Combination treatment with an antibody-drug conjugate (A1mcMMAF) targeting the oncofetal glycoprotein 5T4 and carboplatin improves survival in a xenograft model of ovarian cancer
AffiliationDivision of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, 5th Floor Research, St Mary's Hospital, Oxford Road, Manchester, M13 9WL, UK
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AbstractBACKGROUND: Recurrence occurs in over 75% of women with epithelial ovarian cancer despite optimal treatment. Selectively killing tumour cells thought to initiate relapse using an antibody-drug conjugate could prolong progression-free survival and offer an improved side-effect profile. A1mcMMAF is an antibody-drug conjugate designed to target cells expressing the tumour-associated antigen 5T4. It has shown to be efficacious in various cell line models and have a greater impact when combined with routine chemotherapeutic regimes. OBJECTIVES: This study aims to explore the potential for the use of a 5T4 antibody-drug conjugate in women with ovarian cancer both as a monotherapy and in combination with platinum-based chemotherapy. METHODS: Immunohistochemical analysis was used to assess 5T4 expression in tumours from patients with ovarian cancer. Effectiveness of A1mcMMAF therapy as a single agent and in combination with carboplatin was assessed in vitro in the ovarian cancer cell line SKOV3 and confirmed in vivo using a serial bioluminescence assay in a SKOV3 xenograft model of ovarian cancer. RESULTS: 5T4 is confirmed as suitably expressed in epithelial ovarian cancers prior to adjuvant therapy and is an independent predictor of poor survival. A1mcMMAF showed specific activity, both in vitro and in vivo, against SKOV3 ovarian cancer cells. When used in combination with carboplatin, in vivo tumour growth was inhibited resulting in prolonged survival in a SKOV3 xenograft model. CONCLUSIONS: These data support further investigation of A1mcMMAF in combination with platinum-based chemotherapy in ovarian and other cancer treatments.
CitationWan YL, Sapra P, Bolton J, Chua JX, Durrant LG, Stern PL. Combination treatment with an antibody-drug conjugate (A1mcMMAF) targeting the oncofetal glycoprotein 5T4 and carboplatin improves survival in a xenograft model of ovarian cancer. Target Oncol. 2019 Aug;14(4):465-77.