Monoclonal antibody therapy resistance

There are two major factors predisposing to resistance to monoclonal antibody therapy. One is a tumor-related factor such as antigen loss, complement resistance antigen expression, intrinsic resistance, or tumor burden. Besides tumor-related factors, growing evidence has indicated that patient-related factors may account for the different responses of the patients to monoclonal antibody therapy. For example, differences in ADCC or CDC function according to individuals may increase our understanding of... 

Villamor N, Montserrat E, Colomer D. Mechanism of action and resistance to monoclonal antibody therapy. Semin Oncol2003 30 424 33. 

Nonspecific immunosuppressive therapy in an adult patient is usually through cyclosporin (35), started intravenously at the time of transplantation, and given orally once feeding is tolerated. Typically, methylprednisone is started also at the time of transplantation, then reduced to a maintenance dose. A athioprine (31) may also be used in conjunction with the prednisone to achieve adequate immunosuppression. Whereas the objective of immunosuppression is to protect the transplant, general or excessive immunosuppression may lead to undesirable compHcations, eg, opportunistic infections and potential malignancies. These adverse effects could be avoided if selective immunosuppression could be achieved. Suspected rejection episodes are treated with intravenous corticosteroids. Steroid-resistant rejection may be treated with monoclonal antibodies (78,79) such as Muromonab-CD3, specific for the T3-receptor on human T-ceUs. Alternatively, antithymocyte globulin (ATG) may be used against both B- and T-ceUs. 

The main opportunity for advanced drag delivery systems in this market is in the area of targeted drag delivery. Current research is focused on the development of carriers such as liposomes and on the use of monoclonal antibodies as targeting agents (see Sections 5.2 and 5.3). The eventual market opportunity is considerable—cancer is still one of the commonest fatal diseases, and some of the most deadly forms are resistant to available therapies. The potential market for effective targeting delivery systems may eventually exceed 5 billion. Whether, and how soon, it achieves this figure will depend on the speed with which successful products come to market. 

Trastuzumab (Herceptin) is a humanized monoclonal antibody against the HER2/neu (ErbB-2) member of the epidermal growth factor family of cellular receptors. The internal domain of the HER2/neu glycoprotein encodes a tyrosine kinase that activates downstream signals and enhances metastatic potential and inhibits apoptosis. HER2/neu is overexpressed in up to 30% of breast cancers and is associated with clinical resistance to cytotoxic and hormone therapy. A number of mechanisms of action have... 

Perhaps the most astonishing aspect of this mAh is that it was used for the treatment of acute renal allograft rejection in patients only two years after being raised, on the basis of its ability to block CTLs in vitro, at a time when the structure of the T cell receptor complex was unknown (7). Although, even now it remains as an effective treatment for the reversal of steroid resistant acute allograft rejection, many of the compUcations associated with therapy were either underestimated or not anticipated. Nowadays extensive pre-clinical data is required, often involving primate studies, before a mAb can be used in clinical trials. It is likely that if mAbs to CDS were introduced today rather than in 1981 that they would not have gained a hcence for human use. Monoclonal antibodies to CDS in both human and animal studies have broadly similar effects and are of interest because they elicit many of the complications associated with mAb therapy. How these problems have been circumvented serves a framework for many other mAbs under development. 

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