Colocalized targeting of TGF-β and PD-L1 by bintrafusp alfa elicits distinct antitumor responses

作者：Yan Lan, Tsz-Lun Yeung, Hui Huang, Ansgar Wegener, Somdutta Saha, Mira Toister‐Achituv, Molly H. Jenkins, Li-Ya Chiu, Adam S. Lazorchak, Ohad Tarcic, Hong Wang, Jin Qi, George Locke, Doron Kalimi, Guozhong Qin, Bo Marelli, Huakui Yu, Alec W. Gross, Melissa G. Derner, Maria Soloviev, Mathieu Botte, Aroop Sircar, Hong Ma, Vanita D. Sood, Dong Zhang, Feng Jiang, Kin-Ming Lo · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2022 · DOI：10.1136/jitc-2021-004122 · 被引用次数：43 · 研究领域：Cancer Immunotherapy and Biomarkers、TGF-β signaling in diseases、Cancer Cells and Metastasis

BACKGROUND: Bintrafusp alfa (BA) is a bifunctional fusion protein designed for colocalized, simultaneous inhibition of two immunosuppressive pathways, transforming growth factor-β (TGF-β) and programmed death-ligand 1 (PD-L1), within the tumor microenvironment (TME). We hypothesized that targeting PD-L1 to the tumor by BA colocalizes the TGF-β trap (TGF-βRII) to the TME, enabling it to sequester TGF-β in the tumor more effectively than systemic TGF-β blockade, thereby enhancing antitumor activity. METHODS: Multiple technologies were used to characterize the TGF-β trap binding avidity. BA versus combinations of anti-PD-L1 and TGF-β trap or the pan-TGF-β antibody fresolimumab were compared in proliferation and two-way mixed lymphocyte reaction assays. Immunophenotyping of tumor-infiltrating lymphocytes (TILs) and RNA sequencing (RNAseq) analysis assessing stromal and immune landscape following BA or the combination therapy were performed in MC38 tumors. TGF-β and PD-L1 co-expression and their associated gene signatures in MC38 tumors and human lung carcinoma tissue were studied with single-cell RNAseq (scRNAseq) and immunostaining. BA-induced internalization, degradation, and depletion of TGF-β were investigated in vitro. RESULTS: BA and fresolimumab had comparable intrinsic binding to TGF-β1, but there was an ~80× avidity-based increase in binding affinity with BA. BA inhibited cell proliferation in TGF-β-dependent and PD-L1-expressing cells more potently than TGF-β trap or fr...