Abstract
The role of TGF-β in tumor development and progression is complex. Genetic mutations that disrupt the antiproliferative signaling effects of TGF-β play a key role in the process of malignant transformation for many types of tumors. Paradoxically, this loss of sensitivity to TGF-βs inhibitory actions often leads to TGF-β overexpression by the tumor cells or by normal cells that are recruited to the tumor microenvironment. Elevated concentrations of TGF-β in the tumor microenvironment have been shown to facilitate tumor growth and metastasis. Numerous published studies have provided evidence that inhibition of TGF-β using antibodies, soluble receptors and small molecule inhibitors of TGF-β signal transduction can have beneficial effects in murine models of cancer. Given the pleiotropic nature of TGF-β and its homeostatic role in numerous biological processes, serious concerns have been expressed regarding the safety of administering TGF-β antagonists to human patients. Interestingly, the results of numerous animal toxicology studies of TGF-β antibodies in normal rodents and primates have shown that administration of neutralizing anti-TGF-β antibodies is well tolerated and any adverse effects were reversible or self-limiting. Likewise, administration of a human anti-TGF-β antibody (fresolimumab) in three separate human phase 1 clinical trials has also been shown to be well tolerated.
Keywords: Transforming growth factor-β, cancer, antibody therapy, anti-TGF-β antibodies, melanoma, epithelial hyperplasia, tumor microenvironment, numerous animal toxicology studies, clinical trials, bone morphogenetic proteins (BMPs), hematopoietic cells, cysteine-knot, lymphocytes, cyclin-dependent kinase inhibitors, lung parenchyma
Current Pharmaceutical Biotechnology
Title: Antibody Targeting of TGF-β in Cancer Patients
Volume: 12 Issue: 12
Author(s): Scott Lonning, Joan Mannick and John M. McPherson
Affiliation:
Keywords: Transforming growth factor-β, cancer, antibody therapy, anti-TGF-β antibodies, melanoma, epithelial hyperplasia, tumor microenvironment, numerous animal toxicology studies, clinical trials, bone morphogenetic proteins (BMPs), hematopoietic cells, cysteine-knot, lymphocytes, cyclin-dependent kinase inhibitors, lung parenchyma
Abstract: The role of TGF-β in tumor development and progression is complex. Genetic mutations that disrupt the antiproliferative signaling effects of TGF-β play a key role in the process of malignant transformation for many types of tumors. Paradoxically, this loss of sensitivity to TGF-βs inhibitory actions often leads to TGF-β overexpression by the tumor cells or by normal cells that are recruited to the tumor microenvironment. Elevated concentrations of TGF-β in the tumor microenvironment have been shown to facilitate tumor growth and metastasis. Numerous published studies have provided evidence that inhibition of TGF-β using antibodies, soluble receptors and small molecule inhibitors of TGF-β signal transduction can have beneficial effects in murine models of cancer. Given the pleiotropic nature of TGF-β and its homeostatic role in numerous biological processes, serious concerns have been expressed regarding the safety of administering TGF-β antagonists to human patients. Interestingly, the results of numerous animal toxicology studies of TGF-β antibodies in normal rodents and primates have shown that administration of neutralizing anti-TGF-β antibodies is well tolerated and any adverse effects were reversible or self-limiting. Likewise, administration of a human anti-TGF-β antibody (fresolimumab) in three separate human phase 1 clinical trials has also been shown to be well tolerated.
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Cite this article as:
Lonning Scott, Mannick Joan and M. McPherson John, Antibody Targeting of TGF-β in Cancer Patients, Current Pharmaceutical Biotechnology 2011; 12 (12) . https://dx.doi.org/10.2174/138920111798808392
DOI https://dx.doi.org/10.2174/138920111798808392 |
Print ISSN 1389-2010 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4316 |
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