To supplement the current and future demand of biotherapeutics in dealing with snakebites, the Sehrawat lab at IISER Mohali has generated and selected a less immunogenic but potent anti-Russell Viper Venom single domain antibody from an in-house constructed phage display library of unique antibody derivative also known as Variable region of Heavy chain of Heavy chain antibody (VHH). The selected binder exhibited superior biological, biochemical and biophysical properties. The binder proved valuable in neutralising the toxicity caused by Russell viper venom in acellular and cellular assays as well as in experimentally intoxicated animals. Future goal of the groups is to target multiple targets in the venom to generate a multivalent formulation.
According to the paper, Snakebites inflicted injuries remain a major public health challenge particularly in tropical and subtropical countries leading to more than a hundred thousand deaths annually. Recognizing their impact on human lives, World Health Organization re-inducted snakebites in the list of neglected diseases. Resource-limited population is predominantly affected by snakebites and the management is further complicated by rampant misdiagnosis and under-reporting 2008). The four major venomous snakes i.e., Daboia russelii (Russell’s viper), Naja naja (Spectacled cobra), Bungarus caeruleus (Common krait) and Echis carinatus (Saw scaled viper) belong to the Viperidae and Elapidae families. The dose of the injected venom and the time-lapse post bite majorly contribute to the severity of disease that primarily involves cardiovascular and nervous systems. A majority of snake bite survivors develop one or the more permanent disabilities.
Approximately 70–90% of venom’s dry weight consists of enzymatically active proteins such as the phospholipases, oxidoreductases, transferases, hydrolases, hyaluronidases and lyases. Many of these enzymes act in synergy to cause the toxicity. Therefore, the value of monoclonal antibodies that target specific epitopes has not been generally favored for managing snakebites.
Anti-venom sera (AVS) remain the cornerstone therapy for snakebites for over a century but suffer from potentially life-threatening yet common ill effects such as anaphylaxis and serum sickness. Furthermore, the current demand of AVS exceeds the supply globally, which further underscores the need of discovering effective alternatives. The startling discovery of heavy chain antibodies (HCAbs) in the sera samples of camelids and their efficient antigen binding abilities paved the way for exploiting their unique features for therapies as well as diagnosis.
The group tested whether lesser immunogenic derivatives of such antibodies also known as single domain antibodies (sdAbs) or the nanobodies could neutralize the toxicological effects caused by Russell’s viper venom (RVV). They demonstrated the neutralizing potential of sdAbs selected against secretory phospholipase A2, gp 12B, one of the components of RVV, not only using acellular and cellular assays but also in zebrafish as a vertebrate model organism. Such binders could serve as an effective therapeutic alternative intervention for managing snakebites.
About Dr. Sharvan Sehrawat and his lab
Dr Sharvan is Assistant Professor of Biological Sciences in IISER, Mohali. His lab is working on Induction of an adaptive immune response and its maintenance in the memory phase forms the basis of lasting protective immunity against infectious diseases and provides clue for successful vaccination. After receiving help from CD4 T cells, pathogen-specific CD8 T cells are appropriately activated to control the spread of intracellular pathogens such as viruses. Animal models are used to investigate host-pathogen interaction. For studying the function and differentiation of adaptive T and B cells, one has to secure sufficient number of antigen-specific cells in naive state but in a normal host the frequency of T cells specific to any given antigen is very low and frustrates attempts at isolating such cells in meaningful numbers. His laboratory aim to understand the function and differentiation of CD8 T cells during infection with endemic pathogens such as dengue virus, Chikungunya virus and protozoan parasites such as Plasmodium in addition to herpes viruses, the latter being the most successful pathogen. Employing various molecular and immunological approaches, we try to understand the host-pathogen interaction. His lab is also putting efforts in developing novel animal models to study immunity and immunopathology during viral infections in addition to antibody engineering area.