Abstract
Antibodies are considered as 'magic bullets' because of their high specificity. It is believed that antibodies are too large to routinely enter the cytosol, thus antibody therapeutic approach has been limited to extracellular or secreted proteins expressed by cancer cells. However, many oncogenic proteins are localized within the cell. To explore the possibility of antibody therapies against intracellular targets, we generated a chimeric antibody targeting the intracellular PRL-3 oncoprotein to assess its antitumor activities in mice. Remarkably, we observed that the PRL-3 chimeric antibody could efficiently and specifically reduce the formation of PRL-3 expressing metastatic tumors. We further found that natural killer (NK) cells were important in mediating the therapeutic effect, which was only observed in a nude mouse model (T-cell deficient), but not in a Severe Combined Immunodeficiency' (scid ) mouse model (B- and T-cell deficient), indicating the anticancer effect also depends on host B-cell activity. Our study involving 377 nude and scid mice suggest that antibodies targeting intracellular proteins can be developed to treat cancer.
Highlights
A century ago, Paul Ehrlich proposed the concept of antibodies as ‘magic bullets’, the use of therapeutic monoclonal antibodies against a number of disease targets validated this concept [1,2,3]
We investigated if Fc-binding, cytotoxic natural killer (NK) cells might play a role in the PRL-3 antibody therapy as NK cells are a subset of cytotoxic lymphocytes that constitute a major component of the innate immune system
It is anticipated that the PRL3 chimeric antibody is likely to have broad applications in blocking the progression of different types of PRL-3 positive cancers, in malignancies such as lung cancers and acute myeloid leukemia (AML) that often relapse within short time frames
Summary
A century ago, Paul Ehrlich proposed the concept of antibodies as ‘magic bullets’, the use of therapeutic monoclonal antibodies (mAbs) against a number of disease targets validated this concept [1,2,3]. Overexpression of PRLs has been subsequently shown to have a causative role in promoting cancer metastases and they become potential targets for diverse cancer treatment [15]. As these phosphatases are intracellularly localized, the conventional approach using therapeutic antibodies would seem implausible. To extend our earlier findings, in this current study, we expanded upon the reliability of such targeting strategy using a newly-generated mouse/ human chimeric monoclonal PRL-3 antibody as a potential clinical therapeutic agent against cancer in five important aspects. The results suggest that an evaluation of a wide spectrum of intracellular oncoproteins (such as phosphatases, kinases, transcription factors, and many others) as possible targets for anticancer therapy may be warranted
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