Expert Review of Precision Medicine and Drug Development | 2019
A ‘sandwich’ strategy promises functional cure of chronic hepatitis B
Abstract
Protection against hepatitis B virus (HBV) has been remarkably recognized for more than three decades and has posed successful immunization through vaccination programs in over 180 countries [1,2]. However, vaccine-induced immunity is not 100% sterilizing [2]. Besides, more than 290 million people around the world are chronically infected with HBV, while around one million people die every year as a consequence of HBV-related cancer or end-stage liver diseases [3]. This prevalence highlights the immediate and real needs to upgrade current approaches to combat hepatitis B. As the challenge to completely eliminate HBV in chronic hepatitis B (CHB) patients prevails, ‘functional cure’ for the CHB patients is widely accepted as the attainable goal in the near future. Functional cure refers to sustained, undetectable HBsAg and HBV DNA in serum, and cessation of a finite course of treatment does not lead to spontaneous relapse [4]. Direct and indirect approaches to achieve functional cure of HB are several, including inhibitors of viral transcription and translation, cccDNA targeting, nucleocapsid assembly and inhibitors packaging, and using viral polymerase inhibitors, therapeutic vaccines, innate immunity modulators, checkpoint modulators, entry inhibitors, interferons, nucleic acid polymers, and antibodies [5]. These comprehensive approaches remark the success of thorough studies toward HBV [5]. Still, only two treatments of CHB were licensed, namely anti-HBV nucleosides (nucleotides) drugs and interferon-α (IFN-α) [1]. Although relatively rapid responses of antiviral therapy, long-term treatment is still required for persistent viral infections, bringing problems associated with drug resistant, safety and high cost of antiviral drugs. In the last 20 years, many groups have tried to combine anti-viral therapy with restoration of the immune response. Recent remarkable success of immunotherapy provides the agents that restore adaptive immunity. In order to determine the appropriate tools to achieve the functional cure of HBV, a three-stages approach of CHB therapy was clearly proposed by groups led by Yu-Mei Wen of Shanghai Medical College, Fudan University, namely the ‘sandwich’ approach [1]. In that letter, the authors described the rationale and detailed strategy for the ‘sandwich’ strategy. The uniqueness and efficiency of this strategy attribute to two combinations. The first is the combination between antiviral drugs and immunotherapy. The other is the combination of passive and active immunization. This strategy could give a general and practical guidance to both doctors who confront HBV and patients who are conflicted by HBV. Wen’s group proposed that the first layer of ‘sandwich’ therapy is to employ antiviral drug, such as anti-HBV nucleosides (nucleotides) drugs, to inhibit viral replication throughout the whole therapeutic process [1]. More importantly, their ‘sandwich’ strategy highlights the importance of the second layer of the therapy, which is to employ potent neutralizing monoclonal anti-HBsAg antibodies to decrease serum HBsAg levels [1]. When patients were free from serum HBV DNA and HBsAg, there is a critical transient ‘window stage’ which likely share with normal adults. Potent specific active immunization should then be applied to induce effective host immune responses as proposed by Wen. Indeed, to achieve functional cure, immune therapy should restore effective adaptive immune responses to provide long-term control of HBV against spontaneous relapse after cessation of treatment. Neutralizing anti-HBsAg antibodies are directed toward viral surface antigens [1]. According to two different Fab recognition sites of virions to block viral entry [6], the antiHBsAg antibodies could be categorized into two classes [7]. The first class is consisted of antibodies targeting specific sites in the antigenic loop of HBsAg. The second class of antibodies targets the receptor binding site of the PreS1 domain. They are both capable of blocking viral entry. Aside from the capacity of neutralizing anti-HBsAg human antibodies to block viral entry via Fab recognition of virions, their Fc fragment can further trigger host immune response via mechanisms such as antibody dependent cellular cytotoxicity (ADCC), antibody dependent cell-mediated phagocytosis (ADCP), or complement dependent cytotoxicity (CDC). Two recent studies suggest that two classes of neutralizing anti-HBsAg antibodies lead to the reduction of HBV DNA and HBsAg clearance in mouse models (Class I: G12; Class II: 2H5-A14) [7–9]. The reduction of HBV DNA and HBsAg clearance were withdrawal when FcγR binding deficient mutant was used. Besides facilitating HBsAg clearance and blocking viral spread, an additional potential advantage of anti-HBsAg monoclonal antibody-based therapy relies on the possibility to generate or re-activate effective T cell responses via the formation of immune-complexes (IC) [10,11]. Antigen-antibody ICsmight reinforce the seizure of HBsAg by immature phagocytic cells [8,9]. HBsAg particles can reach a concentration up to 10/ml. It has