Re‐engineering of pathogenic aquaporin 4‐specific antibodies as molecular decoys to treat neuromyelitis optica

The target of the autoimmune response is quite well known for 2 neurological conditions, myasthenia gravis (MG) and neuromyelitis optica (NMO). In both diseases, a highly specific antibody to a critical protein is involved in complement-mediated damage to a key structure. In MG the acetylcholine receptor in the neuromuscular junction is destroyed, whereas in NMO the aquaporin 4 (AQP4) channel in astrocytes is the key anatomic site of pathological damage. In this issue of Annals of Neurology, Tradtrantip and colleagues have created a highly specific form of a molecular decoy for potential translation as a therapy for NMO. Using monoclonal antibodies cloned from plasmablasts sorted from the spinal fluid of patients with NMO, the research team re-engineered the antibodies so that although they would bind to AQP4, they could no longer fix complement or induce antibody-dependent cell-mediated cytotoxicity. In 2 animal models of NMO, these molecular decoys were able to block the pathogenic activity of native human monoclonal antibodies to AQP4, derived from patients with NMO. If these studies could be translated in clinical trials of individuals with NMO, this approach would afford 1 of the first antigen-specific treatments for an autoimmune disease. This strategy, using re-engineered monoclonal antibodies from patients, could have applications to other autoimmune diseases like MG and pemphigus vulgaris, another autoimmune disease mediated by autoantibodies, in this case to desmoglein, located in the epidermis. We often use military metaphors for describing the body’s department of defense, the immune system. Smart weaponry is the operative image. Why use a nuclear weapon—the Big Hammer, if you will—when one could use a smart weapon—a Molecular Scalpel—and thus achieve one’s goals with a great reduction in collateral damage? Modern immunological therapies with monoclonal antibodies, although highly selective for a single target, often decimate a wide population of immune cells, or impair a vital process. Thus therapy with antiCD20 targets a large population of B cells, and therapy with antibody to a4 integrin impairs lymphocyte homing to brain and other vital organs. Do these therapies with a Big Hammer make sense, when we instead could be using a Molecular Scalpel, like that designed to thwart damage by anti-AQP4 antibodies? If we knew that only 1 type of antibody immune response was largely or fully responsible for pathology in a disease, would we need to ablate all of one’s B cells to nullify an attack by this antibody directed to 1 critical antigen? Similarly, why would we want to inhibit the complement pathway, when all that might be needed is a re-engineering of 1 pathological group of antibodies, so that only those antibodies cannot fix complement, whereas other antibodies in our repertoire (eg, to meningococcus) are freely able to mount a response against this deadly microbe? The answers to these questions ought to be logical for anyone who understands the fundamentals of immunology, or who has taken care of a patient with an opportunistic infection resulting from therapy with a Big Hammer. The Big Hammers are exemplified in the treatments that target broad populations of immune cells, such as the B cells with anti-CD20 therapies like rituximab or ocrelizumab. A Big Hammer anti-CD52, alemtuzumab, kills wide populations of B cells, T cells, and other mononuclear cells. Natalizumab, a third example of a Big Hammer, targets a4 integrin, and thus blocks traffic of a broad population of T cells and B cells that home not only to brain, but also travel to other organs like the intestines; natalizumab is approved for both relapsing–remitting MS (RRMS) and inflammatory bowel disease, after all. A clinical trial in NMO is underway with eculizumab, described by Forbes magazine as the world’s most expensive drug at >$400,000 a year, which targets the C5 component of complement in NMO. Such Big Hammers, effective as they may be, are ultimately illogical treatments for those diseases where there is compelling evidence that there is only 1 target at the center of the autoimmune response. Therapy with the Big Hammers is associated with undesirable complications such as progressive multifocal leukoencephalopathy in the case of natalizumab, opportunistic infections including meningococcal meningitis in the case of eculizumab, and new autoimmune conditions like Grave disease and idiopathic thrombocytopenic purpura in the