Abstract 1768: An anti-TGF-β1/2 antibody that spares TGF-β3 retains full anti-tumor efficacy and generates an improved metabolic profile

Abstract

Abstract TGF-β family members are overexpressed in many advanced cancers and correlate with metastasis and poor prognosis. Based on encouraging preclinical data, therapeutics that target the TGF-β pathway are now in early phase clinical trials in oncology. While the three isoforms of TGF-β have essentially identical activities in vitro, there is relatively little known about how they might differ in vivo. Using a panel of twelve mouse allograft models of metastatic breast cancer, we showed that while TGF-β1 protein was consistently up-regulated in mammary tumors compared with normal mammary gland, the opposite was true for TGF-β3. Furthermore, in human breast cancer high TGF-β3 mRNA or protein expression was associated with better outcome, particularly in estrogen-receptor positive breast cancers. Collectively the data suggest that TGF-β1 and TGF-β3 may have opposing effects on breast cancer progression. Using an antibody that selectively neutralizes only TGF-β1 and TGF-β2, we explored the effect of sparing TGF-β3 on therapeutic outcome in the 4T1 and TSAE1 models of metastatic breast cancer. While the TGFβ1,2 antibody and two pan-TGF-β antibodies had similar efficacy against the metastasis endpoint in these very aggressive models, transcriptomic analysis of primary tumors after two weeks of antibody therapy suggested that sparing TGF-β3 might have positive effects on the metabolic profile of treated animals. To address this issue directly, we showed that mice without tumors had a significantly improved glucose tolerance following treatment with anti-TGF-β1/2 antibodies for 2-3 weeks when compared with mice treated with pan-TGF-β antibodies. Addressing potential human relevance, we showed that high expression of transcripts that were selectively upregulated in the primary tumors when TGF-β3 was spared correlated with good outcome in human breast cancer. The data suggest that use of isoform-selective TGF-β antagonists may offer advantages over the use of pan-TGF-β blocking agents for the treatment of breast cancer. Citation Format: Yu-an Yang, Srividya Vasu, Howard Yang, Maxwell P. Lee, Sushil Rane, Amer M. Mirza, Lalage M. Wakefield. An anti-TGF-β1/2 antibody that spares TGF-β3 retains full anti-tumor efficacy and generates an improved metabolic profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1768.