Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses.
Wild-type and mutant transthyretin (TTR) can misfold and deposit in the heart, peripheral nerves, and other sites causing amyloid disease. Pharmacological chaperones, Tafamidis(®) and diflunisal, inhibit TTR misfolding by stabilizing native tetrameric TTR; however, their minimal effective concentration is in the micromolar range. By immune-targeting sparsely populated TTR misfolding intermediates (i.e. monomers), we achieved fibril inhibition at substoichiometric concentrations. We developed an antibody (misTTR) that targets TTR residues 89-97, an epitope buried in the tetramer but exposed in the monomer. Nanomolar misTTR inhibits fibrillogenesis of misfolded TTR under micromolar concentrations. Pan-specific TTR antibodies do not possess such fibril inhibiting properties. We show that selective targeting of misfolding intermediates is an alternative to native state stabilization and requires substoichiometric concentrations. MisTTR or its derivative may have both diagnostic and therapeutic potential.
Princess Margaret Cancer Centre, University Health Network, Departments of Medical Biophysics and Biochemistry, University of Toronto, TMDT 4-305, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
Natalie J
NJ
Galant
Princess Margaret Cancer Centre, University Health Network, Departments of Medical Biophysics and Biochemistry, University of Toronto, TMDT 4-305, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
Antoinette
A
Bugyei-Twum
Department of Chemical and Systems Biology, Stanford University, CA 94305, USA.
Rishi
R
Rakhit
Molecular Structure and Function Program, the Hospital for Sick Children, Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Patrick
P
Walsh
Molecular Structure and Function Program, the Hospital for Sick Children, Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Simon
S
Sharpe
Princess Margaret Cancer Centre, University Health Network, Departments of Medical Biophysics and Biochemistry, University of Toronto, TMDT 4-305, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
Pharhad Eli
PE
Arslan
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Per
P
Westermark
Departments of Biochemistry and Histopathology, Prothena Biosciences Inc., South San Francisco, CA 94080.
Jeffrey N
JN
Higaki
Departments of Biochemistry and Histopathology, Prothena Biosciences Inc., South San Francisco, CA 94080.
Ronald
R
Torres
Departments of Biochemistry and Histopathology, Prothena Biosciences Inc., South San Francisco, CA 94080.
José
J
Tapia
Princess Margaret Cancer Centre, University Health Network, Departments of Medical Biophysics and Biochemistry, University of Toronto, TMDT 4-305, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
Avijit
A
Chakrabartty
D000686:Amyloidosis / Q000175:diagnosis / Q000628:therapy; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D011228:Prealbumin / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D011817:Rabbits
D000906:Antibodies; D011228:Prealbumin