Antibody Targeting of TGF-beta in Cancer Patients

作者：Lonning Scott; Mannick Joan; McPherson John M^*

来源：Current Pharmaceutical Biotechnology, 2011, 12(12): 2176-2189.

DOI：10.2174/138920111798808392

• Transforming growth factor-beta
• cancer
• antibody therapy
• anti-TGF-beta antibodies
• melanoma
• epithelial hyperplasia

The role of TGF-beta in tumor development and progression is complex. Genetic mutations that disrupt the antiproliferative signaling effects of TGF-beta play a key role in the process of malignant transformation for many types of tumors. Paradoxically, this loss of sensitivity to TGF-beta s inhibitory actions often leads to TGF-beta overexpression by the tumor cells or by normal cells that are recruited to the tumor microenvironment. Elevated concentrations of TGF-beta in the tumor microenvironment have been shown to facilitate tumor growth and metastasis. Numerous published studies have provided evidence that inhibition of TGF-beta using antibodies, soluble receptors and small molecule inhibitors of TGF-beta signal transduction can have beneficial effects in murine models of cancer. Given the pleiotropic nature of TGF-beta and its homeostatic role in numerous biological processes, serious concerns have been expressed regarding the safety of administering TGF-beta antagonists to human patients. Interestingly, the results of numerous animal toxicology studies of TGF-beta antibodies in normal rodents and primates have shown that administration of neutralizing anti-TGF-beta antibodies is well tolerated and any adverse effects were reversible or self-limiting. Likewise, administration of a human anti-TGF-beta antibody (fresolimumab) in three separate human phase 1 clinical trials has also been shown to be well tolerated.

• 出版日期2011-12