UNLABELLED: AFRA-DMF5.3 is a human antibody fragment that, as a dimer, specifically binds to the α-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.
UNLABELLED: AFRA-DMF5.3 is a human antibody fragment that, as a dimer, specifically binds to the α-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 cancerpatients with a radiolabeled anti-FR antibody fragment.
Authors: Anthony Cheung; Heather J Bax; Debra H Josephs; Kristina M Ilieva; Giulia Pellizzari; James Opzoomer; Jacinta Bloomfield; Matthew Fittall; Anita Grigoriadis; Mariangela Figini; Silvana Canevari; James F Spicer; Andrew N Tutt; Sophia N Karagiannis Journal: Oncotarget Date: 2016-08-09