Abstract 1759: AVID200, a highly potent TGF-beta trap, exhibits optimal isoform selectivity for enhancing anti-tumor T-cell activity, without promoting metastasis or cardiotoxicity
Authors: Maureen D. O'Connor-McCourt, Gilles Tremblay, Anne Lenferink, Traian Sulea, John Zwaagstra, James Koropatnick
Journal: Cancer Research (2018)

Abstract The purpose of the studies presented here is to examine the ability of the novel TGF-β-neutralizing agent, AVID200, to reverse immunosuppression in the tumor microenvironment, and to determine the safety profile of AVID200 in non-human primates. TGF-β is a secreted protein that is aberrantly produced by tumors, and which promotes cancer progression primarily by suppressing both the innate and adaptive immune systems. AVID200 is a computationally-designed, avidity-enhanced, receptor ectodomain-based trap that binds and neutralizes TGF-β1 and -β3. We demonstrate, in tumor cell-based assays, that AVID200 potently neutralizes TGF-β1 and -β3 with low pM potency. Using a syngeneic 4T1 triple negative breast cancer (TNBC) model, we report that AVID200, in a dose-dependent manner, enhances the capacity of T-cells isolated from draining lymph nodes to specifically recognize and kill 4T1 tumor cells. The anti-tumor T-cell-activating potency of AVID200 was observed to be higher than that of the pan-neutralizing TGF-β antibody, 1D11. AVID200 was designed to have minimal activity against TGF-β2. This isoform specificity was chosen since it has been reported that inhibition of the TGF-β2 isoform can promote metastasis. We report that AVID200 does not increase the number of foci in a metastasis assay, whereas pan TGF-β neutralizing agents do. This supports the concept that blockade of TGF-β2 is undesirable. Also, it has been reported that pan-TGF-β blockers can exhibit cardiac toxicity in animal models and in humans. It has been proposed that this is due to TGF-β2 neutralization since this is the main isoform implicated in normal cardiac function. To determine if AVID200 exhibits cardiotoxicity, we tested AVID200 in a pilot non-human primate study. No adverse cardiac events were observed at doses of up to 30 mg/kg. An update on GLP toxicology studies will be presented at the meeting. In conclusion, AVID200 is a novel TGF-β trap that potently blocks TGF-β-1 and -3 isoforms, which results in reversal of immunosuppression in the tumor microenvironment. It has minimal activity against TGF-β2 and accordingly does not detectably promote cardiac toxicity and metastasis. Thus, AVID200 is a promising new immunotherapy that selectively inhibits the TGF-β1 and -3 isoforms, thereby enhancing desirable anti-tumor immunity, while avoiding the tumor-promoting and cardiotoxic effects resulting from TGF-β2 neutralization. Citation Format: Maureen D. O'Connor-McCourt, Gilles Tremblay, Anne Lenferink, Traian Sulea, John Zwaagstra, James Koropatnick. AVID200, a highly potent TGF-beta trap, exhibits optimal isoform selectivity for enhancing anti-tumor T-cell activity, without promoting metastasis or cardiotoxicity [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 1759.