Antitumor Effects of a Human Dimeric Antibody Fragment ¹³¹I-AFRA-DFM5.3 in a Mouse Model for Ovarian Cancer

Abstract

AFRA-DMF5.3 is a human antibody fragment that, as a dimer, specifically binds to the a-folate receptor (FR) on ovary cancer cells. Pharmacokinetic and biodistribution parameters of 131 I-AFRA-DFM5.3 after intravenous administration in animal models support its potential therapeutic use. We evaluated its preclinical specificity and therapeutic efficacy in tumor models. Methods: A negative control, AFRA-DFM6.1, was obtained by protein engineering. The activity and specificity of 131 I-AFRA-DFMs were evaluated by systemic administration (intravenous) in subcutaneous tumor xenograft-bearing nude mice. Pharmacokinetics, biodistribution, and efficacy were assessed by intraperitoneal administration of 131 I-AFRA-DFM5.3 in nude mice bearing 2 different intraperitoneal ovarian carcinoma xenografts. Treatments were tested at different doses and as single or double administrations 1 wk apart. Results: In subcutaneous models, 131 I-AFRA-DFM5.3, but not the negative control, was found to reside on FR-positive tumor masses and significantly reduced tumor growth. In intraperitoneal models, early accumulation on free-floating clumps of ovarian cancer cells and solid peritoneal masses was evident after 1 h, and tumor uptake was stable for up to 3 h. The high tumor uptake determined the efficacy of 131 I-AFRA-DFM5.3. The best antitumor activity, with more than 50% of treated animals cured, was achieved with 2 locoregional treatments of intraperitoneally growing tumors on days 2 and 9. Conclusion: These results suggest that radioimmunotherapy with 131 I-AFRA-DFM5.3 is feasible and leads to significantly prolonged survival. These preclinical data provide the basis for the rationale design of therapeutic treatments of ovarian cancer patients with a radiolabeled anti-FR antibody fragment.

Anti-miR182 Reduces Ovarian Cancer Burden, Invasion, and Metastasis: An In Vivo Study in Orthotopic Xenografts of Nude Mice

“…Mouse models of ovarian cancer have been studied extensively (19), however the majority of the models using ovarian cancer xenografts utilize either subcutaneous (20) or intraperitoneal (21) injection. Recent development of orthotopic mouse models of ovarian cancer intends to inject human ovarian cancer cells directly into the ovarian intrabursa (22) in order to mimic the optimal cancer environment.…”

Targeting folate receptor alpha for cancer treatment

“…radioimmunotherapy of ovarian cancer because of its relatively small size, which should favor tumor penetration and fast clearance. Due to its fast and high tumor uptake, 131 I-AFRA-DFM5.3 resulted in more than 50% of treated animals cured in a preclinical intraperitoneal model [121]. The human origin of AFRA-DFM5.3 and its efficacy when delivered locoregionally as an 131 I reagent, together with evidence of the feasibility and acceptable toxicity profile of ovarian cancer treatment with anti-FR mAbs, could provide the basis for rational design of new therapeutic modalities.…”

Near-Infrared Fluorescent Imaging of Metastatic Ovarian Cancer Using Folate Receptor-Targeted High-Density Lipoprotein Nanocarriers

“…The pronounced selective uptake of FA-HDL NPs in the IC5-MOSEC tumors and metastatic ascites cells support this rationale. Additional independent studies have also shown that ip.-delivered anti-FR-α antibodies are able to selectively access ovarian cancer tumors and metastatic cells in the peritoneal cavity [66]. Under these conditions, the IC5-MOSEC tumors and metastatic cells experience much more favorable kinetics for pronounced FA-HDL NP uptake over the host tissues.…”