Preclinical Evaluation of Caprylic Acid-Fractionated IgG Antivenom for the Treatment of Taipan (Oxyuranus scutellatus) Envenoming in Papua New Guinea

Abstract

BackgroundSnake bite is a common medical emergency in Papua New Guinea (PNG). The taipan, Oxyuranus scutellatus, inflicts a large number of bites that, in the absence of antivenom therapy, result in high mortality. Parenteral administration of antivenoms manufactured in Australia is the current treatment of choice for these envenomings. However, the price of these products is high and has increased over the last 25 years; consequently the country can no longer afford all the antivenom it needs. This situation prompted an international collaborative project aimed at generating a new, low-cost antivenom against O. scutellatus for PNG.Methodology/Principal FindingsA new monospecific equine whole IgG antivenom, obtained by caprylic acid fractionation of plasma, was prepared by immunising horses with the venom of O. scutellatus from PNG. This antivenom was compared with the currently used F(ab')2 monospecific taipan antivenom manufactured by CSL Limited, Australia. The comparison included physicochemical properties and the preclinical assessment of the neutralisation of lethal neurotoxicity and the myotoxic, coagulant and phospholipase A2 activities of the venom of O. scutellatus from PNG. The F(ab')2 antivenom had a higher protein concentration than whole IgG antivenom. Both antivenoms effectively neutralised, and had similar potency, against the lethal neurotoxic effect (both by intraperitoneal and intravenous routes of injection), myotoxicity, and phospholipase A2 activity of O. scutellatus venom. However, the whole IgG antivenom showed a higher potency than the F(ab')2 antivenom in the neutralisation of the coagulant activity of O. scutellatus venom from PNG.Conclusions/SignificanceThe new whole IgG taipan antivenom described in this study compares favourably with the currently used F(ab')2 antivenom, both in terms of physicochemical characteristics and neutralising potency. Therefore, it should be considered as a promising low-cost candidate for the treatment of envenomings by O. scutellatus in PNG, and is ready to be tested in clinical trials.

Antivenomic Characterization of Two Antivenoms Against the Venom of the Taipan, Oxyuranus scutellatus, from Papua New Guinea and Australia

“…This result might have to do with the fact that ICP O. scutellatus antivenom is a truly monospecific antivenom, whereas CSL antivenom has been shown to be polyspecific, because horses have been also used for immunization with other Australian snake venoms. However, although ICP antivenom shows a higher potency than CSL antivenom in terms of milligrams of venom neutralized per milligram of antivenom protein, 8,14 our antivenomics analyses highlighted a stronger pattern of immunoreactivity of CSL antivenom against Australian O. scutellatus venom when the same amount of antivenom protein is linked to the affinity column. This apparent discrepancy might be caused by the different conditions in which these two types of tests are performed.…”

“…8 Our estimation of the concentration of specific anti-O. scutellatus antibodies present in antivenoms provides a partial explanation of this observation, because only 16% of total proteins were specific anti-O.…”

“…8 In general terms, the widespread immunorecognition revealed by antivenomics correlates with the capacity of these two antivenoms to neutralize lethal, coagulant, myotoxic, and PLA 2 activities of PNG and Australian O. scutellatus venoms. 8,14 Moreover, these antivenomic patterns correlate with the lethality neutralization tests previously described, because these antivenoms present similar potencies (in terms of milligrams of venom neutralized per milliliter antivenom) for the venom of PNG O. scutellatus, whereas the CSL antivenom has a higher potency than ICP antivenom when pre-incubated with O. scutellatus venom from Australia. 14 The ability of antivenoms to neutralize the lethal effect of O. scutellatus venom depends, to a large extent, on their capacity to neutralize taipoxin, the most potent neurotoxin in the venoms of both populations of taipan.…”

“…The physicochemical characteristics and neutralizing potency of these antivenoms were described by Vargas and others. 8 CSL antivenom is made of F(ab') 2 antibody fragments prepared by pepsin digestion and ammonium sulphate precipitation. ICP antivenom is a wholeIgG preparation obtained by caprylic acid precipitation of non-IgG plasma proteins.…”

“…It is a whole-IgG preparation generated by caprylic acid fractionation of the plasma of horses immunized with this venom. 8 A comparative pre-clinical assessment of the ability of ICP and bioCSL antivenoms to neutralize the venom of PNG taipan revealed a similar potency for the neutralization of lethality and myotoxicity in mouse tests and phospholipase A 2 (PLA 2 ) activity, although the ICP whole-IgG antivenom showed a higher efficacy in the neutralization of in vitro coagulant activity. 8 These antivenoms are currently being tested in a randomized trial to assess their safety and efficacy in the clinical setting.…”