Naturally occurring antibodies as therapeutics for neurologic disease: can human monoclonal IgMs replace the limited resource IVIG?

Abstract

Naturally occurring autoantibodies (NAbs) are common in normal humans. The majority of NAbs are IgMs, but a small proportion are IgGs. Therefore a certain portion of pooled whole human IgG (IVIG) can be considered NAbs. While the applications of IVIG to modulate human disease have increased dramatically, the use of IgMs as drugs has lagged. In fact, much of the contaminating IgM component of IVIG is disposed of as waste. However, a number of model studies, including those targeting Alzheimer and multiple sclerosis (MS) suggest that IgMs may better modulate disease at much lower doses than IVIG. Our own studies in a model of MS show that polyclonal human IgM promotes better remyelination than IVIG and that monoclonal IgMs promote greater remyelination than monoclonal IgGs containing identical variable region sequences. We propose that this difference is due to the ability of IgM to cross link cell surface antigens better than IgGs and induce signals in nervous system cells. Monoclonal antibodies (mAbs) that promote remyelination induce a transient Ca(2+) influx in myelin forming cells, whereas IgGs with identical variable sequences do not. MAbs that promote remyelination were identified in human serum and in EBV-immortalized human B-cell lines obtained from normal adults, fetal cord blood, and rheumatoid arthritis and MS patients. Therefore therapeutic mAbs are present and common in normal circulation. All therapeutic mAbs were IgMs and bound to nervous system cells, however, the tissue binding patterns suggest that binding any one of multiple antigens induces repair. An expression vector was constructed that can manufacture gram quantities of recombinant monoclonal human IgM. Therefore the technology exists to determine whether human monoclonal NAbs can modulate human disease. IVIG can modulate neurologic disease, but using IVIG to treat these chronic diseases is unsustainable. A long-term solution is to identify the functional component of IVIG and test whether a recombinant human monoclonal can replicate its efficacy.