Therapeutic elimination of
amyloid deposits: is it possible?
XIII International Myeloma Workshop
Paris, May 2011
Professor Mark Pepys FRS FMedSci
UCL Centre for Amyloidosis and Acute Phase Proteins
UK NHS National Amyloidosis Centre
Conflict of interest
ˇInventor of granted and pending patents on use
of CPHPC alone and in combination with anti-
SAP antibodies for treatment of amyloidosis and
amyloid-associated diseases
ˇFounder, Director and share holder in Pentraxin
Therapeutics Ltd, UCL spin out company which
owns these patents and has licensed them to
GlaxoSmithKline for clinical development
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Amyloidosis
ˇ Disease caused by amyloid deposits:
local or systemic
ˇ Diagnosis usually late
ˇ Treatment very challenging
ˇ Major recent advances & better
outcomes in specialist centres
ˇ Still a major unmet medical need
Amyloidosis & amyloid-associated
diseases
ˇ Systemic amyloidosis: acquired or hereditary
ˇ Local amyloidosis: acquired or hereditary
ˇ Type 2 diabetes
ˇ Alzheimer's disease
ˇ Transmissible spongiform encephalopathies
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Progress in amyloidosis 1976-2010
ˇ Better diagnosis but usually still very late
ˇ Better retention & replacement of organ
function but often not sufficient
ˇ Much better control of precursor protein
abundance but often difficult & dangerous
ˇ Better survival but systemic amyloidosis still
usually fatal
ˇ Important unmet medical need
Amyloid deposits
ˇ Amyloid fibrils
ˇ Heparan/dermatan
sulphate PGs
ˇ Serum amyloid P
component (SAP)
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Amyloid fibrillogenesis in vivo
ˇ Sustained high concentration of normal
protein: SAA, 2M, TTR
ˇ Acquired production of abnormal protein: AL
(myeloma, other plasma cell dyscrasias)
ˇ Hereditary production of variant protein: TTR,
fibrinogen, apoAI, lysozyme, gelsolin, etc
ˇ Misfolding & aggregation with typical cross-
polypeptide core structure
The mystery of amyloid persistence
ˇ Persistent production of fibril precursor
proteins causes accumulation
ˇ But why is amyloid not cleared?
ˇ No local or systemic inflammatory reaction,
no immunological response
ˇ But macrophages & giant cells are
sometimes present
ˇ Amyloid deposits can regress
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Treatment of amyloidosis
ˇ No amyloid: no disease
More amyloid: disease progression & death
Amyloid regression: clinical benefit, survival
ˇ Physical presence of amyloid is directly
damaging to tissues and organ function
ˇ Early diagnosis, maintain/replace organ
function
ˇ Control supply of fibril precursor
Serum amyloid P component (SAP)
ˇ Highly conserved plasma glycoprotein
ˇ Pentraxin protein family, with CRP
ˇ Homopentamer, lectin fold, 20-40 mg/l in
plasma, t ~24 h, synthesized & catabolized
1/2
only by hepatocytes
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SAP and amyloid
ˇ SAP binds to all amyloid fibrils (1979)
ˇ Specifically concentrated in amyloid deposits
in plasma -
albumin : SAP ~2000 : 1
in amyloid -
albumin : SAP <1 : 10
ˇ Equilibrium: SAP in amyloid & circulation
ˇ Plasma and ECF SAP = ~100 mg
Amyloid SAP = up to 20,000 mg
ˇ Radiolabelled SAP, injected intravenously,
localises specifically to amyloid (1988)
Regression of amyloid
AA
AL
Hawkins et al. 1993. SAP scintigraphy and turnover studies demonstrate regression of
amyloidosis." Nucl. Med. Commun. 14: 259-60; Scintigraphic quantification and serial monitoring of
human visceral amyloid deposits provide evidence for turnover and regression. Q.J. Med. 86: 365-
74; Serum amyloid P component scintigraphy and turnover studies for diagnosis and quantitative
monitoring of AA amyloidosis in juvenile rheumatoid arthritis. Arthritis Rheum. 36: 842-51.
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New treatments for amyloidosis?
ˇ Inhibition of fibrillogenesis
small molecules, antibodies
stabilisation of precursor native fold
inhibition of precursor synthesis
by siRNA, ASO, etc
ˇ Enhancement of amyloid regression
antibodies to fibril proteins
disaggregating peptides
targeting SAP
SAP & amyloidogenesis
ˇ SAP is universal in amyloid deposits
ˇ SAP production correlates with amyloid
deposition in mice and hamsters
ˇ SAP in amyloid deposits is not degraded
ˇ SAP binding stabilises amyloid fibrils in vitro
ˇ SAP is an anti-opsonin
ˇ SAP promotes fibrillogenesis in vitro
ˇ Amyloid deposition reduced in SAP knockouts
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1984: SAP ligand as a drug?
Hind et al, Specific chemical dissociation of fibrillar and non-fibrillar
components of amyloid deposits. Lancet, 1984, 2(8399):376-8
1995-2000
O
CPHPC O
OH
N
N
Kd 10 nM
O
HO
O
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Effect of CPHPC on plasma SAP
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Clinical study of CPHPC in systemic
amyloidosis (2001-4)
ˇ No adverse clinical effects in 31 patients,
>45 patient years
ˇ Plasma SAP depleted throughout; ~90% of
SAP removed from amyloid
ˇ No laboratory test or organ function
abnormalities attributable to CPHPC or
persistent SAP depletion in >5 yrs
ˇ No new amyloid accumulation, most patients
remain stable but no amyloid regression
Gillmore et al. Br. J. Haematol, 2010, 148: 760-767
Curing amyloidosis in mice (2005-8)
ˇ Human SAP transgenic C57BL/6 mice
with AA amyloidosis
ˇ CPHPC clears SAP from plasma but
leaves some SAP in amyloid
ˇ Antibodies to SAP can reach the amyloid
ˇ Amyloid deposits disappear!
Bodin et al. Nature 2010, 468: 93-97
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Day 28 post antibody
Control IgG
Anti-SAP
antibody
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Day 1 post antibody
Congo red
F4/80
Day 4 post antibody
H & E
CD68
control CD68
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Day 4 post antibody
Congo red
H & E
Day 4 post antibody
SAA
C3
CD68
SAA green
CD68 red
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k
l
14
m
n
15
o
p
16
q
r
17
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Elimination of amyloid deposits
ˇ CPHPC depletes circulating SAP but leaves
some SAP in amyloid
ˇ Anti-SAP abs then safely target deposits
ˇ Antibody binding triggers complement and
macrophage dependent clearance of amyloid
ˇ Clinical development with GSK for FITH trials
in systemic amyloidosis
ˇ Potential use in all amyloid-associated
diseases
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Therapeutic elimination of amyloid
deposits is possible
ˇ In mice with AA amyloidosis so far
ˇ Fully humanised monoclonal anti-SAP antibody
ˇ First human studies are coming
ˇ Acknowledgements: Patients and NHS NAC,
colleagues and collaborators, UK Medical
Research Council, The Wolfson Foundation,
The Wellcome Trust, UCL Amyloidosis
Research Fund, GlaxoSmithKline
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