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Current Pharmaceutical Biotechnology

Volume 12 Issue 12
ISSN: 1389-2010
eISSN: 1873-4316

 

   All Titles

  Antibody Targeting of TGF-β in Cancer Patients
  pp.2176-2189 (14) Authors: Scott Lonning, Joan Mannick, John M. McPherson
 
 
      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-β's 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
  Affiliation: Genzyme Corporation, 1 Mountain Rd., Framingham, MA 01701, USA.
 
  Key: New Content Free Content Open Access Plus Subscribed Content

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