Antibody Fc-chimerism and effector functions: When IgG takes advantage of IgA

Abstract

Recent advances in the development of therapeutic antibodies (Abs) have greatly improved the treatment of otherwise drug-resistant cancers and autoimmune diseases. Antibody activities are mediated by both their Fab and the Fc. However, therapeutic Abs base their protective mechanisms on Fc-mediated effector functions resulting in the activation of innate immune cells by FcRs. Therefore, Fc-bioengineering has been widely used to maximise the efficacy and convenience of therapeutic antibodies. Today, IgG remains the only commercially available therapeutic Abs, at the expense of other isotypes. Indeed, production, sampling, analysis and related in vivo studies are easier to perform with IgG than with IgA due to well-developed tools. However, interest in IgA is growing, despite a shorter serum half-life and a more difficult sampling and purification methods than IgG. Indeed, the paradigm that the effector functions of IgG surpass those of IgA has been experimentally challenged. Firstly, IgA has been shown to bind to its Fc receptor (FcR) on effector cells of innate immunity with greater efficiency than IgG, resulting in more robust IgA-mediated effector functions in vitro and better survival of treated animals. In addition, the two isotypes have been shown to act synergistically. From these results, new therapeutic formats of Abs are currently emerging, in particular chimeric Abs containing two tandemly expressed Fc, one from IgG (Fcγ) and one from IgA (Fcα). By binding both FcγR and FcαR on effector cells, these new chimeras showed improved effector functions in vitro that were translated in vivo. Furthermore, these chimeras retain an IgG-like half-life in the blood, which could improve Ab-based therapies, including in AIDS. This review provides the rationale, based on the biology of IgA and IgG, for the development of Fcγ and Fcα chimeras as therapeutic Abs, offering promising opportunities for HIV-1 infected patients. We will first describe the main features of the IgA- and IgG-specific Fc-mediated signalling pathways and their respective functional differences. We will then summarise the very promising results on Fcγ and Fcα containing chimeras in cancer treatment. Finally, we will discuss the impact of Fcα-Fcγ chimerism in prevention/treatment strategies against infectious diseases such as HIV-1.

Bi-isotype immunoglobulins enhance antibody-mediated neutrophil activity against Plasmodium falciparum parasites

“…The mechanism by which the IgG–IgA cross isotype may induce higher levels of ADRB is not completely understood. Our favored hypothesis is that the cross IgG–IgA isotype enhances activation of the immunoreceptor tyrosine-based activation motif (ITAM) in a similar fashion to IgA ( 39 , 47 – 49 ). It is thought that since the stoichiometry of the IgA : FcαRI interaction is in a 1:2 ratio, a single cross-isotype mAb would result in the activation of four ITAM molecules, while an IgG : FcγRIIa interaction only engages a single ITAM ( 47 – 49 ).…”

“…Here, we aimed to isolate mAbs that targeted merozoites and simultaneously induced antibody-dependent neutrophil function. We then tested whether this ADRB activity would be enhanced through an IgG–IgA bi-isotype approach that in theory would result in the engagement of a broader panel of Fc receptors ( 37 – 39 ). We first screened adults from malaria-endemic areas in coastal Kenya to identify individuals with total IgG antibodies that induced high ADRB levels against P. falciparum merozoites in vitro .…”

Fc-Engineered Therapeutic Antibodies: Recent Advances and Future Directions

“…The field of antibody therapy is rapidly evolving, and it is likely that we will see even more effective and targeted antibody-based therapies in the future. Apart from the here-mentioned clinical examples, there are some future trends that have a good chance of being translated to clinical products, such as IgA-IgG hybrids or chimeras, for more IgArelated effector functions, such as NETosis, complement and mucosal immunity [165]. The benefit of IgA is stronger FcR signaling, and the presence of both Fcα and Fcγ would give the resulting chimeric antibodies the ability to bind to a greater number of FcR molecules than the parental antibodies, resulting in the increased killing of target cells, such as cancer.…”

Lupus IgA1 autoantibodies synergize with IgG to enhance pDC responses to RNA-containing immune complexes

“…Because both FcαR and FcgRIIa signal through ITAMs, either in the associated FcRg chain for FcαR or in the intracellular tail for FcgRIIa, it is not apparent why there is such strong synergy when co-signaling through these receptors when both IgG and IgA1 are present in ICs. A possible explanation for why IgA enhances the IC-mediated IFNa response is because the affinity for multimeric antigenbound IgA for FcaR is greater than similarly complexed IgG for FcgRIIa (50)(51)(52). This could result in immune complexes containing both IgA1 and IgG having a higher overall avidity for pDC FcRs than those containing only IgG.…”

“…IgA1 and IgG have different characteristics, which may result in qualitative changes in ICs containing both IgA1 and IgG autoantibodies compared to those without IgA1. IgA1 shares 90% sequence identity to IgA2 with the major difference being that IgA1 has a longer hinge region with no disulfide bonds allowing for increased flexibility compared to IgA2 and IgGs ( 51, 55, 56 ). While IgG3 also has longer hinge region, it retains the disulfide bonds ( 57 ).…”