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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3099_Библиотеки_им_академика_М_И_Перельмана.pdf
Novel Therapies for Amyloidosis in the Era of RNAi …
37
reduction in SAP in 2 evaluable amyloid organs without adverse effects.
Interestingly, in Afib, proteinuria was reduced with improved renal survival
compared to historical controls. However, few patients had a change in whole
body amyloid load by
123
I-labeled SAP scintigraphy [67].
Although CPHPC depletes circulating SAP efficiently and removes SAP
from amyloid fibrils, some SAP remains bound. After 5 days of CPHPC-
mediated SAP depletion, transgenic mice for human SAP with AA
amyloidosis received 1 dose of IgG fraction of monospecific polyclonal sheep
anti-human SAP antibody. The combination of CPHPC and anti-SAP antibody
triggered massive removal of visceral amyloid deposits on histology after 28
days without obvious adverse effects [68]. A clear immune-reaction to the
amyloid deposits were seen with dense infiltration of deposits with
mononuclear inflammatory cells and macrophages in 24 hours [68].
Multinucleate giant cells which are specialized for complement-mediated
phagocytosis and large target destruction [69], were seen on day 2 [68]. The
process was thought to be Fc-, complement- and macrophage-dependent [68].
Other anti-SAP antibodies were tested with similar results [68].
Given promising pre-clinical results of the combination of CPHPC and
anti-SAP antibody, a small phase I single-dose escalation, open-label study
was conducted with 15 systemic amyloidosis patients (8 AL, 4 Afib, 2 AA)
[70]. Patients with cardiac amyloidosis were excluded due to safety concerns.
CPHPC was given until SAP was < 2.0 mg/L, usually after 3 days, then 1 dose
of fully humanized monoclonal IgG
1
anti-SAP antibody was administered.
After that, CPHPC treatment continued until SAP antibody fell below 300
ug/L, around 4-16 days later. No serious adverse events were reported.
Infusion reactions were observed though were reduced after slowing the
infusion. Amyloid deposits were cleared from the liver, kidney, and lymph
node [70]. Four of 8 patients had major reductions in hepatic amyloid, as well
as decreases in C3 and increases in CRP, suggesting inflammatory responses.
At 6 weeks, patients had decreased liver stiffness as measured with
elastography as well as reductions in hepatic amyloid load by
123
I-labeled SAP
scintigraphy. Reduction of kidney amyloid by
123
I-labeled SAP scintigraphy
and shrinkage of an amyloid-laden lymph node were also observed [70].
Regression of amyloid deposits has been demonstrated in vitro and in
patients [71-74], a process that occurs slowly clinically. The use of passive
immunity to interfere with the aggregation of fibril formation [75, 76] and to
improve amyloidolysis by a monoclonal antibody has been shown in Aβbeta
amyloid disease in vivo [77] likely by a macrophage-related process.
Furthermore, human sera, pooled human IgG and pharmacologic formations of
Sandy W. Wong and Raymond L. Comenzo
38
immune globulin all contain antibodies that specifically recognize AL, ATTR
and AA amyloid but do not react with these molecules in their native
nonfibrillar forms [78]. The purified antibodies immunostain human amyloid
tissue specimens and inhibit in vitro fibrillogenesis [78]. These observations
set the precedent for developing a monoclonal antibody against amyloid fibrils
themselves.
11-1F4 is a IgG
1
κ monoclonal antibody prepared by immunizing mice
with a denatured human κ4 LC (Len) [79, 80]. Although this antibody was
developed against a κ4 LC, it reacted regardless of κ or λ constant (C
L
) region
isotype or V
L
subgroup but did not recognize native LC except for κ4 LC [79-
81]. Further characterization of 11-1F4 by epitope mapping revealed that this
antibody recognizes a neo-epitope exposed on LC fibrils and partially
denatured LC [80]. The conformational epitope is contained within the first 18
amino acids of misfold LC at the N-terminal. The peptide Len (1-18) but not
intact protein or other LC, inhibited binding of the antibody to fibrils [80]. A
highly conserved prolyl residue at position 8, a structural feature common to
kappa and lambda [80, 82], contributes to 11-1F4’s unique reactivity. The
authors posit that the binding site for 11-1F4 involves an inducible N- terminal
main chain reversal that results in the formation of a proline anchored β-turn
[80]. In vitro, 11-1F4 potently inhibits LC fibrillogenesis causing unraveling
of fibrils to form protofilaments [83].
In vivo, on fluorescein tagging, 11-1F4 binds specifically to the
amyloidoma tumor in mice [79, 80]. Furthermore, injections of 11-1F4 in mice
with human AL λ or κ amyloidomas led to up to four-fold more rapid
elimination than control. Over 90% reduction in an AL κ1 amyloidoma within
4 days of antibody injection was observed compared to control [84]. AL λ
amyloidomas required multiple doses of antibody but nonetheless 11-1F4
decreased the tumors four-fold more quickly than control [84]. Histologically,
profound neutrophil infiltration in amyloid deposits was seen in 11-1F4
animals compared to controls, a process that was Fc-dependent. Prior anti-LC
antibodies recognized amyloid fibrils and expedited amyloidolysis but were
restricted to removal of AL λ or κ LC. 11-1F4 uniquely quickens the removal
of both AL λ and κ amyloid [85]. 11-1F4 also accelerated removal of TTR and
AA amyloid fibrils [86]. Notably, 11-1F4 recognized other forms of amyloid
by IHC such as AA, ATTR, Alys, AApoA1 and Aβ-containing tissues [85].
Likewise, other conformational antibodies generated against Aβ amyloid
fibrils could bind to other types of amyloid fibrils from AL, TTR and β2m, but
not to native protein precursors [87]. These antibodies including 11-1F4 are
likely directed to a universal epitope on all amyloid fibrils [87]. These features
Novel Therapies for Amyloidosis in the Era of RNAi …
39
of 11-1F4 may endow this antibody with potential broad applicability in
systemic amyloidosis. Even in the presence of SAP and heparan sulfate which
are thought to be immunoprotective [62, 88, 89], 11-1F4 could still elicit an
immune-mediated reduction of amyloid [84].
Eventually, mouse 11-1F4 was chimerized without loss of specificity and
retained the ability to accelerate amyloidolysis in mice with human AL λ or κ
amyloidomas [86]. There was little to no reactivity of chimeric 11-1F4 with
human tissue [86]. Chimeric 11-1F4 was also tested in mice bearing systemic
AA deposits which results in marked reduction of amyloid burden without
toxicity [90]. As seen previously, macrophage and neutrophil infiltration was
far greater in treated mice compared to controls. Reactivity to both λ (λ8) and
κ-derived (κ4) amyloid deposits in human tissue was preserved [90]. Like the
parent antibody, chimeric 11-1F4 failed to bind native LC with the exception
of κ4 LC [90]. Antibody reactivity with other human tissues such as liver,
kidney and muscle was mild and less than rituximab [90], a chimeric CD20
antibody FDA-approved for lymphoma treatment [91].
More recently, chimeric 11-1F4 is being studied in an on-going phase 1
dose-escalation clinical trial in AL patients with relapsed refractory disease to
evaluate for MTD (NCT02245867) of one infusion [92]. As of July 2015, 6
patients have completed the study. The antibody was well tolerated with no
grade 3/4 adverse effects. One notable adverse effect involved a patient with
grade 2 rash for 11 days during which a skin biopsy showed cutaneous
amyloid deposits and a neutrophilic infiltrate. Two cardiac and one GI
organ response were reported in 3 of the first 6 patients treated, a promising
result [92].
Radioiodinated 11-1F4 with
125
I or
124
I has also been studied as a potential
radiotracer for PET/CT and SPECT/CT imaging. In a preclinical study, the
radiolabeled antibody was injected into AL amyloidoma-bearing mice, then
imaged [93]. The radiolabeled 11-1F4 localized predominantly in amyloid
tumors and accumulation was readily visible in small-animal PET/CT and
SPECT/CT. However, greater accumulation was seen in AL kappa than in AL
lambda amyloidomas [93], which is consistent with in vivo data [84]. In a
phase 1 trial
124
I-labeled murine 11-1F4 was used in 18 AL patients and
imaging by PET/CT scan in 9 subjects showed uptake in liver, lymph node,
bone marrow, intestine, and spleen. However, there is no uptake in kidneys or
heart which are the most common organs afflicted by amyloidosis [94], thus
potentially limiting its applicability.
Originally developed as a radiotracer for imaging AA deposits, 2A4 is an
IgG
2
antibody against amyloid fibrils, developed using the 5 C-terminal
Sandy W. Wong and Raymond L. Comenzo
40
residues (residues 71-75) of murine AA as an immunogen [95]. As such, 2A4
does not recognize native full-length SAA, only the truncated AA peptide
found in amyloid fibrils [95]. Despite being generated from murine SAA, 2A4
binds avidly to human AA amyloid tissues. The epitope is thought to be
derived from a cleavage site of SAA that becomes exposed when SAA
undergoes proteolytic cleavage during deposition of AA amyloid [95]. Like
11-1F4, 2A4 also reacts strongly with both κ and λ human amyloid, including
synthetic fibrils derived from Wil and Jto λ6 LC variable domans and
glycosaminoglycan-coated human AL extracts [96]. However, 2A4 bound
significantly better to AL λ than κ on amyloid extracts though more
radiolabeled 2A4 was bound to AL κ compared to λ in mice amyloidomas
[96]. There is no interaction with soluble light chain proteins [96]. Treatment
with 2A4 led to rapid regression of AL κ amyloidomas in mice with evidence
of macrophage-mediated immune response by histology [96]. 2A4 did not
react with healthy patient tissues on frozen section [97].
The antibody 2A4, in its humanized form known as NEOD001, was
studied in a phase I/II of AL patients with ≥ hematologic partial response but
with persistent organ dysfunction [98]. Twenty-seven patients were placed in 7
dose-escalation cohorts. Primary objective was to determine MTD and
safety/tolerability. NEOD001 was infused monthly without toxicities. MTD
was not reached and recommended dosing was 24mg/kg. Of 14 cardiac-
evaluable pt, 57% had a cardiac response and 43% stable disease [98]. In the
responders, median NT-proBNP, a validated cardiac biomarker in AL
amyloidosis [99], decreased from 1,768.5 to 1,054 pg/ml at best response [98].
There was a 48% mean reduction in NT-proBNP from baseline. Of 15 renal-
evaluable patients, 60% had renal responses. Of the responders, median
proteinuria decreased from 4,834 gm/24 hr to 1,647 gm/24 hr at best response
[98]. There was a 62% mean reduction in 24 hour urine total protein from
baseline [98]. A planned open-label expansion component to enroll 40 more
patients at dose of 24mg/kg every 28 days is planned (NCT02613182). Organ
responses observed in this study appear to be better than historical controls
[100, 101]. A randomized placebo-controlled double-blind phase III trial
(VITAL, NCT02312206) has been opened where newly diagnosed AL patients
with cardiac involvement are randomized to cyclophosphamide, bortezomib
and dexamethasone ± NEOD001. Primary endpoint is a composite of all-cause
mortality and cardiac hospitalizations. Also, a phase 2b, randomized, double-
blind, placebo-controlled study of NEOD001 in previously treated subjects
with AL amyloidosis with persistent cardiac dysfunction (PRONTO,
Novel Therapies for Amyloidosis in the Era of RNAi …
41
NCT02632786) is also planned with the primary endpoint as best cardiac
response by NT-proBNP.
CONCLUSION
In conclusion, amyloidosis is a disease for which treatment continues to be
insufficient for improving end-organ dysfunction and reducing mortality.
Opportunities exist however to develop new treatments for this disease by
applying siRNA technology and immunotherapy. There are advantages and
disadvantages to these modalities of novel treatment. Nonetheless, these
treatments hold promise for ameliorating mortality and morbidity by reducing
amyloid-forming precursor proteins and enabling immunologic clearance of
amyloid fibrils and deposits.
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