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Abstract
Much work has been done to develop tumor-targeting antibodies by selecting a phage antibody library on cancer cell lines. However, when tumor cells are removed from their natural environment, they may undergo genetic and epigenetic changes yielding different surface antigens than those seen in actual cases of cancer. We developed a strategy that allows selection of phage antibodies against tumor cells in situ on both fresh frozen and paraffin-embedded tissues using laser capture microdissection. By restricting antibody selection to binders of internalizing epitopes, we generated a panel of phage antibodies that target clinically represented prostate cancer antigens. We identified ALCAM/MEMD/CD166, a newly discovered prostate cancer marker, as the target for one of the selected antibodies, demonstrating the effectiveness of our approach. We further conjugated two single chain Fv fragments to liposomes and demonstrated that these nanotargeting devices were efficiently delivered to the interior of prostate cancer cells. The ability to deliver payload intracellularly and to recognize tumor cells in situ makes these antibodies attractive candidates for the development of targeted cancer therapeutics.
Highlights
Much work has been done to develop tumor-targeting antibodies by selecting a phage antibody library on cancer cell lines
We aimed to identify phage antibodies that bind to tumor epitopes present on actual cases of cancer and to further identify a subset of functional phage antibodies that bind to internalizing epitopes so that they may be exploited to deliver payload to the interior of tumor cells
A sublibrary was generated that is enriched for binders to cell surface receptors including those that are internalizing. This was accomplished by counterselecting a naıve phage antibody library containing 5 ϫ 108 unique scFv fragments on a panel of non-tumorigenic epithelial cell lines to remove binders to common cell surface antigens followed by selecting on a panel of live tumor cell lines such as the hormone refractory prostate cancer lines PC3 and Du-145 [1, 14, 34, 35]
Summary
Much work has been done to develop tumor-targeting antibodies by selecting a phage antibody library on cancer cell lines. Wide range of antigenic determinants with high affinity and specificity and are able to discern subtle differences in antigen structure and conformation, they can be used to efficiently map the tumor cell surface epitope space [1]. Isolating these epitopes enables the antibodies to achieve specific binding to neoplastic cells, an ability that could be utilized in applications such as induction of antibody-dependent cell cytotoxicity [7] or inhibition of signaling pathways involved in tumor cell migration, growth, and survival [8, 9]. Tissue sections from cancer patients would be an ideal selection target in the development of cancer-specific antibodies; most tissues taken during surgeries, biopsies, or autopsies are composed of heterogeneous cell populations. This seemingly poses a serious obstacle to selection methods that would target cancer cells in tissue
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