Specificity delivers: therapeutic role of tumor antigen-specific antibodies in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDA) is among the most deadly cancers with less than 5% of the patients living beyond 5 years post-diagnosis. Lack of early diagnostic biomarkers and resistance to current therapies help explain these disappointing numbers. Thus, more effective and better-targeted therapies are needed quickly. Monoclonal antibodies offer an attractive alternative targeted therapy option for PDA because they are highly specific and potent. However, currently available monoclonal antibody therapies for PDA are still in their infancy with a low success rate and low likelihood of being approved. The challenges faced by these therapies include the following: lack of predictive and response biomarkers, unfavorable safety profiles, expression of targets not restricted to the cancer cells, flawed preclinical model systems, drug resistance, and PDA's complex nature. Additionally, discovery of novel PDA-specific antigen targets, present on the cell surface or in the extracellular matrix, is needed. Predictive and response markers also need to be determined for PDA patient subgroups so that the most appropriate effective therapy can be delivered. Serologic approaches, recombinant antibody-producing technologies, and advances in antibody engineering techniques will help to identify these predictive biomarkers and aid in the development of new therapeutic antibodies. A combinatorial approach simultaneously targeting antigens on the PDA cell, stroma, and immunosuppressive cells should be employed.

Figure 1. The application of seroproteomics for the discovery of PDA-specific antigens and novel monoclonal antibody therapies using the PDA-GVAX study as a representative example

2-dimensional electrophoresis (2-DE) is performed using the cell lysate obtained from the PDA GVAX cell lines. Discovery patient sera is obtained from patients that have favorable clinical and immune responses to the vaccine. Pre- and post-vaccination discovery patient sera is used for the western blot analysis. Mass-spectrometry analysis is used to identify PDA-specific antigens that elicit a favorable antibody response in patients. These antigens are subsequently validated using recombinant protein technology and sera from other patients in the clinical trial (both responders and non-responders to the vaccine). Next, the PDA antigen is subjected to immunohistochemical and functional studies to establish it as a biomarker whereas a monoclonal antibody, against the antigen, is tested as a potential antibody therapy. Sideway arrows indicate the flow of reagents into the process whereas vertical arrows represent the process flow.