Fresolimumab is a high-affinity humanized monoclonal antibody that binds to and inhibits all isoforms of the protein transforming growth factor β (TGFβ)[1]. The Kd values of Fresolimumab for TGFβ1, TGFβ2, and TGFβ3 are 1.7±0.6nM, 3.0±1.2nM, and 2.0±1.2nM, respectively[2]. Fresolimumab can treat idiopathic pulmonary fibrosis (IPF), focal segmental glomerulosclerosis, and cancer[3, 4].
In vitro, treatment of esophageal adenocarcinoma OE19 and 031M cells with Fresolimumab (10μg/mL) for 1 week reversed the mesenchymal morphology of the cells and reduced the expression of the mesenchymal marker VIM[5]. Fresolimumab (12.5, 50nM) treated MC38, EMT6 and HCT116 cells expressing human TGFβRII blocked TGFβ1-induced SMAD2/3 phosphorylation[6].
In vivo, Fresolimumab (10, 25, 50mg/kg) treated mice with human colon cancer Lovo cell xenografts by intraperitoneal injection significantly reduced TGFβ levels in tumors[6].
References:
[1] Lacouture M E, Morris J C, Lawrence D P, et al. Cutaneous keratoacanthomas/squamous cell carcinomas associated with neutralization of transforming growth factor β by the monoclonal antibody fresolimumab (GC1008)[J]. Cancer Immunology, Immunotherapy, 2015, 64: 437-446.
[2] Moulin A, Mathieu M, Lawrence C, et al. Structures of a pan‐specific antagonist antibody complexed to different isoforms of TGFβ reveal structural plasticity of antibody–antigen interactions[J]. Protein Science, 2014, 23(12): 1698-1707.
[3] Trachtman H, Goyal S, Finn P, et al. Neutralizing TGF-β in fibrotic renal disorders: focus on fresolimumab[J]. Drugs Future, 2012, 37(787): 10.1358.
[4] Vincenti F, Fervenza F C, Campbell K N, et al. A phase 2, double-blind, placebo-controlled, randomized study of fresolimumab in patients with steroid-resistant primary focal segmental glomerulosclerosis[J]. Kidney international reports, 2017, 2(5): 800-810.
[5] Steins A, Ebbing E A, Creemers A, et al. Chemoradiation induces epithelial‐to‐mesenchymal transition in esophageal adenocarcinoma[J]. International journal of cancer, 2019, 145(10): 2792-2803.
[6] Greco R, Qu H, Qu H, et al. Pan-TGFβ inhibition by SAR439459 relieves immunosuppression and improves antitumor efficacy of PD-1 blockade[J]. Oncoimmunology, 2020, 9(1): 1811605.
Fresolimumab是一种高亲和力的人源化单克隆抗体，能够结合并抑制蛋白转化生长因子β（TGFβ）的所有亚型[1]。Fresolimumab对TGFβ1、TGFβ2和TGFβ3的Kd值分别为1.7±0.6nM、3.0±1.2nM、2.0±1.2nM[2]。Fresolimumab能够治疗特发性肺纤维化（IPF）、局灶节段性肾小球硬化和癌症[3, 4]。
在体外，Fresolimumab（10μg/mL）处理食管腺癌OE19、031M细胞1周，逆转了细胞的间充质形态，降低了间充质标志物VIM的表达[5]。Fresolimumab（12.5，50nM）处理表达人TGFβRII的小鼠细胞系MC38、EMT6和人HCT116 细胞，阻断了TGFβ1诱导的SMAD2/3磷酸化[6]。
在体内，Fresolimumab（10，25，50mg/kg）通过腹腔注射治疗人结肠癌Lovo细胞异种移植小鼠，显著了降低肿瘤内TGFβ水平[6]。