Development of AVID200, a novel TGF-ß targeting immunotherapy: Characterization of immunomodulatory effects

Background: Elevated TGFβligand promotes 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 TGFβand 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. We sought to design a trap that preferentially blocks TGFβ1 and 3 and not TGFβ2, the isoform that is important for maintenance of normal cardiac function. Methods: AVID200 is a computationally designed avidity-enhanced receptor-based trap that binds and neutralizes TGFβ1 and 3 with low pM potency. The AVID200 lead candidate was selected based on the analysis of several trap formats, with each format exhibiting varying characteristics, including differing circulating half-lives and in vitro blocking potencies. AVID200 was evaluated for single agent effects on tumor growth and T-cell infiltration 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 4T1 tumor-bearing animals. Finally, AVID200 is being tested for its ability to promote sensitivity to immune checkpoint inhibitors in combination studies. Results: In efficacy studies using the syngeneic 4T1 TNBC model, AVID200 was 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 AVID200 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: The novel computational design of AVID200 results in a trap with low pM in vitro neutralization potency for TGFβ1 and 3. Additionally, AVID200 markedly promotes the T-cell-inflamed" tumor state in vivo. Combination studies with immune checkpoint inhibitors will be presented.