Passive immunotherapy of viral infections: 'super-antibodies' enter the fray

Abstract

Antibodies have been used for more than 100 years in the therapy of infectious diseases, but a new generation of highly potent and/or broadly cross-reactive human monoclonal antibodies (sometimes referred to as 'super-antibodies') offers new opportunities for intervention. The isolation of these antibodies, most of which are rarely induced in human infections, has primarily been achieved by large-scale screening for suitable donors and new single B cell approaches to human monoclonal antibody generation. Engineering the antibodies to improve half-life and effector functions has further augmented their in vivo activity in some cases. Super-antibodies offer promise for the prophylaxis and therapy of infections with a range of viruses, including those that are highly antigenically variable and those that are newly emerging or that have pandemic potential. The next few years will be decisive in the realization of the promise of super-antibodies.

Figure 1. Technologies for monoclonal antibody generation.

a | Combinatorial display libraries. Human antibody heavy-chain and light-chain genes are amplified by reverse transcription (RT)-PCR, and antibody fragments are displayed on the surface of a particle or cell in which the antibody genes are found (such as phage, yeast or mammalian cells^,,,). Successive rounds of enrichment are performed to select for clones that bind to the target antigen. Genes encoding antibodies of interest are cloned into human IgG expression vectors to produce monoclonal antibodies (mAbs). b | Human immunoglobulin transgenic mice are generated by introducing human immunoglobulin loci into the mouse genome^,. Upon immunization, the transgenic mice produce fully human antigen-specific antibodies. The B cells harvested from the immunized mice are fused with myeloma cells to generate antibody-secreting hybridomas, which are then screened for binding or functional activity. c | Single B cell cloning. Antigen-specific memory B cells or plasmablasts are single-cell sorted by flow cytometry, and cognate heavy-chain (Vh) and light-chain (Vl) variable genes are amplified by single-cell PCR^,,. The antibody variable genes are cloned into human IgG expression vectors to produce mAbs. d | Memory B cell immortalization. Memory B cells are immortalized by Epstein–Barr virus (EBV), and B cell culture supernatants are screened for binding or functional activity. Positive cultures are subcloned by limiting dilution. e | Memory B cell culture. Single B cells are activated and cultured, and B cell supernatants are screened for binding or functional activity^,. Antibody variable genes are amplified from clones of interest by PCR and cloned into human IgG expression vectors to produce mAbs. FACS, fluorescence-activated cell sorting. PowerPoint slide

Figure 2. Structures of super-antibodies bound to their target antigens.

a | Cryoelectron microscopy structure of the broadly neutralizing anti-HIV-1 antibody PGT145 in complex with a recombinant HIV envelope (Env) trimer. PGT145 binds to a glycan-dependent quaternary epitope at the trimer apex. b | Crystal structure of the influenza virus group 1 and group 2 neutralizing antibody CR9114 in complex with influenza virus haemagglutinin (HA). CR9114 recognizes a highly conserved epitope in the HA stem^,. c | Crystal structure of the respiratory syncytial virus (RSV) and human metapneumovirus cross-neutralizing antibody MPE8 in complex with a stabilized RSV prefusion fusion glycoprotein trimer. d | Crystal structure of the Zika virus and dengue virus cross-neutralizing antibody C8 in complex with a soluble Zika virus Env ectodomain. C8 targets a quaternary epitope that bridges two Env protein subunits. Part a is adapted from Ref. , CC-BY-4.0. Part b is adapted with permission from Ref. , AAAS. Part c is adapted from Ref. , Macmillan Publishers Limited. Part d is adapted from Ref. , Macmillan Publishers Limited. PowerPoint slide