Revolutionizing snakebite care with novel antivenoms: Breakthroughs and barriers

Abstract

Snakebite envenoming (SBE) is a global public health concern, primarily due to the lack of effective antivenom for treating snakebites inflicted by medically significant venomous snakes prevalent across various geographic locations. The rising demand for safe, cost-effective, and potent snakebite treatments highlights the urgent need to develop alternative therapeutics targeting relevant toxins. This development could provide promising discoveries to create novel recombinant solutions, leveraging human monoclonal antibodies, synthetic peptides and nanobodies. Such technologies as recombinant DNA, peptide and epitope mapping phage display etc) have the potential to exceed the traditional use of equine polyclonal antibodies, which have long been used in antivenom production. Recombinant antivenom can be engineered to target certain toxins that play a critical role in snakebite pathology. This approach has the potential to produce antivenom with improved efficacy and safety profiles. However, there are limitations and challenges associated with these emerging technologies. Therefore, identifying the limitations is critical for overcoming the associated challenges and optimizing the development of recombinant antivenoms. This review is aimed at presenting a thorough overview of diverse technologies used in the development of recombinant antivenom, emphasizing their limitations and offering insights into prospects for advancing recombinant antivenoms.

Keywords: Antibodies; Antivenom; Nanobodies; Recombinant antivenom; Snake venom; Traditional antivenom.

Graphical abstract

Fig. 1

Antibody formats. (A) Complete IgG (immunoglobulin G) made up of VH and VL (the heavy and light variable domains of antibodies respectively) as well as the CL (constant domain of light chains) and CH_n (constant domain of heavy chains) (B) Pepsin digestion cleaves IgG at a distinct site within the hinge region, resulting in a bivalent fragment that retains both binding sites, known as F (ab')₂. (C) Papain digestion cleaves disulfide bonds located near the hinge region, producing a crystallizable fragment composed of the constant segments of two H chains (Fc) and two antigen-binding fragments (Fab). The schematic diagram was created with biorender.com.

Fig. 2

Traditional antivenom production steps.

Fig. 3

Immunoglobulin formats used in modern technologies. (A) scFv monoclonal antibody fragment is a fusion protein formed by combining the variable regions of heavy and light chains of immunoglobulins using a short linker peptide. (B) Nanobody is an antigen-binding VHH fragments originating from the heavy chain of IgG antibodies. (C) Nanobody fused to the Fc region of human immunoglobulin. (D) Heavy chain antibodies (HCAbs) recognize target antigens using a single chain containing a variable element referred to as camelid single domain antibody (VHH). (E) Bispecific nanobodies consist of two nanobodies designed to bind to distinct antigens simultaneously. VH and VL denote the heavy and light variable domains of antibodies. Other abbreviations include: CL (constant domain of light chains), CH_n (constant domain of heavy chains), Fc (crystallizable fragment of antibodies), scFv (single-chain antibody fragment), VHH (heavy chain variable domain antibodies), HCAb (Camelid heavy chain antibody derived formats) and IgG (immunoglobulin G). The schematic diagram was created with biorender.com.

Fig. 4

Major steps involved in pluribody technology. The numbers represent ordered steps involved. PBMC denote peripheral blood mononuclear cell and VHH is heavy chain variable domain antibodies. Schematic diagram was created with biorender.com.

Fig. 5

Steps involved in phage display technology. V_H and V_L are variable heavy chain and variable light chain respectively. The schematic diagram was developed with biorender.com.