Evolved treatments for Alzheimer’s
Zurich-based NeurImmune AG follows unconventional routes – for example, the company doesn’t rely on VC investors. And Neurimmune has also turned the drug discovery process upside down by taking its drug candidates from healthy humans that have developed an immune response to pathogenic proteins like Abeta. Biogen Idec is building on NeurImmune’s expertise, and has already signed two agreements.
The deposition of pathogenic protein aggregates derived from physiological brain proteins is a common theme underlying most neurodegenerative diseases. These protein clusters deposited in the brains of human patients include, for example, Abeta (Ab)and tau in Alzheimer’s disease and Down syndrome, a-synuclein in Parkinson’s disease and dementia with Lewy bodies, and superoxide dismutase 1 in amyotrophic lateral sclerosis. Disease-causing mutations in the genes encoding these proteins point to their central roles in the etiology of neurodegeneration. Both genetic and the more frequent “sporadic” variants of neurodegeneration are associated with the conversion of misfolded physiological proteins into pathogenic aggregates.
Synaptic connections by which neuronal networks communicate are among the most vulnerable structures affected, resulting in the progressive deterioration of neuronal network activities. When released from affected cells, the pathogenic aggregates can enter unaffected neighbouring cells, bind to their cognate physiological protein counterparts, and force them to adopt pathological conformations as well. This thermodynamically driven process of prion-like infectivity drives the spatiotemporal spreading of protein aggregation from cell to cell and throughout the central nervous system. Unexpectedly, this metamorphosis from physiologic to pathogenic structural conformations of endogenous proteins can be accompanied by humoral immune responses generating B-cells encoding high-affinity antibodies that specifically bind and neutralise such pathogenic protein aggregates. This observation provides a basis for asking the questions of how healthy elderly subjects succeed in preserving intact cognitive functions during aging, and how such knowledge can be used pharmacologically to prevent neurodegeneration in subjects at risk. NeurImmune studied immune responses directed against pathogenic protein aggregates in cohorts of healthy elderly subjects with either excellent cognitive performance or recovery from initial signs of cognitive decline. Up to 80% of healthy elderly subjects had established B-cell memory against aggregated Ab, thus allowing for the cloning of human monoclonal antibodies targeting these aggregates. Recombinantly produced human monoclonal antibodies with high affinity and selectivity for aggregated Ab crossed the blood-brain barrier in transgenic mouse models of Alzheimer’s disease and accumulated on Ab deposits in the brain. Brain-resident microglial cells were recruited to antibody-labeled aggregates, and removed them by means of phagocytosis paralleled by signs of neuronal recovery and restored behavioral functions. The pharmacological effects of these human monoclonal antibodies are currently being studied in human patients with early signs of cognitive decline. In addition to immune responses against aggregated Ab, healthy elderly subjects also mounted immune responses against misfolded or aggregated forms of a-synuclein, superoxide dismutase 1, tau and TAR DNA-binding protein 43. The corresponding high affinity human monoclonal antibodies were cloned, sequenced, produced recombinantly and validated in vitro and in vivo. As an example, chronic treatment of transgenic mice with signs of amyotrophic lateral sclerosis established rescue of alpha-motor neurons along with increased overall survival. Likewise, recombinant human antibodies against a-synuclein decreased alpha-synuclein pathology and improved motor functions in transgenic mouse models of Parkinson’s disease. Pharmacological intervention using recombinant human antibodies against disease-causing toxic protein aggregates provides a promising concept for the treatment and prevention of neurodegeneration.
In November 2007, Biogen Idec closed a first partnership with NeurImmune for the development of antibodies to treat Alzheimer’s disease. Neurimmune could receive an aggregate of US$380m in up-front and success-based milestone payments. In December 2010, Biogen acquired a NeurImmune subsidiary that contained the global rights to three preclinical candidates targeting neurodegenerative diseases.