Blackwell Science, LtdOxford, UK

TAPTherapeutic Apheresis and Dialysis1091-66602003 International Society for Apheresis

71February 2003
017
PEPTIDES IN IMMUNOADSORPTION
W. RÖNSPECK ET AL.
10.1046/j.1091-6660.2003.00017.x
Original Article9197BEES SGML

Therapeutic Apheresis and Dialysis

7(1):91–97, Blackwell Publishing, Inc.
© 2003 International Society for Apheresis

Peptide Based Adsorbers for Therapeutic Immunoadsorption

*Wolfgang Rönspeck, *Roland Brinckmann, *Ralf Egner, *Frank Gebauer, *Dirk Winkler,
*Petra Jekow, †Gerd Wallukat*, §Johannes Müller, and *Rudolf Kunze
*Affina-Immuntechnik GmbH, Berlin, †Max-Delbrück-Center for Molecular Medicine Berlin-Buch,
§German Heart Center, Berlin, Germany

Abstract: Peptides as ligands for immunoadsorption
exhibit several potential advantages over native proteins.
Two newly developed adsorbers are based on peptides
covalently coupled to sepharose CL-4B. Globaffin is capa-
ble of binding immunoglobulins independent from their
antigen specificity and thus, applicable in transplant recip-
ients and several antibody mediated autoimmune diseases.
Among others, the most important disorders suitable for
the treatment with Globaffin are rheumatoid arthritis, sys-
temic lupus erythematosus, and acute renal transplant
rejection. Coraffin is a specific adsorber using two linear
peptide ligands mimicking epitopes of the b1-adrenergic
receptor, that bind corresponding autoantibodies from
patients suffering from idiopathic dilated cardiomyopathy.
Specific immunoadsorption has been shown to be benefi-
cial for patients with dilated cardiomyopathy. Coraffin can
be used as a new therapeutic option for these patients,
who get only limited benefit from medical therapy. Both
adsorbers may be combined with all approved apheresis
control devices available. Key Words: Apheresis—
Autoantibodies—Autoimmunity—Epitopes—Immuno-
globulins—Immunoadsorption—Protein-A.

Immunoadsorption (IA), the therapeutic removal vated risk for infections. Therefore, some therapy
of Ig from plasma, has been proven to be a useful protocols instruct the complementary administration
treatment option in several autoimmune disorders or of external Ig which is expensive and associated with
in renal transplant recipients. Among these, severe the risk for viral infections (6).
rheumatoid arthritis, systemic lupus erythematosus, In certain diseases, specific epitopes can be defined
acute renal transplant rejection, idiopathic dilated for the corresponding pathogenetic autoantibodies
cardiomyopathy (DCM), and idiopathic thrombocy- (7). Once identified, such epitopes can be used as a
topenia are the most prominent diseases (1–5). lead structure for the development of a specific pep-
Therapeutic IA has most commonly been carried tide ligand in an IA device that avoids the temporary
out using adsorbents on the basis of bacterial pro- humoral immunosuppression due to the removal of
tein-A or sheep antibodies directed to human immu- Ig.
noglobulin (Ig). Both ligands have to be purified Here we describe a new generation of adsorbents
from biological sources harboring potential infection for autoantibody elimination based on synthetic pep-
risks due to cross-contamination of the purified tides and their use in IA therapy. The adsorber
ligand. A synthetic adsorber should combine safety Coraffin is the first adsorber for specific removal of
advantages and an improved production technology. b1-adrenergic autoantibodies (b1-AAB) in DCM,
The working principle of most commercially whereas Globaffin is an adsorber for the removal of
adsorber types for the treatment of antibody-medi- Ig in antibody-mediated disorders in which a wide
ated autoimmune diseases is the removal of Ig in a spectrum of antibody reactivity is found, like rheu-
non-specific manner (1–4). The decreased concentra- matoid arthritis or acute renal transplant rejection.
tion of Ig after therapy results in a temporary ele-
GENERAL PRINCIPLES
Materials and structure
Received December 2002. Globaffin and Coraffin use the same construction
Address correspondence and reprint requests to Dr Roland
Brinckmann, Affina-Immuntechnik GmbH, Volmerstrasse 9, D- of the adsorber housing (Membrana GmbH, Wup-
12489 Berlin, Germany. Email: rbrinckmann@affina.de pertal, Germany, Fig. 1) and the same core technol-

91
92 W. RÖNSPECK ET AL.
3 sepharose CL-4B. The manufacturing of the adsorb-
4 ronmental conditions. The qualified sterilization
5 duction process.
2 The biocompatibility of both adsorbers developed
4 sensitization and hemocompatibility.
1
FIG. 1. General construction of Globaffin and Coraffin. The
adsorbers consist of a polycarbonate housing (1). The inward lying,
damp matrix (2) is held between two polyester sieves (3). A Luer-
lock connection (female) for the inlet and outlet (4) is found on
the adsorber lids. Both of these connections are provided with
tamper proof seals to realize a sterile and pyrogenic-free flow-
path. The filling nozzle is only used during the manufacturing
process (5).
ogy, but use two different working principals. Both
adsorber types are running with plasma controlled by
a plasma therapy device, but Globaffin, which binds
a wide spectrum of Ig, is designed as a regenerative
twin column system to repeatedly eliminate a large
amount of antibodies. Coraffin is designed as a single
column system to eliminate specific b1-AAB.
The polycarbonate housing of both adsorbers is
filled with peptide ligands immobilized to 60 mL of
cross-linked agarose (Sepharose CL-4B, Amersham
Pharmacia Biotech AB Upsala, Sweden) suspended
in the corresponding sterile storage solution,
10 mmol/L sodium citrate pH 4.0 (for Globaffin) or
0.9% NaCl (for Coraffin). The symmetrically built
adsorber housing has a volume of 67 mL, permitting
resuspension of the matrix due to the additional
space of 7 mL.
A Globaffin adsorber contains at least 250 mg of
the ligand peptide PGAM146. Coraffin, however,
has a lower peptide density due to its specific
interaction with antibodies via their antigen binding
site. The matrix of Coraffin contains at least 7.5 mg
of the ligand peptides PDCM349 and PDCM075,
respectively.
Manufacturing process
The peptide ligands are produced by the solid
phase synthesis using the Fmoc-strategy. After puri-
fication by reverse phase HPLC, they are coupled to
Ther Apher & Dial, Vol. 7, No. 1, 2003
the matrix via the cyanogen bromide activation of
ers is performed under controlled hygienic and envi-
process (121∞C, 15 min) of the assembled adsorbers
ensures the sterility assurance level of the products
based on the microbiological validation of the pro-
Biocompatibility
was proved according to the requirements of the ISO
10993 and the US-Pharmacopoeia, reflecting differ-
ent items such as the acute and subchronic toxicity,
REMOVAL OF IMMUNOGLOBULINS BY
GLOBAFFIN
Performance characteristics
Globaffin can be combined in principle with all
approved apheresis devices that operate a regenera-
tive twin column system. Currently, Globaffin is
approved in combination with the ADAsorb plasma
therapy device of medicap clinic GmbH (Ulrichstein,
Germany). The application scheme for Globaffin is
shown in Fig. 2. In principle, venous blood is drawn
from the patient, mixed with appropriate anticoagu-
lants, and subsequently separated into cells and
plasma by a blood cell separator device. Controlled
by the plasma therapy device, the plasma is passed
through the first column, while the second column is
purged and regenerated. The Ig-depleted plasma is
passed through a filter unit before it will be remixed
with the blood cells and reinfused to the patient.
Typically, 250 mL of plasma (corresponding to
about four column volumes) at a flow rate of about
20 mL/min is processed. The time necessary to regen-
NaCl Glycin
PBS
anticoagulation
0.9% HCl
blood cell plasma
separator
apheresis
control device
with
cells GLOBAFFIN
columns
filter
AB-depleted
plasma
waste
FIG. 2. Treatment scheme of Globaffin.
 PEPTIDES IN IMMUNOADSORPTION
kDa 1 2 3 4 5 6 7 The peptide shows competition with protein-A and
200
117
97
66
IgGH
45
31 IgGL
FIG. 3. Binding characteristics of the Globaffin matrix. Human
serum samples were loaded on columns filled with the respective
carrier capable of binding Ig. After washing the bound proteins
were eluted and prepared for subsequent separation by SDS poly-
acrylamide gel electrophoresis under reducing conditions and
stained with Coomassie blue. Lane 1, molecular mass markers;
lane 2, IgG; lane 3, human serum; lane 4, sepharose coupled with
antihuman-IgG from egg yolk; lane 5, sepharose coupled with
antihuman-IgG from sheep; lane 6, sepharose coupled with pro-
tein-A; lane 7, sepharose coupled with Ig-binding peptide; IgGH,
IgG-heavy chain; IgGL, IgG-light chain.
erate the second adsorber is adjusted to the resulting
plasma loading time of 12 min allowing an optimum
process management. The loading volume of 250 mL
plasma allows the system to operate at an optimum
ratio of column capacity and time consumption.
Using this adjustment, the adsorber operates at a
60% level of its maximum binding capacity of about
1.2 g Ig. However, according to the menu of the
plasma therapy device ADAsorb, the flow rates and
loading volumes can be varied individually.
A purging and regeneration cycle carried out by
the ADAsorb device consists of four steps: (i) the
replacement of residual plasma by 0.9% NaCl solu-
tion; (ii) the elution of bound Ig by glycine-HCl
buffer at pH 2.8; (iii) the neutralization by PBS; and
(iv) the replacement of PBS again by 0.9% NaCl
solution. The waste is collected via a separate outlet.
As a regenerative twin column system, Globaffin
can be used for multiple treatment sessions. There-
fore, at the end of each therapy session it is necessary
to rinse the adsorber with 0.01% sodium azide solu-
tion in PBS as preservative. The adsorber is stored in
the preservation solution at 2–8∞C until reuse.
As shown in Fig. 3, the peptide ligand PGAM146
of Globaffin coupled to a sepharose matrix shows
comparable binding characteristics as protein-A-
sepharose or chicken antibodies and sheep antibod-
ies directed to human IgG, respectively. The peptide
matrix is also capable of binding immune complexes,
IgA and IgM (data not shown). PGAM146 has been
tested for competition with known ligands for IgG.
93
protein-G suggesting that these ligands share at least
a part of a common binding site.
Clinical applications
Globaffin has been developed for the extracopo-
real treatment of antibody-mediated diseases, espe-
cially autoimmune diseases. Today, the superior
performance of IA over plasmapheresis is widely
accepted (2,8,9). Moreover, the reduction of plasma
components other than Ig, such as coagulation fac-
tors, albumin or hormones, is avoided by IA (10,11).
Globaffin binds IgG and immune complexes and to
a lesser extent IgA and IgM. In clinical practice the
elimination rates have been shown to depend of the
intensity of the treatment scheme as well as the
resynthesis and redistribution rate of the Ig (2,12).
The IA device Globaffin is generally applicable to
the disease states displayed in Table 1. One impor-
tant field for IA today is refractory autoimmune dis-
eases or diseases that can not adequately treated with
pharmacological immunosuppressants. Regarding
the heterogeneous individual courses of autoimmune
diseases, the therapy schemes for IA differ in clinical
practice. Therapy schemes are often adjusted accord-
ing to the clinical response or the course of autoan-
tibody levels (2,12,13).
In most reported studies an initial treatment block
(3–5 consecutive days) is carried out. The processed
plasma volume per day, usually is equivalent to 1.0–
1.5 of the patient’s plasma volume. In acute disease
states such as renal transplant rejection, Goodpas-
ture syndrome, rapidly progressive glomerular
nephritis or in the prophylactic perioperative Ig
depletion in presensitized renal transplant recipients,
a more intensive treatment equivalent to 2–3 plasma
volumes per daily session may be necessary and often
more than 20 therapy sessions are carried out in a
relatively short period (3,14–16).
In the therapy of chronic disorders the IA treat-
ment has to be carried out periodically repeating or
varying the initial treatment scheme according to the
individual disease course (2,13). Furthermore, IA
therapy has to be considered in the context of immu-
nosuppressive pharmacotherapy. In studies reported
for systemic lupus erythematosus and rheumatoid
arthritis IA has enabled a reduction and even a dis-
continuation of cytostatic therapy (1,2).
Immunoadsorption is a therapy with few side-
effects, the most frequent adverse events reported in
IA are related to the extracorporeal therapy in gen-
eral (1,2,10,17). During IA care should be taken for
the veins and for sensitizing reactions. Volume
effects, due to loss of plasma or infusion of saline
Ther Apher & Dial, Vol. 7, No. 1, 2003
94
TABLE 1. Clinical Applications for Immunoadsorption
Disease
Rheumatoid arthritis
Scleroderma
Systemic lupus erythematosus
Coagulation factor inhibitors
Idiopathic thrombocytopenic purpura
Cryoglobulinemia
Myasthenia gravis
Lambert–Eaton myasthenic syndrome
Bullous pemphigoid
Pemphigus vulgaris
Goodpasture’s syndrome
Rapidly progressive glomerulonephritis
Recurrent focal and segmental glomerulosclerosis
Renal transplant recipients
Renal transplant rejection
The indications for immunoadsorption were extensively reviewed in (5). The strongest evidence is usually given by controlled clinical
trials. For rare diseases, however, well documented uncontrolled trials were accepted for evidence. Recently, additional reports have been
published as indicated by the references. Tx, transplantation.
during therapy and plasma dilution are minimized by
the relatively small volume of the Globaffin adsorber
and automatic process control of the plasma therapy
device.
A potential risk due to the elimination of consid-
erable amounts of Ig is the temporary suppression of
the humoral immune system. Infections are rare
events, varying from 0 to about 1% of all treatment
sessions in studies (1,2,13,18). To overcome this dis-
advantage, in some trials intravenous Ig (IVIG)
preparations were given to the patients at the end of
an IA treatment block (18,19). Intravenous Ig is
applicable for prevention of infection and for
immune modulation in patients with autoimmune
diseases and bone marrow transplant recipients. A
controlled trial with bone marrow transplant recipi-
ents revealed that 0.25 mg IVIG per kg body mass
per week is sufficient to prevent infections (20).
However, currently no generally accepted dosage
recommendation exists for IVIG in combination
with IA.
The interaction of IA with the immune system still
remains unclear. But it has been shown that the ther-
apy can achieve long lasting improvements in
autoimmune hemophilia (21), rheumatoid arthritis
(22), lupus nephritis (2), and renal transplant rejec-
tion (3).
Immunoadsorption can influence antibody-pro-
ducing B-cells and the differentiation of several T-
cell subpopulations (23,24). The infiltration pattern
of lymphocytes is also changed after IA (25); how-
ever, these immunological findings have to be
extended by further investigations.
Ther Apher & Dial, Vol. 7, No. 1, 2003
W. RÖNSPECK ET AL.
Specification Reference
therapy refractory (5)
systemic, therapy refractory (5)
therapy refractory (13)
– (35)
– (5)
– (5)
therapy refractory (5)
– (5)
therapy refractory (36)
therapy refractory (37 38);
– (16)
– (5)
– (5)
donor specific alloantibody-positive, before Tx (14 15);
after Tx (3)
SPECIFIC IMMUNOADSORPTION BY
CORAFFIN IN DCM
Origin of the ligand
Coraffin has been developed on the basis of pep-
tide epitopes binding to b1-AAB, which are found in
patients suffering from idiopathic DCM (Fig. 4).
There is some evidence that b1-AAB are involved in
the development and progression of idiopathic DCM
(26). Coraffin contains two different peptide ligands.
Peptide PDCM349 is related to the extracellular loop
1 of the b1-adrenergic receptor and PDCM075 to the
extracellular loop 2. Sequence variation, that is sub-
stitution of cysteine by serine and N-terminal acety-
lation, resulted in a peptide which retained its
autoantibody-binding activity with improved stabil-
ity and purification characteristics (data not shown).
Performance characteristics
Coraffin is designed as a disposable single use
adsorber. A Coraffin set consists of five adsorbers
that are intended to be used in a treatment block of
five IA sessions on five consecutive days. In principle,
Coraffin can be combined principally with IA devices
approved for single use columns. Currently, the
ADAsorb plasma therapy device (medicap clinic
GmbH, Ulrichstein, Germany) is approved in com-
bination with Coraffin.
The application scheme for Coraffin is shown in
Fig. 5. Venous blood is drawn from the patient, mixed
with appropriate anticoagulants, and subsequently
separated into cells and plasma by a blood cell sepa-
rator. The plasma obtained is passed through the
 PEPTIDES IN IMMUNOADSORPTION
15
209
C S S
S
S
loop loop
1 C 131 2
cell
membrane I II III IV V VI
cytosol
FIG. 4. Origin of the peptide ligands of Coraffin. The b1-adrener-
gic receptor is a typical G-protein coupled receptor, consisting of
four extracellular and four intracellular domains and seven trans-
membrane helices. Functional active autoantibodies can only be
directed to the extracellular parts of the receptor. The epitopes of
the agonist-like autoantibodies of patients suffering from DCM
are directed to loop 1 and 2. Peptides containing the amino acid
residues 125–133 and 206–218 have been shown to compete with
the functional effect of the autoantibodies (34). Anti-peptide anti-
bodies raised in rabbits show a similar functional activity. The N-
terminal extracellular domain and the third extracellular loop
have no functional implication (34).
column. Then the plasma depleted for b1-AAB is
passed through a filter unit before it will be remixed
with the blood cells and reinfused to the patient.
Two additional steps are necessary when using
Coraffin: (i) rinsing the adsorber with 0.9% NaCl
solution prior to treatment; and (ii) replacement of
residual plasma by 0.9% NaCl solution at the end of
the treatment. Waste is collected via a separate out-
let.
During a treatment block the equivalent of a
patient’s plasma volume is processed per treatment
session. Using the recommended plasma flow rate of
20 mL/min, a treatment session will usually last about
4 h. However, according to the menu of the plasma
therapy device ADAsorb, the flow rates and loading
volumes can be varied individually.
Clinical applications
Coraffin has been developed for the treatment of
idiopathic DCM. This severe and progressive heart
disease is characterized by dilation of the left ventri-
cle and strongly reduced heart function. Although
there is some progress in pharmacotherapy, the mor-
tality among patients suffering from DCM is still
20–25% within a 5-year period (27,28). Dilated car-
diomyopathy accounts for about half of heart
transplantations.
Autoantibodies exhibiting an agonist-like effect
on the b1-adrenergic receptor are suggested to play a
95
pathophysiological role in DCM (26,29). From
immunological studies it has been assumed that these
NH2
b1-AAB are able to induce and maintain the course
of the disease (30).
C
C
215
216
According to the published clinical trials, about
200 patients with DCM were treated with IA (for
loop review see 31). In these trials, up to 90% of all Igs
3
were removed by the treatment. Usually, after 5 days
VII of treatment the level of b1-AAB has significantly
declined and their concentration did not raise during
post-treatment observation time of 1 year (4). These
trials also showed a significant improvement of car-
diac function as measured via left ventricular ejection
COOH
fraction and the left ventricular enddiastolic diame-
ter (4).
Corresponding to cardiac improvement following
IA, a significant reduction of leukocyte infiltration as
well as CD4+ and CD8+ lymphocyte infiltration was
observed in myocardial biopsies of patients 3 months
after IA (32). These results suggest that the removal
of Ig including the b1-AAB in patients with DCM
leads to an improvement in cardiac function and
causes a morphological regeneration of the myocar-
dium.
As already mentioned, the therapeutic method of
unspecific IA holds a temporary elevated risk for
infections due to the removal of all Ig. Coraffin
avoids this risk by the use of peptide ligands mimick-
ing the specific autoantibody binding sites in the b1-
adrenergic receptor. Recently, a pilot trial for specific
IA of b1-AAB in patients suffering from DCM using
a prototype of Coraffin has been completed success-
fully (33). After a treatment block of 5 days, the
patients were observed for 12 months. This treatment
showed the same effectivity for the removal of b1-
AAB as the case-controlled study of Müller et al. (4)
using an apheresis system that removes all types of
Ig (Fig. 6a). The b1-AAB levels did not rise again
NaCl
0.9%
anticoagulation
plasma
blood cell
separator
apheresis
control device
with
CORAFFIN
cells
column
filter
AB-depleted
plasma
waste
FIG. 5. Treatment scheme of Coraffin.
Ther Apher & Dial, Vol. 7, No. 1, 2003
96 W. RÖNSPECK ET AL.

(a) tion. Adsorber devices using synthetic peptide

7 ligands, like Globaffin and Coraffin have several
potential advantages over adsorbers using native
6
proteins. Globaffin and Coraffin are sterilized and
b1-receptor-AAB [LU]

5 avoid risks that may come from these proteins puri-

fied from biological sources. Globaffin can be used
4
for the treatment of diseases in which several patho-
3 physiologically relevant antigens exist or the antigen
is not sufficiently characterized, to justify the devel-
2
opment of a specific adsorber device. The design as
1 a regenerative twin column system enables the
removal of varying amounts of Ig and circulating
0
before after after after after after
immune complexes from the patient’s plasma.
IA 5 days 3 months 6 months 9 months 12 months There is great attraction of specific adsorbers if the
(b) antigen targeted by the autoantibodies is known as
50.0 in the case of idiopathic DCM. Agonist-like autoan-
p<0.001 p<0.05
tibodies directed to the b1-adrenergic receptor are
strongly suggested to be causally involved in the
40.0
pathogenesis as shown by immunological investiga-
tions (29), animal models (30) and human therapy
LVEF [%]

30.0
20.0
10.0
t=0 t=12 mo t=0 t=12 mo
control group unspecific IA
FIG. 6. Decline of autoantibodies and clinical response after spe-
cific immunoadsorption (IA) of b1-adrenergic autoantibodies.
Patients with idiopathic dilated cardiomyopathy (DCM), exhibit-
ing NYHA class II-III and left ventricular ejection fraction
(LVEF) £ 30%, were treated by IA for five consecutive days. (a)
The level of the b1-AAB was determined before the first IA,
immediately after the last IA at day 5, and at follow up as indi-
cated. The laboratory unit of the b1-AAB (LU) is defined as the
increase in number of cardiomyocyte beats per 15 s (± SEM). The
cut off limit of the bioassay has been determined at 2.5 LU
(dashed line). Closed circles, specific IA (N = 8); open rhombs,
non-specific IA (n = 17). (b) The LVEF was determined by
echocardiography immediately before the first IA and at follow
up as indicated. The LVEF is shown as percent of the left ventric-
ular volume of the heart ejected in systole (triangles ± SEM).
Patient groups: control treatment (n = 17), non-specific IA (n = 15),
specific IA (n = 8) (data from 4,33).
during the observation period and a significant
improvement of cardiac function was observed. No
statistically significant differences between the treat-
ment groups in both studies could be shown in the
left ventricular ejection fraction (Fig. 6b).
CONCLUSIONS
Immunoadsorption has been developed as a useful
therapeutic option in severe autoimmune diseases
and in the prevention of acute renal transplant rejec-
studies. Coraffin is the first specific adsorber for the
treatment of DCM on the market. It can be used to
remove b1-AAB without evoking a temporary
humoral immune suppression. The design as a spe-
cific adsorber for single use provides a better defense
to the risk of infections in the patients.
t=0 t=12 mo
Coraffin is a new treatment option for patients
specific IA suffering from idiopathic DCM. It shows a favorable
risk benefit relation and a relatively easy application
procedure.
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