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In the current global emergency due to SARS-CoV-2 outbreak, passive immunotherapy emerges as a promising treatment for COVID-19. Among animal-derived products, equine formulations are still the cornerstone therapy for treating envenomations due to animal bites and stings. Therefore, drawing upon decades of experience in manufacturing snake antivenom, we developed and preclinically evaluated two anti-SARS-CoV-2 polyclonal equine formulations as potential alternative therapy for COVID-19. We immunized two groups of horses with either S1 (anti-S1) or a mixture of S1, N, and SEM mosaic (anti-Mix) viral recombinant proteins. Horses reached a maximum anti-viral antibody level at 7 weeks following priming, and showed no major adverse acute or chronic clinical alterations. Two whole-IgG formulations were prepared via hyperimmune plasma precipitation with caprylic acid and then formulated for parenteral use. Both preparations had similar physicochemical and microbiological quality and showed ELISA immunoreactivity towards S1 protein and the receptor binding domain (RBD). The anti-Mix formulation also presented immunoreactivity against N protein. Due to high anti-S1 and anti-RBD antibody content, final products exhibited high in vitro neutralizing capacity of SARS-CoV-2 infection, 80 times higher than a pool of human convalescent plasma. Pre-clinical quality profiles were similar among both products, but clinical efficacy and safety must be tested in clinical trials. The technological strategy we describe here can be adapted by other producers, particularly in low- and middle-income countries.

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Abstract. A comparative study was performed on the ability of IgG and F(abЈ) 2 antivenoms to neutralize lethal and myotoxic activities of Micrurus nigrocinctus venom. Both antivenoms were adjusted to a similar neutralizing potency in experiments where venom and antivenoms were preincubated prior to injection. No significant differences were observed between IgG and F(abЈ) 2 antivenoms concerning neutralization of lethal effect in rescue experiments, i.e., when antivenom was administered intravenously after envenomation. However, F(abЈ) 2 antivenom was more effective in prolonging the time of death when subneutralizing doses were administered immediately after venom injection. Both products partially reversed the binding of M. nigrocinctus ␣-neurotoxins to acetylcholine receptor in vitro. The IgG and F(abЈ) 2 antivenoms effectively neutralized venom-induced myotoxicity when administered intravenously immediately after envenomation, although neutralization was poor if antivenom injections were delayed. Intramuscular injection of venom promoted diffusion of antivenom antibodies throughout muscle tissue, and F(abЈ) 2 diffused to a higher extent than IgG molecules. Thus, despite the observation that F(abЈ) 2 antivenom was more effective than IgG antivenom in prolonging the time of death when subneutralizing doses were administered immediately after envenomation, no major differences were observed in antivenom neutralization of lethal and myotoxic effects or in their capacity to reverse neurotoxin binding to the acetylcholine receptor.Antivenoms constitute the mainstay for treating snakebites 1 and many antivenoms are currently produced around the world. 2,3 The majority of these products are made of F(abЈ) 2 antibody fragments resulting from pepsin digestion of equine immunoglobulins, 4 although some manufacturers produce whole IgG antivenoms. 5 Pharmacokinetic studies show that F(abЈ) 2 fragments have a more convenient profile than whole IgG preparations since they have larger volumes of distribution and reach the tissue compartment at a faster rate. 6,7 Thus, it has been assumed that F(abЈ) 2 antivenoms are more effective than IgG products in reaching and neutralizing toxins within tissues. However, León and others 8 described that IgG and F(abЈ) 2 polyvalent antivenoms do not differ in their ability to neutralize local hemorrhage, edema, and myonecrosis induced by the venom of the crotaline snake Bothrops asper. It is therefore important to test this assumption in a variety of venom-antivenom systems.Coral snakes (genus Micrurus) are the representatives of the family Elapidae in America, 9 inflicting a number of accidents on this continent. [10][11][12] Although poorly studied, Micrurus venoms induce typical neurotoxic effects, with blockade of the neuromuscular synapse by ␣-neurotoxins that bind cholinergic receptors at the motor endplate. 13-15 Micrurus ␣-neurotoxins are similar to those of other elapids. 14,15 They are low molecular weight proteins that rapidly spread throughout tissues and bind acetylcholine r...

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