The Parkinson's protein gateway and an antibody already tested in humans

Cancer Research UK, the British cancer research charity, ran a phase I/II trial of the antibody BI-1206 in patients with B-cell lymphoma. BI-1206 blocks the receptor FcγRIIb (also called CD32b). On September 25, a paper from the University of Southampton in Acta Neuropathologica showed that the same receptor is the gateway through which neurons take up fibrils of alpha-synuclein, the protein whose spread drives Parkinson's disease.

Alpha-synuclein aggregates pass from neuron to neuron, forcing healthy copies of the protein to misfold, and kill the dopaminergic cells of the substantia nigra (a midbrain structure). The loss of those cells produces the tremor and rigidity of Parkinson's, the second most common neurodegenerative disorder after Alzheimer's, affecting nearly 12 million people. In mice lacking the FcγRIIb gene, spread of the pathological protein fell by 70% in the substantia nigra and by nearly 99% in the frontal and motor cortex over three months. In neuronal cultures free of immune cells, removing the receptor reduced formation of pathological protein by 88%: the receptor is needed by the neuron itself. Knockout mice were also protected functionally: their dopaminergic neurons survived, and in tests of motor function and exploratory behavior the animals were indistinguishable from healthy controls.

Knocking out the gene is not an option in humans, so the team tested blocking antibodies. Mice carrying the human receptor received two antibody variants (one with a functional Fc tail, one disabled) at the same time as the fibrils, and both reduced accumulation of the pathological protein by 90%. The protection appears to come from physically blocking the site where the fibril docks onto the receptor; whether the Fc tail was functional made no difference. An important caveat: the antibodies were given together with the fibrils, not after the pathology had spread. The experiment establishes the receptor as a viable blocking point, but the data say nothing about efficacy in established disease.

Earlier antibodies targeting alpha-synuclein itself, prasinezumab (Roche) and cinpanemab (Biogen), failed to slow disease progression in phase II trials; cinpanemab was discontinued in 2021. The Southampton team chose a different intervention point: the receptor through which fibrils enter the cell. FcγRIIb is the only inhibitory Fc receptor conserved across species, which simplifies translating results from mice to humans.

Cancer Research UK has already tested BI-1206 in humans for an oncological indication; the antibody BI-1607, targeting the same receptor, completed a phase I trial in HER2-positive tumors. This does not establish safety or efficacy in Parkinson's disease, but the molecule does not start the clinical path from zero. The research was funded by a 2018 grant from the Michael J. Fox Foundation, the world's largest private Parkinson's research program (founded by the actor after his diagnosis at age 29). Whether anyone opens a Parkinson's trial remains an open question.

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Sources
[1] doi.org