Marjolein Van Egmond, Professor of Oncology and Inflammation, Amsterdam University Medical Center
Time to Reconsider Therapeutic Potential of IgA Antibodies
IgA antibody-based therapies could mobilize an “army” of neutrophils against cancer according to new research.
Most therapeutic antibodies on the market or in development are based on the serum antibody IgG. This focus is understandable given that, in nature, IgGs function by binding pathogens, viruses, bacteria, and fungi circulating in the serum, thereby preventing infection.
This contrasts with IgA antibodies, which have previously not been a focus for drug developers because they are most thought of as being membrane associated rather than circulatory.
But the industry needs to reassess IgAs as they could mobilize neutrophils against cancer , according to Professor Marjolein Van Egmond from Amsterdam University Medical Center, who told delegates at the Antibody Engineering and Therapeutics conference.
Neutrophil Therapeutics?
“Why are we interested in using neutrophils in tumor therapy? By themselves, they are not great at recognizing tumor cells and it is even believed they have a negative role because there are immunosuppressive.
“However, with an antibody they could induce ADCC [Antibody-dependent cellular cytotoxicity]. A great advantage of neutrophils is their sheer number. So 60 to 70 percent of our circulating cells white blood cells are neutrophils and this is the tip of the iceberg because there is a whole depot in the bone marrow.”
This neutrophil depot can be easily mobilized using an injection of granulocyte colony-stimulating factor according to Van Egmond, who said “you can create a huge army of effector cells potentially.
“In addition, neutrophils can secrete all kinds of chemokines and cytokines. What we hope to achieve is not only tumour cell death, but also a kind of an in-situ vaccination so we can create an adaptive immune response.”
This is where IgA antibodies come into play according to Van Egmond, who shared study data indicating they are much more effective at inducing neutrophils to attack tumour cells than the IgG-based drug cetuximab.
The researchers also looked at how IgA induction works by incubating beads coated IgA, IGG or a BSA with neutrophils and then measured the release of cytokines and chemokines.
And the findings were significant according to Van Egmond, who said, “Only when the cells were incubated with the IcA coated beads did we see release of IL-8, CLC 2, CLC 3, CLC4 and CNF Alpha, not with the IgG coated beads.”
A similar pattern was seen when the beads were incubated with monocytes, indicating that the effect of IgA is not neutrophil-specific. Indeed, Van Egmond’s team found that IgA-coated beads upregulated the expression of many genes associated with immune response while those coated with IgG did not.
All of which means that IgA’s status as a low concentration, short lived activator of complement activity needs to be rethought according to Van Egmond.
“The fact that we have less IGA does not mean it is redundant, maybe it simply reflects its potency and the fact that we have so much IgG with long half-life, and maybe the necessity to activate complement is because maybe it is not that potent at all.”
