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New Drugs in Myeloproliferative Disorders
Published in Richard T. Silver, Ayalew Tefferi, Myeloproliferative Disorders, 2007
Srdan Verstovsek, Ruben A. Mesa
TGF-β1 plays a central role in the prominent bone marrow stromal reaction observed in the patients with PMF. Several compounds, originally designed for the treatment of other profibrotic conditions, inhibit TGF-β1–mediated signaling. GC-1008 is one such agent, as is a pan-specific human anti-TGF-β1 antibody. GC-1008 is currently undergoing clinical evaluation for several indications, including pulmonary fibrosis, renal cancer, melanoma of the skin, and also for PMF (50). Alternatively, metelimumab (CAT-192) is a human TGF-β1 monoclonal antibody that is currently undergoing phase I/II trials for patients with scleroderma. A different approach is the employment of TGF-β1–specific antisense oligonucleotides. AP-11014 is such an example and is currently being developed for human non–small-cell lung, colorectal, and prostate cancers (51). However, delivery and tissue-penetration issues for these antisense therapies might limit their application (50). Several studies have shown the efficacy of using small molecules such as LY580276 (IC50 175 nM) (52), pyrazole 2 (IC50 18 nM) (53), SB-505124 (IC50 47 nM) (54), and SD-208 (55) to inhibit the TGF-β type-I receptor kinase ALK5. Although promising, all these compounds are in preclinical phases of development and their in vivo activity and tolerability are yet to be determined.
Next-generation immunotherapy for solid tumors: combination immunotherapy with crosstalk blockade of TGFβ and PD-1/PD-L1
Published in Expert Opinion on Investigational Drugs, 2022
Hue Tu Quach, Zhaohua Hou, Rebecca Y. Bellis, Jasmeen K. Saini, Alfredo Amador-Molina, Prasad S. Adusumilli, Yuquan Xiong
Monoclonal antibodies and soluble TGFβ receptor II were employed to neutralize excessive TGFβ from tumors and fibroblasts [4]. Genzyme developed three monoclonal antibodies, including lerdelimumab, metelimumab, and fresolimumab (GC1008); the development of the two former antibodies was stopped in 2005 after an unsuccessful trial [39,40]. A human derivative of the 1D11 antibody, GC1008, can trap all three forms of TGFβ ligands [4,6]. Five clinical trials investigated GC10008 for the treatment of patients with primary brain tumors, pleural malignant mesothelioma, advanced renal cell carcinoma, melanoma, and breast cancer (NCT01472731, NCT01112293, NCT00923169, NCT00356460, NCT01401062) [6]. Phase I trials with fresolimumab showed partial response in patients with malignant melanoma [41]. In addition, fresolimumab with radiotherapy exhibited a better overall survival of patients with breast cancer [6,42]. AVID200 is an innovative, computationally designed receptor that specifically neutralizes TGFβ1/3 but not TGFβ2 [43,44]. AVID200 was found to kill 4T1 tumor cells in a syngeneic triple-negative breast cancer model in a dose-dependent manner, with a better killing efficacy than that of 1D11 neutralizing antibody. No treatment-related cardiotoxicity was recorded at doses up to 30 mg/kg in a non-human primate study [44]. An ongoing phase I trial is investigating the safety and efficacy of AVID200 for the treatment of patients with advanced malignant solid tumors [6]. Another agent that is being investigated in an early-stage clinical trial is BETA-PRIME, a TGF-β trap fusion protein.
Structure-based engineering to restore high affinity binding of an isoform-selective anti-TGFβ1 antibody
Published in mAbs, 2018
Dana M. Lord, Julie J. Bird, Denise M. Honey, Annie Best, Anna Park, Ronnie R. Wei, Huawei Qiu
There are three TGFβ isoforms in humans (TGFβ1, TGFβ2, and TGFβ3), which all signal through the same serine/threonine kinase type I and type II cell surface receptors.4,6 While having similar cellular targets, biological studies have demonstrated that the isoforms have different expression profiles. Of the three isoforms, TGFβ1 is the most abundant and ubiquitously expressed.4 Metelimumab, also known as CAT192, is a human IgG4 monoclonal antibody that was designed to selectively neutralize TGFβ1. CAT192 was tested for the treatment of diffuse cutaneous systemic sclerosis, also known as scleroderma, but demonstrated insufficient efficacy.7