Folate Receptor Βeta: A New Surface Molecule for Selective Targeting of Activated Macrophages in Inflammatory Diseases and Cancer
Abstract
Ever since the concept of alternatively activated macrophages (AAMs or M2-Macrophages) was proposed, their prominent roles in the pathology of tumor progression, allergic inflammatory disorders and fibrotic diseases have been well-documented. Consequently, AAM has become a prime target for therapeutic interventions, but the question is how to develop a more effective and more specific AAM-directed therapeutic approach. Our lab unexpectedly discovered that a subpopulation of macrophages isolated from sites of inflammation expresses the β isoform of folate receptor (FR-β), whose expression has also been found to be elevated the in the lung tissue from mice with allergic asthma that is caused or aggravated by a massive accumulation of AAMs. So our central hypothesis is that FR-β could serve as a marker for AAM and enable the selective targeting of AAM in vivo. To test this hypothesis, we adopt this well-established mouse model of allergic asthma and found the restricted expression of FR-β on the infiltrated macrophages in the asthmatic lung tissue. Further examination of these FR-β + macrophages demonstrates that they also express a mannose receptor (CD206) and arginase 1, suggesting that they fall into the class of AAM. Moreover, the overexpressed FR-β on these AAMs can be exploited for selective delivery of folate-conjugated imaging agents to diseased tissue. As an extension of folate targeting strategy, we isolated a fully human anti-human FR-β monoclonal antibody, m909, with relatively high affinity and avidity to human FR-β but neither human FR-α nor mouse FR-β. M909 is not only able to efficiently select FR-β-positive synovial macrophages from rheumatoid arthritis patients, but also able to mediate ADCC towards FR-β-positive cells. Because m909 does not compete with folate for receptor binding, it can be used with folate-drug conjugates in a combination therapy. Interestingly, performance of FR-β immunohistochemistry (IHC) in a variety of human tumor tissues as well as inflamed tissues revealed that FR-β is not only expressed on several types of malignant cells but also on the tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), which is consistent with the animal data that FR-β acts as a marker for macrophages with alternatively activated phenotype. With this novel monoclonal antibody m909, we further showed that FR-β expression is restricted to the classic CD14highCD16 - monocytes but no other cells in the human peripheral blood. However, few, if any, FR+ circulating blood monocytes were found in mice (neither Balb/c nor C57BL/6J). Our findings suggest that FR-β could be an ideal target molecule for manipulating AAM, and folate ligation can facilitate delivery of attached compounds into AAM to minimize off-target toxicity.
Degree
Ph.D.
Advisors
Low, Purdue University.
Subject Area
Chemistry
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