IgA-Mediated Inflammatory Disorders

In current drug development, we are educated and trained to follow identical development strategies that have been proven to be successful in the past and assume a guaranteed success for the future. However, as we see with the stock market, past successes do not guarantee anything for the future and a case-by-case customized approach is essential. For example, consider the biology around IgA-IgA receptor (CD89 or FcαR1) interaction in which there are significant differences in species. Ample information has been published over the last 3 decades to show that levels and appearance of autoantigen specific IgA antibodies correlate very well with disease severity in over a dozen of different clinical autoimmune indications in humans. For this reason, it is difficult to understand why absolutely no therapeutic development efforts have been initiated to target the interaction between IgA and CD89. It becomes even more surprising when one considers the significant body of data that proves the functionality of the IgA-CD89 biology using human patient cells in in vitro experiments. It becomes even further surprising when you realize that auto-antigen IgA responses are already measured in a clinical setting and reported to for over thirty years to correlate with disease severity. The auto-antigen IgA antibody response, measured as antigen-specific IgA antibodies in patient serum, is a ready-made companion diagnostic (CDx) that provides the opportunity to stratify patients for interference of IgA-CD89. The question remains why in spite of all the evidence no development to target this pathway has been initiated? In the case of CD89, this is most probably due to the fact that the CD89 receptor is completely absent in murine models and therefore impossible to perform preclinical in vivo studies in mice or rat disease models, a presumed essential part of current drug development. Apparently, this has been viewed as a major roadblock, because the supportive human in vitro data has not resulted in the development of a specific drug for these patients with high IgA autoantibodies. Blindly follow the identical route without considering a detour may end up at a roadblock, like with geese that colliding with the wind turbines and are dying because the always follow the identical route. In my view, not a major issue, since geese that fly into a stationary wind turbine can be categorized into the group of “stupid geese” because they always follow the same route, and ultimately we can let natural selection take care of it since there is a group of “smart geese” that exist, which are fast, flexible, creative and adapt easily to new situations that will escape a tragic death following a collision with a wind turbine. For the development of a drug like anti-CD89 a detour around the roadblock of preclinical in vivo evidence is needed and behavior like a fast, flexible and creative smart goose is needed.

We have faced many examples where accumulating evidence proceeds protective action. With age, we can become more nostalgic, how many of us have heard elderly parents lament the current state of society and refer to the GOOD OLD DAYS when life was so much better or so it seemed. Wouldn’t it be interesting to go back in time and be a fly on the wall during the so called GOOD OLD DAYS to witness what was so good. For those of us of a certain age, we can recall jumping into a car without seatbelts, flying through the streets on motorbikes without a helmet and not a care in the world. The tobacco industry was able to convince people of the benefits of smoking, and whether you were convinced by that or not, you were subjected to other people’s smoke in close confinement such as aircraft cabins or entertainment venues. Alcohol was seen as a tonic, in particular doctors would encourage pregnant ladies to take a Guinness a day and excessive consumption was seen as a virtue. There was no understanding of  the link between LDL cholesterol and heart disease, the so called benefits of fatty foods outweighed any negative impacts. Many of the chemicals that we came into contact with on a day to day basis were deemed to be safe and useful, asbestos, in particular, had a place in many homes across Europe.

All of this flies in the face of what we currently understand, and it is only through a scientific endeavour that enabled a change in public health. Let’s remember, the pioneering epidemiologists, Doll and Hill first published a series of ground breaking papers on the impact of environmental and lifestyle factors on health in 1954, yet a complete change in perception of these practices was not fully accomplished until the 1990s, and in some nations, the dated perceptions linger.

The historical resemblance of the involvement of IgA-autoantibodies in autoimmune disease, especially in rheumatoid arthritis (RA) and the serum levels of IgA autoantibodies (e.g., IgA-rheumatoid factor (IgA-RF)), is remarkable. It is curious to note that the link between high serum levels of anti-RF IgA antibodies and the severity of RA was established over 30 years ago, and yet no one has really exploited this in delivering therapeutic interventions. Strong neutrophil-driven and CD89-mediated effector functions of IgA antibodies have been reported. The activation of neutrophils through IgA autoantibody-CD89, resulting in an excessive innate immunity response and has pathological consequences in autoimmunity. This justifies antagonizing the potent damaging and pathogenic effector functions of autoantigen specific IgA antibodies in autoimmunity by an antagonist anti-CD89.

RA is the most common autoimmune disease, affecting 0.5 to 1.0% of the world population, it is characterized by chronic inflammation in the symmetric joints and by the appearance of autoantibodies and infiltration of inflammatory cells. Blocking TNFα in RA patients has remarkably improved treatment outcomes for RA patients. Still, about 25-30% of anti-TNFα treated RA patients, do not effectively respond to treatment and for this non-responsive group, RA is a highly personalized disease with regard to its flare ups and periods of remission. Each patient's unique disease pathology requires a high level of personalization in terms of treatment, which can be achieved by stratifying patients according to biomarker profiles through the use a CDx. Precision medicine treatments are rapidly shifting the treatment of many diseases from a ‘one-size-fits-all’ to a ‘targeted testing and treatment’ approach. Since the determination of various isotypes of autoantibodies (e.g., IgM-RF, IgG-RF and sometimes IgA-RF) in RA patients is included in current standard diagnostic practice, potential effector cells and mechanisms responding to autoantibody complexes can be predicted and novel therapeutics developed. Local autoantibody complexes provide a highavidity matrix for homing of cells expressing the corresponding Fc-receptor. These cells subsequently locally get activated inducing collateral tissue damage and aggravating and broadening the inflammatory response. Interestingly, high pre-treatment levels of IgA RF are associated with a poor clinical response to TNFα inhibitors. Whereas patients with low IgA-RF and those with negative IgA-RF had a good response rate, patients with high positive IgA-RF were poor responders to anti-TNF treatments. This perfectly shows how already available CDx (anti-RF IgA) and clinical unresponsiveness to current treatment can enable a personalized medicine approach for patients receiving JJP-1212. The absence of IgA autoantibodies renders JJP-1212 into a non-relevant treatment in these specific IgA negative patients. By excluding these IgA negative patients, potential adverse events of the negative group will be excluded and potential adverse events are limited to the IgA positive patients in which JJP-1212 can have its clinical efficacy. Such a personalized medicine approach, supported by the failure to respond to a current treatment and a relevant CDx, provides a strategy that optimizes clinical development with respect to efficacy, risk and costs. For note in the realm of personalized medicine, costs are associated with failure to effectively treat patients such that the symptoms of a chronic disease have to be continually treated palliatively, additionally giving a targeted treatment to a biologically irrelevant individual in which a CDx does not support its use, can cause more damage than simply administering a placebo. The massive and impressive amount of data which associates IgA autoantibodies to severity of disease in RA, makes it hard to understand why no therapeutic interventions were designed to antagonize this pathway. The considerable species differences  in the IgA-CD89 axis may have contributed to this, since in vivo evidence is hard to obtain when biology is completely different between species. So despite having evidence of the causal link between IgA autoantibodies and disease severity for many years, little has been done with this data to address and treat the progression of disease in this cohort of patients. It seems therefore inevitable to subdivide high titre IgA autoantibody RA patients in a new clinical indication: IgA-mediated RA and subsequently customized their treatment protocol to their disease specifically supporting a personalized medicine approach.

With all these positive points it is incomprehensible why targeting this pathway has been completely ignored. The answer to this lies in the fact that there is considerable species difference in the biology and that mice do not have CD89. Hence it becomes difficult to get in vivo proof of concept data for this pathway in mouse models. Since both venture capital funds and large pharma due diligence teams stipulate that in vivo proof of concept is essential to support their investment analysis, the absence of animal models to support IgA-CD89 as a target has been drowned by development dogma. Targeting the CD89 receptor needs an unconventional approach in which animal experiments can only be done using transgenic animals delivering limited information, and therefore a custom approach is obligatory that needs fast and flexible adaptation and creativity in development.

The parallel between the situation with our bad habits from the GOOD OLD DAYS, for which healthcare professionals were able to initiate changes in public health with massive and impressive amounts of data which conclusively demonstrated causal links, is remarkable. They succeeded to discourage and reduce smoking, reduce consumption of alcohol and junk food and obliged the use of safety belts and helmets over time. Improvements in current diagnosis, application of RF-IgA as CDx and treatment in RA using JJP-1212 in the future will make us smile retrospectively and make us conclude that the GOOD OLD DAYS when anti-TNFα therapies and small molecule treatments prevailed in the treatment of severe RA and were not always that good.

By following a standard, so called tried and tested drug development route, new therapies with significant potential such a targeted antagonist anti-CD89 antibody are at risk of being lost. The IgA-CD89 example shows that drug developers that blindly follow the same established pathway without adapting diverting onto an alternative route are consigning themselves to the same fate of as the “stupid goose” that is found lying dead under a turbine. It’s up to you to decide which category of geese you would like to belong! Unevidentely, this will result in joining and supporting the “SMART GOOSE” community.

--Issue 01--