Enhanced Antitumor Activity of an Anti-5T4 Antibody-Drug Conjugate in Combination with PI3K/mTOR inhibitors or Taxanes.

PURPOSE

Targeted treatment of solid or liquid tumors with antibody-drug conjugates (ADCs) can lead to promising clinical benefit. The aim of the study is to investigate combination regimens of auristatin-based ADCs in preclinical models of cancer.

EXPERIMENTAL DESIGN

An auristatin-based anti-5T4 antibody conjugate (5T4-ADC) and auristatin payloads were combined with the dual PI3K/mTOR catalytic site inhibitor PF-05212384 (PF-384) or taxanes in a panel of tumor cell lines. Drug interactions in vitro were evaluated using cell viability assays, apoptosis induction, immunofluorescence, mitotic index, and immunoblotting. Breast cancer cells treated with auristatin analogue or 5T4-ADC were profiled by total- and phospho-proteomics. Antitumor efficacy of selected combinations was evaluated in 5T4-positive human breast or lung tumor xenografts in vivo.

RESULTS

In vitro, auristatin-based agents displayed strong synergistic or additive activity when combined with PF-384 or taxanes, respectively. Further, treatment of 5T4-ADC plus PF-384 resulted in stronger induction of apoptosis and cell line-specific attenuation of pAKT and pGSK. Interestingly, proteomic analysis revealed unique effects of auristatins on multiple components of mRNA translation. Addition of PF-384 further amplified effects of 5T4-ADC on translational components, providing a potential mechanism of synergy between these drugs. In human tumor xenografts, dual targeting with 5T4-ADC/PF-384 or 5T4-ADC/paclitaxel produced substantially greater antitumor effects with longer average survival as compared with monotherapy treatments.

CONCLUSIONS

Our results provide a biologic rationale for combining 5T4-ADC with either PI3K/mTOR pathway inhibitors or taxanes and suggest that mechanisms underlying the synergy may be attributed to cellular effects of the auristatin payload.