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- W864499992 abstract "Proc Amer Assoc Cancer Res, Volume 47, 20065574 One class of emerging investigational therapies for cancer treatment has involved the mobilization of the immune system to first recognize and then attack the malignancy. The broad distribution of folate receptor (FR) expression among human neoplasms, along with its pronounced over-expression in malignant tissues and extremely limited distribution among normal epithelium, suggests an exciting potential for a FR-based immunotherapy against epithelial cancers. We have developed an immunotherapy strategy that utilizes a small folate-hapten conjugate (folate-FITC) to redirect endogenously produced anti-hapten antibody to FR-positive tumor cells. In an effort to optimize the therapeutic folate-FITC dosing regimen, pharmacokinetic studies were performed by administering radiolabeled folate-FITC to both tumor- and non-tumor bearing mice that were either naive or FITC-immunized. We found that the folate-FITC conjugate itself displays moderate nonspecific binding to serum proteins, and it is not significantly distributed to erythrocytes. In naive (non-immunized) mice, folate-FITC eliminates quickly through the liver and kidneys; but, in immunized mice, folate-FITC forms immune complexes with FITC-specific antibodies which in turn decreases its plasma clearance rate. The degree of anti-FITC antibody occupancy by circulating folate-FITC (i.e. the immune complex formation) was detectable ex-vivo by ELISA analysis using folate binding protein-coated plates. Here, we learned that excessive folate-FITC dosing simultaneously leads to (i) the saturation of circulating FITC-specific antibodies, and (ii) saturation of the tumor-associated FRs. Under these dosing conditions, “anchoring” of anti-FITC antibody to the FR-positive tumor cells is compromised. Folate-FITC exhibited a linear pharmacokinetics that was dependent on both the dose and the anti-FITC antibody titer. The extended plasma duration of folate-FITC in immunized mice can be viewed as an advantage for maintaining a long-lasting accumulation of folate-FITC on FR-positive tumors. By extending the duration of treatment and optimizing the doses of therapeutic components (folate-FITC in combination with cytokines), enhanced antitumor activity with minimal toxicity was observed in mice bearing established subcutaneous tumors. Overall, our on-going research may allow for the identification of a more therapeutically effective, folate-hapten dosing regimen when given as immunotherapy in patients with FR-positive metastatic tumors." @default.
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- W864499992 date "2006-04-15" @default.
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- W864499992 title "Folate-hapten conjugate targeted immunotherapeutics: pharmacokinetics, biodistribution, and enhanced antitumor activity." @default.
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