Reformatting palivizumab and motavizumab from IgG to human IgA impairs their efficacy against RSV infection in vitro and in vivo

Abstract

Respiratory syncytial virus (RSV) infection is a leading cause of hospitalization and mortality in young children. Protective therapy options are limited. Currently, palivizumab, a monoclonal IgG1 antibody, is the only licensed drug for RSV prophylaxis, although other IgG antibody candidates are being evaluated. However, at the respiratory mucosa, IgA antibodies are most abundant and act as the first line of defense against invading pathogens. Therefore, it would be logical to explore the potential of recombinant human IgA antibodies to protect against viral respiratory infection, but very little research on the topic has been published. Moreover, it is unknown whether human antibodies of the IgA isotype are better suited than those of the IgG isotype as antiviral drugs to combat respiratory infections. To address this, we generated various human IgA antibody formats of palivizumab and motavizumab, two well-characterized human IgG1 anti-RSV antibodies. We evaluated their efficacy to prevent RSV infection in vitro and in vivo and found similar, but somewhat decreased efficacy for different IgA subclasses and formats. Thus, reformatting palivizumab or motavizumab into IgA reduces the antiviral potency of either antibody. Moreover, our results indicate that the efficacy of intranasal IgA prophylaxis against RSV infection in human FcαRI transgenic mice is independent of Fc receptor expression.

Breast Milk Prefusion F Immunoglobulin G as a Correlate of Protection Against Respiratory Syncytial Virus Acute Respiratory Illness

“…The difference in protection across antibody isotypes is in accordance with studies specific to RSV and other pathogens, such as human immunodeficiency virus [ 27 ] and cytomegalovirus [ 28 ]. Likewise, recombinant palivizumab IgA offers less effective protection following intranasal administration than IgG in mice [ 22 ].…”

“…Breast milk was added (100 μL/well) in duplicate, at 2–3 dilutions and incubated for 1.5 hours at room temperature. Recombinant palivizumab IgA1 and recombinant palivizumab IgA2 were synthesized by cloning variable heavy and light chain sequences of palivizumab into Lonza expression vector, followed by production in HEK293T cells, and purification by KappaSelect and high pressure size exclusion chromatography [ 22 ]. Recombinant palivizumab IgA1 and IgA2 and palivizumab (Synagis, MedImmune) were used to generate a standard curve on every plate.…”

The role of IgG Fc receptors in antibody-dependent enhancement

“…Although complement-mediated pathways have been implicated as a key component of VAERD pathogenesis, there is insufficient evidence to suggest a pathogenic role for Fc-FcγR interactions in driving VAERD and, consequently, acute lung injury. Indeed, several in vivo studies have failed to demonstrate any pathogenic activity of passively administered mAbs against RSV G proteins or F proteins [136][137][138][139] . In contrast to vaccine-elicited, non-neutralizing polyclonal anti-RSV IgG antibodies, anti-RSV mAbs exhibit minimal pathogenic activity, induce anti-inflammatory responses and protect mice from lethal RSV challenge 136 .…”

Antibody development for preventing the human respiratory syncytial virus pathology

“…A recent study used the Fab regions of palivizumab and motavizumab to generate recombinant monomeric, dimeric and secretory IgA molecules (Jacobino et al 2018). The main particularity of these molecules was their capacity to recognize the same epitopes as palivizumab and motavizumab but displaying the functional features of an IgA molecule.…”

“…The main particularity of these molecules was their capacity to recognize the same epitopes as palivizumab and motavizumab but displaying the functional features of an IgA molecule. Such isotype change resulted in a decrease effectivity of these recombinant IgA antibodies, as compared to the IgG1 palivizumab and motavizumab (Jacobino et al 2018). Reduced in vitro and in vivo antiviral responses in the mouse model also discouraged further studies for these recombinant IgA molecules (Jacobino et al 2018).…”