Introduction: Elevated TGF-beta ligand markedly augments cancer progression primarily by suppressing the immune system in the tumor microenvironment, in particular by suppressing T-cell recruitment and/or activation. We developed AVID200, a novel decoy receptor trap that potently blocks TGF-beta and induces T-cell infiltration into tumors. This promotes the “T-cell-inflamed” tumor state, which is expected to render tumors sensitive to immune checkpoint inhibitors and other immunotherapeutics.
Experimental Procedures: AVID200 is a computationally designed novel class of avidity-enhanced receptor-ectodomain-based trap that binds and neutralizes TGF-beta 1 and 3 with low pM potency. Several trap formats have been produced and tested, with each format exhibiting varying characteristics, including differing circulating half-lives and in vitro blocking potencies. AVID200 was evaluated for efficacy in in vivo studies using the syngeneic 4T1 triple negative breast cancer (TNBC) tumor model. Additionally, ex vivo studies were performed on CD4+ and CD8+ T-cells harvested from the draining lymph nodes of treated animals.
Results: In efficacy studies using the syngeneic 4T1 TNBC model, novel TGF-beta traps were shown to promote significant T-cell infiltration into tumors. This infiltration resulted in reduced primary tumor growth as well as significant reductions in metastatic lesions. Additionally, ex vivo studies revealed that trap treatment decreased T-cell apoptosis, promoted T-cell proliferation in response to tumor cell lysates in the presence of dendritic cells, as well as increased the capacity of T-cells to specifically lyse 4T1 tumor cells.
Conclusion: AVID200 is a novel computationally-designed TGF-beta trap that neutralizes TGF-beta 1 and 3 with pM potency and markedly promotes the “T-cell-inflamed” tumor state. Combination studies with immune checkpoint inhibitors are ongoing.
Citation Format: Maureen D. O'Connor-McCourt, Anne E.G. Lenferink, John Zwaagstra, Traian Sulea, Jason Baardsnes, Catherine Collins, Christiane Cantin, Lucie Couture, Limei Tao, Yves Durocher, Renu Singh, James Koropatnick. Development of AVID200, a novel and highly potent TGF-beta neutralizing immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B058.
- ©2016 American Association for Cancer Research.