Preclinical pharmacokinetics, tissue distribution, and antitumor activity of a folate-hapten conjugate-targeted immunotherapy in hapten-immunized mice.
Folic acid (pteroylglutamic acid) represents a useful ligand for targeted cancer therapies because it binds to a common epithelial tumor antigen known as the folate receptor. We previously devised an immunotherapy strategy that uses a bispecific ligand, a folate-hapten (FITC) conjugate, to redirect endogenously induced anti-FITC antibodies to folate receptor-positive tumor cells following parenteral administration. Here, we present results from preclinical pharmacokinetic and tissue biodistribution studies using a radioactive folate-FITC conjugate and results from dose optimization studies done in tumor-bearing animals. Folate-FITC was found to be rapidly eliminated in non-immunized mice; however, in immunized hosts, folate-FITC was shown to form immune complexes with FITC-specific antibodies, the consequence of which was a approximately 173-fold increase in drug exposure (i.e., area under the curve). Using a newly developed ELISA assay, the extent of circulating anti-FITC antibodies occupied by parenterally given folate-FITC was determined to be proportional to the given dose. Furthermore, high doses of folate-FITC were found to promote the cosaturation of tumor cell surface folate receptors and circulating FITC-specific antibodies, blocking the immune recognition of tumor cells and thereby reducing antitumor activity. Nonetheless, by extending the duration of treatment and administering subsaturating doses of folate-FITC, enhanced antitumor response was observed in mice bearing established folate receptor-positive M109 tumors. Overall, results from the present study may help to guide clinicians through on-going clinical investigations of folate-targeted immunotherapy.
Lu
Yingjuan
Y
Endocyte, Inc., Suite A1-100, 3000 Kent Avenue, West Lafayette, IN 47906, USA.
Xu
Le-Cun
LC
Parker
Nikki
N
Westrick
Elaine
E
Reddy
Joseph A
JA
Vetzel
Marilynn
M
Low
Philip S
PS
Leamon
Christopher P
CP
D000818:Animals; D016207:Cytokines / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000493:pharmacokinetics; D005492:Folic Acid / Q000493:pharmacokinetics* / Q000494:pharmacology; D006241:Haptens / Q000494:pharmacology; D018796:Immunoconjugates / Q000493:pharmacokinetics* / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D014018:Tissue Distribution; D014316:Tritium
D016207:Cytokines; D006241:Haptens; D018796:Immunoconjugates; D014316:Tritium; D005492:Folic Acid; D016650:Fluorescein-5-isothiocyanate