A novel computationally-designed TGF beta trap promoting anti-tumor T cell activity

From National Research Council Canada

DOIResolve DOI: https://doi.org/10.1158/1538-7445.AM2017-4688
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Name affiliation
  1. National Research Council of Canada. Human Health Therapeutics
FormatText, Abstract
Proceedings titleProceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC
Series titleCancer Research; Volume 77
ConferenceAmerican Association for Cancer Research Annual Meeting 2017, April 1-5, 2017, Washington, DC, USA
ISSN0008-5472
1538-7445
Article numberAbstract nr 4688
Abstract
AVID200 is a computationally-designed, avidity-enhanced, receptor ectodomain-based trap that binds and neutralizes TGF-beta 1 and 3 with low pM potency. Of the three TGF-beta isoforms, blockade of TGF-beta 2 has been shown to promote cancer metastasis. Therefore, AVID200 is designed to inhibit TGF-beta 1 and 3 only. TGF-beta is a strongly immunosuppressive molecule that, when expressed by cancers, mediates escape from immune surveillance. Increased TGF-beta ligand promotes cancer progression by suppressing anti-tumor immunity, predominantly by suppressing recruitment and activation of anti-tumor T cells. Consequently, TGF-beta is an important therapeutic target in cancer.AVID200 immunotherapy blocks the capacity of TGF-beta 1 and 3 ligands to interact with their receptors. That blockage induces T cell infiltration into tumors, thereby promoting a "T cell-inflamed" tumor state. Multiple trap formats with differing in vitro blocking potency, biophysical traits, and circulating half-lives in rodents have been designed, synthesized, and tested. On the basis of favorable characteristics, the AVID200 molecule was selected for in vivo assessment of efficacy in inhibiting growth of syngeneic 4T1 triple negative breast cancer (TNBC) homografts in immunocompetent host mice. In addition, CD4+ and CD8+ T cells isolated from draining lymph nodes of 4T1 tumor-bearing mice, treated and untreated with AVID200 and other candidate TGF-beta traps, were assessed for activities important in anti-tumor immune activity. We report that AVID200 immunotherapy decreased T-cell apoptosis, stimulated T-cell proliferation in response to tumor cell lysate-loaded dendritic cells, and enhanced the capacity of T-cells to specifically recognize and kill 4T1 tumor cells in ex vivo 2D cultures. The effect of combining AVID200 with immune checkpoint inhibitors in the treatment of syngeneic homografts in immune-competent mice is being assessed. AVID200 is a promising new immunotherapy to selectively inhibit the TGF-beta 1 and 3 isoforms, thereby enhancing desirable anti-tumor immunity while avoiding the tumor-promoting effects resulting from TGF-beta 2 neutralization.
Publication date
PublisherAmerican Association for Cancer Research
LanguageEnglish
Peer reviewedYes
NPARC number23002151
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