Antibody therapies for the prevention and treatment of viral infections

Salazar, Georgina; Zhang, Ningyan; Fu, Tong-Ming; An, Zhiqiang

ral B cells of a convalescent donor who survived the 2014 EBOV Zaire outbreak. 118 These highly potent neutralizing mAbs could serve as promising candidates for prophylactic and therapeutic interventions against Ebola. The outbreak of Zika in 2015-2016 and its association with congenital abnormalities also increased awareness of the urgent need to take measures against emerging infectious diseases. 119 Similar to combating Ebola and other viral infections, development of vaccines is the top priority to protect the population from Zika infection. 120 Antibody-based therapeutics are also proposed as an option for the treatment of Zika infection. 23 For example, two antibodies with potent ZIKV-specific neutralization, isolated from a single patient, provided postexposure protection to mice in vivo. 23 Structural studies revealed that Z23 and Z3L1 bound to tertiary epitopes in envelope protein domain I, II, or III, indicating potential targets for ZIKV-specific therapy. 23 Rabies occurs worldwide and it is almost invariably fatal once clinical symptoms develop. 121, 122 Rabies is mostly preventable if post-exposure prophylaxis (PEP) is administered before clinical symptoms develop. PEP consists of thorough wound cleansing followed by immediate administration of rabies immune globulin (RIG), together with a full course of rabies vaccination. 123 However, due to the lack of education and availability of RIGs and vaccines, it was estimated that global canine rabies causes about 59,000 deaths mostly in Asia and Africa. 121 As the supply of human RIG (HRIG) and equine RIG (ERIG) is often limited, it is desirable to develop potent neutralizing human mAbs to replace RIGs. 123 CL184 is mixture of two human mAbs:CR57 and CR4098. Mab CR57, which binds to an epitope of the rabies glycoprotein, was isolated from a EBV-transformed memory B cell from a human subject vaccinated with inactivated rabies virus. 27, 124, 125 MAbCR4098, which recognizes a non-overlapping epitope of mAbCR57, was isolated from phage-displayed antibody libraries constructed from PBMCs of rabies virus vaccinated human subjects. 126 CL184 has been evaluated in multiple Phase 1/2 clinical studies to be safe and efficacious. 123, [127] [128] [129] HuMab 17C7, also known as RAB1 which was generated from transgenic mice carrying human immunoglobulin, is another potent rabies virus neutralizing mAb that has been tested in multiple clinical trials in India (CTRI/2009/091/000465 and CTRI/2012/05/002709). 130, 131 There are continuing efforts to identify more potent and broadly neutralizing mAbs against rabies. For example, two antibodies with potency and broad-spectrum reactivity, RVC20 and RVC58, were identified from immortalized B cells of vaccinated donors. 132 RVC20 and RVC58 were able to neutralize all 35 strains of rabies virus in vitro. Furthermore, they showed higher potency and breadth compared to antibodies under clinical development, including CR57, CR4098, and RAB1. 132 Hepatitis B can establish both acute and chronic infections that lead to serious liver disease. Maternal to fetal transmission is one important route keeping prevalence high in regions where the hepatitis B is endemic. Hepatitis B immunoglobulin antibody preparations are one form of countermeasure under investigation. 133 mAbs are also under development to supplement the suite of tools available to control the spread of HBV and associated disease. 134, 135 Dengue. Dengue is the world's most prevalent mosquito-b