Therapeutic strategies that target pathways of protein misfolding and the toxicity of intermediates
along these pathways are mainly at discovery and early development stages, with the exception of
monoclonal antibodies that have mainly failed to produce convincing clinical benefits in late stage trials.
The clinical failures represent potentially critical lessons for future neurodegenerative disease drug development.
More effective drugs may be achieved by pursuing the following two strategies. First, conformational
targeting of aggregates of misfolded proteins, rather than less specific binding that includes
monomer subunits, which vastly outnumber the toxic targets. Second, since neurodegenerative diseases
frequently include more than one potential protein pathology, generic targeting of aggregates by shape
might also be a crucial feature of a drug candidate. Incorporating both of these critical features into a
viable drug candidate along with high affinity binding has not been achieved with small molecule approaches
or with antibody fragments. Monoclonal antibodies developed so far are not broadly acting
through conformational recognition. Using GAIM (General Amyloid Interaction Motif) represents a
novel approach that incorporates high affinity conformational recognition for multiple protein assemblies,
as well as recognition of an array of assemblies along the misfolding pathway between oligomers
and fibers. A GAIM-Ig fusion, NPT088, is nearing clinical testing.
A novel approach for rapid high-throughput selection of recombinant functional rat monoclonal antibodies
