Digoxin-specific antibody fragments (DSFab) are indicated for the management of patients with digoxin and digitoxin toxicity, as well as toxicity from other pharmaceutical, plant, and animal cardioactive steroids (CASs, eg, ouabain, dogbane, oleander, squill, and Bufo and Birgus species). Digoxin-specific antibody fragments have an excellent record of efficacy and safety, and they should be administered early in both established and suspected CAS poisoning.
The production of antibody fragments to treat patients poisoned with digoxin followed the development of digoxin antibodies for measuring serum digoxin concentrations by radioimmunoassay (RIA).21 This RIA technique permitted the correlation between serum digoxin concentrations and clinical digoxin toxicity.10,31,38,91 In 1967, Butler and Chen suggested that purified antidigoxin antibodies with a high affinity and specificity should be developed to treat digoxin toxicity in humans.21 The digoxin molecule alone, with a molecular weight of 780 Da, was too small to be immunogenic. But digoxin could function as a hapten when joined to an immunogenic protein carrier such as albumin. These investigators immunized sheep with this conjugate to generate antibodies.115,117 The immunized sheep subsequently produced a mixture of antibodies that included antialbumin antibodies and antidigoxin antibodies. The antibodies were separated and highly purified to retain the digoxin antibodies while removing the antibodies to the albumin and all other extraneous proteins. The antibodies that were developed had a high affinity for digoxin and sufficient cross-reactivity with digitoxin and other CASs to be clinically useful for the treatment of all CAS poisonings.23,106,107
Intact IgG antidigoxin antibodies reversed digoxin toxicity in dogs.22 Unfortunately, the urinary excretion of digoxin was delayed, and free digoxin was released after antibody degradation occurred. Furthermore, there was significant concern with regard to the development of hypersensitivity reactions. To make such antibodies both safer and effective in humans, whole IgG antidigoxin antibodies were cleaved with papain, yielding two antigen-binding fragments (Fab) and one (discarded) Fc fragment.22 Affinity chromatography was used to isolate and purify the DSFab after papain digestion. Because the Fc fragment does not bind antigen and increases the potential for hypersensitivity reactions, it was eliminated. When compared with whole IgG antibodies, the advantages of DSFab included a larger volume of distribution (Vd) and distribution to the extravascular space, more rapid onset of action, diminished risk of adverse immunologic effects, and more rapid elimination.22,76,79,83,117 In 1976, Digibind was used with clinical success,116 and it became commercially available in 1986, before being discontinued in 2011.59 Another commercial product, DigiFab, approved by the US Food and Drug Administration (FDA) in 2001, is currently available.20
Chemistry and Preparation
DigiFab is prepared from the blood of healthy sheep that were immunized with a digoxin derivative, digoxin-dicarboxymethoxylamine (DDMA)....