Therapeutic effect of an anti-human-TNF-alpha antibody and itraconazole on feline infectious peritonitis

Abstract

Feline infectious peritonitis (FIP) is a fatal disease in wild and domestic cat species. Although several drugs are expected to be useful as treatments for FIP, no drugs are available in clinical practice. In this study, we evaluated the therapeutic effect of combined use of adalimumab (an anti-human-TNF-alpha monoclonal antibody, ADA) and itraconazole (ICZ), which are presently available to veterinarians. The neutralizing activity of ADA against fTNF-alpha-induced cytotoxicity was measured in WEHI-164 cells. Ten specific pathogen-free (SPF) cats were inoculated intraperitoneally with type I FIPV KU-2. To the cats that developed FIP, ADA (10 mg/animal) was administered twice between day 0 and day 4 after the start of treatment. ICZ (50 mg/head, SID) was orally administered daily from day 0 after the start of treatment. ADA demonstrated dose-dependent neutralizing activity against rfTNF-alpha. In an animal experiment, 2 of 3 cats showed improvements in FIP clinical symptoms and blood chemistry test results, an increase in the peripheral blood lymphocyte count, and a decrease in the plasma alpha 1-AGP level were observed after the beginning of treatment. One of the cats failed to respond to treatment and was euthanized, although the viral gene level in ascites temporarily decreased after the start of treatment. ADA was found to have neutralizing activity against rfTNF-alpha. The combined use of ADA and ICZ showed a therapeutic effect for experimentally induced FIP. We consider these drugs to be a treatment option until effective anti-FIPV drugs become available.

Fig. 1

Experimental schedule of treatment and FIPV inoculation of cats

Fig. 2

Comparison of amino acid sequence of feline and human TNF-alpha. *: residues that interact with adalimumab

Fig. 3

Neutralization dose-response curve against recombinant fTNF-alpha. The neutralizing activity of ADA against fTNF-alpha-induced cytotoxicity was measured in WEHI-164 cells. WEHI-164 cells were treated with mixtures of serial dilutions of ADA and fTNF-alpha, and the level of TNF-alpha-induced cytotoxicity was measured after 24 h

Fig. 4

Changes in body temperature and weight of cats. †: The cat was euthanized because its clinical condition had reached the humane endpoint

Fig. 5

Changes in WBC and lymphocyte counts in cats. †: The cat was euthanized because its clinical condition had reached the humane endpoint

Fig. 6

Changes in plasma alpha1-acid glycoprotein (AGP) concentration in cats. †: The cat was euthanized because its clinical condition had reached the humane endpoint

Fig. 7

Changes in plasma vascular endothelial growth factor (VEGF) concentration in cats. †: The cat was euthanized because its clinical condition had reached the humane endpoint

Fig. 8

Changes in viral RNA levels in ascites and cells from ascites collected from CAT No. 6. The viral RNA levels in the supernatant and cells from ascites collected from cat no. 6 were quantified using qRT-PCR. (A) supernatant of the ascites. (B) cells from the ascites

Fig. 9

Blood chemistry panel. The white areas of the graphs represent the normal ranges. †: The cat was euthanized because its clinical condition had reached the humane endpoint