Anti–Transforming Growth Factor β Receptor II Antibody Has Therapeutic Efficacy against Primary Tumor Growth and Metastasis through Multieffects on Cancer, Stroma, and Immune Cells

Abstract

Purpose: Transforming growth factor β (TGFβ) is a pleiotropic cytokine that affects tumor growth, metastasis, stroma, and immune response. We investigated the therapeutic efficacy of anti-TGFβ receptor II (TGFβ RII) antibody in controlling metastasis and tumor growth as well as enhancing antitumor immunity in preclinical tumor models.Experimental Design: We generated neutralizing antibodies to TGFβ RII and assessed the antibody effects on cancer, stroma, and immune cells in vitro. The efficacy and mechanism of action of the antibody as monotherapy and in combination with chemotherapy in suppression of primary tumor growth and metastasis were evaluated in several tumor models.Results: Anti-TGFβ RII antibody blocked TGFβ RII binding to TGFβ 1, 2, and 3, and attenuated the TGFβ-mediated activation of downstream Smad2 kinase, invasion of cancer cells, motility of endothelial and fibroblast cells, and induction of immunosuppressive cells. Treatment with the antibody significantly suppressed primary tumor growth and metastasis and enhanced natural killer and CTL activity in tumorbearing mice. Immunohistochemistry analysis showed cancer cell apoptosis and massive necrosis, and increased tumor-infiltrating T effector cells and decreased tumor-infiltrating Gr-1+ myeloid cells in the antibody-treated tumors. Fluorescence-activated cell sorting analysis indicated the significant reduction of peripheral Gr-1+/CD11b+ myeloid cells in treated animals. Concomitant treatment with the cytotoxic agent cyclophosphamide resulted in a significantly increased antitumor efficacy against primary tumor growth and metastasis.Conclusions: These preclinical data provide a foundation to support using anti-TGFβ RII antibody as a therapeutic agent for TGFβ RII-dependent cancer with metastatic capacity.

TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

“…The notion that TGFβ1 high /lncRNA-LET low /miR-145 low signature in clinical samples were correlated with poor prognosis reinforces the importance of this regulatory axis for UBC patients. Interestingly, forced expression of lncRNA-LET maintained the sensitivity of UBC cells to GEM and delaying tumor relapse, suggesting that either targeting TGFβ signaling pathway, restoration of lncRNA-LET expression or reintroduction of its downstream target miRNA could be an attractive anti-tumor approach for integrated cancer therapy (49,52,53).…”

Signaling Receptors for TGF-β Family Members

“…Such inhibitors include inhibitory antibodies against TGF-b or TGF-b receptors (Zhong et al 2010) or ligand traps consisting of soluble extracellular domains of TGF-b receptors. A soluble TbRII extracellular domain has been shown to inhibit tumor progression in animal tumor models (Saunier and Akhurst 2006), and a soluble ALK-1 extracellular domain has been shown to have antiangiogenic properties and to inhibit tumor growth in mouse models (Cunha et al 2010).…”

Targeting TGF-β Signaling for Therapeutic Gain

“…The other drug class that has received considerable attention in the clinic (Table 2) is the TGF-b ligand-and receptor-blocking antibodies, including the pan-TGF-b1/2/3 blocking antibody, fresolimumab (Genzyme/Sanofi) (Morris et al 2014), the TGF-b1-specific blocking antibody LY2382770 (Eli Lilly) (Cohn et al 2014;Tampe and Zeisberg 2014), and the TbRII blocking antibody LY3022859, also called IMC-TR1 (Eli Lilly, NCT01646203) (Zhong et al 2010). Other companies followed their lead with the development of alternative TGF-b ligand blocking antibodies, such as an anti-TGF-b1/2 antibody that is not cross reactive with TGF-b3, developed by Xoma/ Novartis (Bedinger et al 2016).…”

“…Metastatic melanoma was not included in the LY2382770 study, so it is possible that discordant results with fresolimumab (Morris et al 2014) relate to the distinct tumor types investigated between the two studies, with melanoma being particularly sensitive to TGF-b inhibition. A TbRII antibody (IMC-TR1, also known as LY3022859) has also been developed, and the murinized derivative showed an excellent response in mouse models of breast and colon cancer (Zhong et al 2010). This drug is in phase I trial for patients with advanced solid tumors who have failed standard therapies (NCT01646203).…”