Abstract
There is considerable interest in the characterization of novel tumor-associated antigens that lend themselves to antibody-mediated pharmacodelivery strategies. Delta-like 1 homolog protein (DLK1), which exists both as transmembrane protein and in soluble form, shows a restricted pattern of expression in healthy organs, while being overexpressed in some tumors. We have generated a human antibody specific to DLK1 using phage display technology. This reagent was used for a comprehensive characterization of DLK1 expression in freshly frozen sections of normal human adult tissues and of xenografted human tumors. DLK1 was virtually undetectable in most organs, except for placenta which was weakly positive. By contrast, DLK1 exhibited a moderate-to-strong expression in 8/9 tumor types tested. Our analysis shed light on previous conflicting reports on DLK1 expression in health and disease. The study suggests that DLK1 may be considered as a target for antibody-mediated pharmacodelivery strategies, in view of the protein’s limited expression in normal tissues and its abundance in the interstitium of neoplastic lesions.
Highlights
Monoclonal antibodies represent the fastest growing segment of pharmaceutical biotechnology products [1,2]
The protein was purified from culture supernatants using Protein A resin, yielding preparations of acceptable quality for subsequent antibody selection experiments, as demonstrated by SDS-PAGE and FPLC analysis (Figure 1c,d)
The mass spectrometry analysis confirmed the identity of the human Delta-like 1 homolog protein (DLK1) protein in the expressed DLK1-Fc fusion protein (Table 1)
Summary
Monoclonal antibodies represent the fastest growing segment of pharmaceutical biotechnology products [1,2]. DLK1 has been shown to inhibit Notch activity, controlling a wide range of developmental processes including cell fate determination, terminal differentiation and proliferation [6,7]. Both transmembrane and soluble forms of DLK1 are active [8] and are involved in adipogenesis [9], muscle development and injury healing [10], as well as in the development of liver [11], lung and pancreas [12]. This report motivated us to generate fully human antibodies against DLK1 and to characterize staining patterns in freshly frozen tissue sections. An immunofluorescence analysis of human healthy tissues as well as human cancer xenograft specimens revealed that DLK1 is virtually undetectable in normal adult tissues, while being strongly expressed in neoplastic lesions
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