Abstract
BackgroundRecurrence 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.ObjectivesThis 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.MethodsImmunohistochemical 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.Results5T4 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.ConclusionsThese data support further investigation of A1mcMMAF in combination with platinum-based chemotherapy in ovarian and other cancer treatments.Electronic supplementary materialThe online version of this article (10.1007/s11523-019-00650-8) contains supplementary material, which is available to authorized users.
Highlights
Epithelial ovarian cancer (EOC) is one of the most common gynaecologic malignancies, with 50% of all cases occurring in women aged older than 65 years
We have demonstrated that the 5T4-targeting Antibody–drug conjugates (ADCs), A1mcMMAF, has effect both in vivo and in vitro
Using paired wild-type and 5T4 knockout SKOV3 cells, we demonstrated that the specificity of A1mcMMAF is conferred by the antibody portion, whilst the anti-proliferative effect is conferred by the drug conjugate
Summary
Epithelial ovarian cancer (EOC) is one of the most common gynaecologic malignancies, with 50% of all cases occurring in women aged older than 65 years. It is the eighth most frequent cause of cancer death in women [1]. 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. 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
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