Thursday, 24 September 2015

Nabs is it Nads

Wootla B, Watzlawik JO, Warrington AE, Wittenberg NJ, Denic A, Xu X, Jordan LR, Papke LM, Zoecklein LJ, Pierce ML, Oh SH, Kantarci OH, Rodriguez M.Naturally Occurring Monoclonal Antibodies and Their Therapeutic Potential for Neurologic Diseases. JAMA Neurol. 2015 Sep 21. doi: 10.1001/jamaneurol.2015.2188. [Epub ahead of print]

IMPORTANCE:Modulating the immune system does not reverse long-term disability in neurologic disorders. Better neuroregenerative and neuroprotective treatment strategies are needed for neuroinflammatory and neurodegenerative diseases.
OBJECTIVE: To review the role of monoclonal, naturally occurring antibodies (NAbs) as novel therapeutic molecules for treatment of neurologic disorders.
EVIDENCE REVIEW: Peer-reviewed articles, including case reports, case series, retrospective reviews, prospective randomized clinical trials, and basic science reports, were identified in a PubMed search for articles about NAbs and neurologic disorders that were published from January 1, 1964, through June 30, 2015. We concentrated our review on multiple sclerosis, Parkinson disease, Alzheimer disease, and amyotrophic lateralsclerosis.
FINDINGS: Many insults, including trauma, ischemia, infection, inflammation, and neurodegeneration, result in irreversible damage to the central nervous system. Central nervous system injury often results in a pervasive inhibitory microenvironment that hinders regeneration. A common targeted drug development strategy is to identify molecules with high potency in animal models. Many approaches often fail in the clinical setting owing to a lack of efficacy in human diseases (eg, less than the response demonstrated in animal models) or a high incidence of toxic effects. An alternative approach is to identify NAbs in humans because these therapeutic molecules have potential physiologic function without toxic effects. NAbs of the IgG, IgA, or IgM isotype contain germline or close to germline sequences and are reactive to self-components, altered self-components, or foreign antigens. Our investigative group developed recombinant, autoreactive, natural human IgM antibodies directed against oligodendrocytes or neurons with therapeutic potential for central nervous system repair. One such molecule, recombinant HIgM22, directed against myelin and oligodendrocytes completed a successful phase 1 clinical trial without toxic effects with the goal of promoting remyelination in multiple sclerosis.
CONCLUSIONS AND RELEVANCE: Animal studies demonstrate that certain monoclonal NAbs are beneficial as therapeutic agents for neurologic diseases. This class of antibodies represents a unique source from which to develop a new class of disease-modifying therapies.

Naturally occurring antibodies are good, if they are protecting and repairing and HIgM22 has been around for a long time, the question is does the the antibody work as a remyelinatation agent. This has been reported in some animal models and the only way to find out is to try it. The question is, how much will get to the brain as an IgM molecule is big and so it may not penetrate the CNS very well. 

However, it is clear to me that not all Nabs are beneficial in MS as we can purify the antibody out and inject them into animals and they can cause neurological problems, so in that case they are clearly pathogenic.

The function of antibodies is the protection against infection, some may stimulate cells to do good things others don't, such as they can stimulate the thyroid gland to make too much thyroid hormones. 

So the answer is proof is in the pudding and the makers of HIgM22 need to prove it is of use in MS in a phase II study.

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