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Published on: June 13, 2014
Antitumor activity of a humanized, bivalent immunotoxin targeting fn14-positive solid tumors
Hong Zhou1, Walter N Hittelman, Hideo Yagita
1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
The TNF-like weak inducer of apoptosis (TWEAK; TNFSF12) receptor Fn14 (TNFRSF12A) is expressed at low levels in normal tissues but frequently highly expressed in a wide range of tumor types such as lung, melanoma, and breast, and therefore it is a potentially unique therapeutic target for these diverse tumor types. We have generated a recombinant protein containing a humanized, dimeric single-chain anti-fibroblast growth factor-inducible 14-kDa protein (Fn14) antibody fused to recombinant gelonin toxin as a potential therapeutic agent (designated hSGZ). The hSGZ immunotoxin is a highly potent and selective agent that kills Fn14-positive (Fn14(+)) tumor cells in vitro. Treatment of cells expressing the MDR protein MDR1 (ABCB1B) showed no cross-resistance to hSGZ. Induced overexpression of Fn14 levels in MCF7 cells through HER2 (ERBB2) signaling translated to an improved therapeutic index of hSGZ treatment. In combination with trastuzumab, hSGZ showed an additive or synergistic cytotoxic effect on HER2(+)/Fn14(+) breast cancer cell lines. Also, hSGZ treatment inhibited Erb3/Akt signaling in HER2-overexpressing breast cancer cells. Pharmacokinetic studies in mice revealed that hSGZ exhibited a biexponential clearance from plasma with a rapid initial clearance (t1/2α = 1.26 hours) followed by a seven-fold longer plasma half-life (t1/2β = 7.29 hours). At 24, 48, and 72 hours after injection, uptake of the hSGZ into tumors was 5.1, 4.8, and 4.7%ID/g, with a tumor-to-muscle ratio of 5.6, 6.2, and 9.0, respectively. Therapeutic efficacy studies showed significant tumor inhibition effects using an MDA-MB-231/Luc breast cancer xenograft model. Our findings show that hSGZ is an effective anticancer agent and a potential candidate for clinical studies.
Insights
A novel immunotoxin targeting the Fn14 receptor shows potent and selective killing of Fn14-positive tumor cells. This agent, hSGZ, demonstrates efficacy in preclinical models and holds promise for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The TNF-like weak inducer of apoptosis (TWEAK) receptor Fn14 is highly expressed in various tumors, presenting a potential therapeutic target.
- Fn14 expression is linked to diverse cancer types, including lung, melanoma, and breast cancer.
Purpose of the Study:
- To develop and evaluate a novel immunotoxin, hSGZ, targeting Fn14 for cancer therapy.
- To assess the potency, selectivity, and therapeutic efficacy of hSGZ in preclinical cancer models.
Main Methods:
- Generation of a recombinant dimeric single-chain antibody fused to gelonin toxin (hSGZ) targeting Fn14.
- In vitro cytotoxicity assays on Fn14-positive tumor cells, including assessment of multidrug resistance (MDR) and HER2 signaling.
- Pharmacokinetic studies in mice and therapeutic efficacy studies in a breast cancer xenograft model.
Main Results:
- hSGZ demonstrated potent and selective killing of Fn14-positive tumor cells in vitro, with no cross-resistance to MDR1.
- hSGZ showed additive or synergistic effects with trastuzumab in HER2-positive/Fn14-positive breast cancer cells and inhibited Erb3/Akt signaling.
- Pharmacokinetic studies showed favorable plasma half-life, and in vivo studies demonstrated significant tumor inhibition in a breast cancer xenograft model.
Conclusions:
- hSGZ is a potent and selective anticancer agent targeting Fn14.
- hSGZ exhibits promising preclinical efficacy and pharmacokinetic properties, warranting further clinical investigation for cancer treatment.
