Abstract
Recruitment of immune cells to tumor cells targeted by a therapeutic antibody can heighten the antitumor efficacy of the antibody. For example, p185(her2/neu)-targeting antibodies not only downregulate the p185(her2/neu) kinase (ERBB2) but also trigger complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) through the antibody Fc region. Here, we describe a generalized strategy to improve immune cell recruitment to targeted cancer cells, using a modified scFv antibody we call a "Grababody" that binds the target protein and endogenous immunoglobulins. The model system we used to illustrate the use of this platform recognizes p185(her2/neu) and includes an IgG binding domain. The recombinant scFv Grababody that was created recruited circulating human IgGs and attracted immune cells carrying Fc receptors to tumor cells that expressed p185(her2/neu). The presence of the IgG binding domain significantly enhanced CDC and ADCC activity and improved antitumor activity in vivo. Our results illustrate a novel general approach to improve antibody-like proteins for therapeutic applications.
Highlights
Antibody-based cancer therapies, which in general target cell surface tumor antigens with recombinantly engineered monoclonal antibodies, have changed the paradigm of treatments for many types of tumors [1]
Recombinant antibodies have to be expressed in mammalian cells to obtain proper glycosylation, which is required to keep the Fc region of the IgG molecule in an "open" conformation to interact with Fc receptors [2]
For Fc fusion proteins, current clinical data on the use of whole antibody molecules provide information on the expected clinical efficacy and indicate that the haplotype of Fc receptor in patients can limit the activity of Fc fusion proteins
Summary
Antibody-based cancer therapies, which in general target cell surface tumor antigens with recombinantly engineered monoclonal antibodies, have changed the paradigm of treatments for many types of tumors [1]. These monoclonal antibodies (mAb), either as humanized antibodies or chimeric molecules, contain the Fc region of human IgG molecules that is required to induce cytotoxic mechanisms, such as ADCC and CDC. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Depending on the cell culture conditions, the produced mAbs can have varied glycosylation [3], which can either extend or shorten the serum half-life of the antibodies [4,5,6] and cause side effects in some antibody-based treatments [7].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
