-1 targeted monoclonal antibody linked to the potent cell-killing agent monomethyl auristatin E (MMAE).
Trippe-negative breast cancer
Breast cancer is the most common cancer among women worldwide, with an estimated 1.7 million new cases per year. About 15 to 20% of all breast cancers are triple negative. This means that that the cancer cells have tested negative for three different receptors that are commonly found on breast cancer cells: the estrogen receptor (ER), the progesterone receptor (PR) and the human epidermal growth factor (HER-2).
The expression of these three breast cancer-associated proteins generally serves as key therapeutic targets for treatment. As a result, when these receptors are not present on the cell, non-chemotherapy treatments that block these receptors, such as hormone therapy or targeted therapy, do not work and the only treatment available is chemotherapy.
Lack of targeted therapies
?A key challenge in triple-negative breast cancer, or TNBC, is the lack of available novel targeted treatments. People with this disease generally have poor prognoses. Moreover, current therapies are not curative and only delay disease progression,? explained Robert Lechleider, M.D., Senior Vice President, Clinical Development of Seattle Genetics.
?We have phase I data showing that SGN-LIV1A is active as monotherapy in patients with heavily pretreated, metastatic TNBC. Now, under this new collaboration, we will evaluate the potential to expand therapeutic benefit to these patients through combination therapy with atezolizumab.?
SGN-LIV1A administered in combination with atezolizumab will be evaluated in a phase Ib/II clinical study as second-line therapy in patients with metastatic TNBC who have not been previously treated with immunotherapy. This randomized, controlled study is anticipated to enroll up to 45 patients in the treatment arm. Seattle Genetics and Genentech will test the experimental combination in MORPHEUS, Roche’s Novel Cancer Immunotherapy Development Platform. MORPHEUS is a phase 1b/2 adaptive platform to develop combinations of cancer immunotherapies rapidly and efficiently.
Under the terms of the collaboration agreement, Genentech will manage the study operations for the phase Ib/II trial. Seattle Genetics will retain global development and commercialization rights to SGN-LIV1A.
Last editorial review: July 24, 2017
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