The patent situation concerning the treatment of diseases associated with autoantibodies directed against G-protein-coupled receptors.

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The patent situation concerning the treatment of diseases associated with autoantibodies directed against G-protein-coupled receptors Annekathrin Haberland1*, Gerd Wallukat2 & Ingolf Schimke1 Agonist-like autoantibodies against receptors of the G-protein-coupled signal cascade have been identified as the pathogenic principle for a variety of diseases, especially those of the heart and vascular system. Consequently, the elimination or neutralization of such autoantibodies is an advised goal for causal therapeutic intervention. This article provides a short, noncomplete overview about remarkable developmental strategies and technical solutions for the therapy of diseases, associated with G-protein-coupled receptor autoantibodies. According to the immunoglobulin nature of the therapeutic target, several strategies are possible, such as the use of the autoantibody epitope sequences as competitors or binding molecules for specific autoantibody-elimination by apheresis. Complete immuno globulin elimination, as is currently being tested in autoantibodypositive cardiomyopathy patients, would be a nonspecific solution as would the use of immunosuppressant agents. The use of autoantibody-binding molecules on an aptamer basis for neutralization or elimination is a newly developed specific therapeutic option. G-protein-coupled receptor autoantibodies & their corresponding diseases

Antibodies that lack the tolerance to their own tissue and target structures of the native body are called autoantibodies and are a long known fact. One of the first studies to describe such autoimmune processes was that by Metalnikoff [1] , who observed and described autoantibodies against sperm as early as 1900. Further observations followed and were the subject of scientific discussion in the context of the actual doctrine of the disbelief in the occurrence of autoimmune reactions brought up by Paul Ehrlich’s theory of ‘horror autotoxicus’, questioning such conditions. This dispute and early steps of development in autoimmune cognition was fondly reviewed from a modern point of view by Silverstein in 2005 [2] . Since the time of Macfarlane Burnett (1899–1985) an increasingly accepted fact is that autoantibodies target proteins of their own body and initiate a self-destruction process, which results via different pathways in the pathologic decomposition of the affected protein, cell or tissue. However, a different type of autoantibody has also been discovered, which targets receptors and interacts with the receptor’s functionality. When the affected receptors belong to the class of receptors coupled with the G protein signal cascade, they are referred to as ‘G-protein-coupled receptor autoantibodies’. Such autoantibodies are currently assumed to dimerize two receptors in the activated condition and arrest the agonistic effect (Figure 1) , thereby circumventing the physiological counter-regulation mechanisms, such as receptor down-regulation [3] . The superfamily of G protein-receptors is the largest known gene-superfamily of humans to date, being classified into five families according to the glutamate,

10.4155/PPA.12.88 © 2013 Future Science Ltd

Pharm. Pat. Analyst (2013) 2(2), 231–248

Department of Medical Chemistry & Pathobiochemistry, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany 2 Max-Delbrück-Center for Molecular Medicine Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin, Germany *Author for correspondence: Tel.: +49 30 450 513147 E-mail: [email protected] 1

ISSN 2046-8954

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Haberland, Wallukat & Schimke

investigated by Unal et al. [6] would be the perfect explanation. It might also be a possible explanation for NH2 NH2 the observation that ischemic conditions, such as they occur under renal ischemia or during kidney Extracellular transplantation led to an multifold increase in AT1-receptor autoanCell tibody induced vascular contracmembrane tion, as it has been observed under Intracellular experimental conditions [8] . Investigations of receptor di- and oligo-merization [9] , as well as receptor polymorphisms will be an additional basis for future developCOOH COOH ment of more specific drugs as is G-protein already the case with the receptor COOH polymorphisms being the basis for Effect the developoment of bucindolol as β1-receptor autoantibody epitope regions: a polymorphism specific b-blocker Second exteracellular loop: RAESDEARRCYNDPKCCDFYTN (for review see [10]). IDCM: RAESDEARRCYNDPKCCDFYTN G-protein-coupled receptors are Chagas´ CM: RAESDEARRCYNDPKCCDFYTN Peripartum CM: RAESDEARRCYNDPKCCDFYTN involved in almost all regulations of the body; from the reception of senses to the regulation of cell Figure 1. Current theory of G-protein-coupled receptor-autoantibody-caused receptor movement and death. One class of activation by receptor dimerization. Autoantibody epitope regions of the second extracellular receptors is susceptible to neuro loop of the adrenergic b1-receptor, specific for different cardiomyopathy-types are identified. CM: Cardiomyopathy; IDCM: Idiopathic dilated cardiomyopathy. transmitters and hormone binding Reprinted with permission from [3]. © Elsevier B.V. (2012). and regulation. The extracellular domains of the seven transmemrhodopsin, adhesion, frizzled/taste2, and secretin brane receptor proteins are the targets of autoimmune (GRAFS) classification system [4] . A total of several recognition under certain conditions. Therefore, a hundred receptors are included, which are targets for variety of different G-protein- coupled receptor auapproximately 30% of all prescription drugs [4] or more toantibodies have been found at different pathologic than 50% of the drugs used in the treatment of chronic conditions, often connected with the heart and circudiseases [5] . Plentiful research has been implemented in latory system, and recently summarized by Xia and the last couple of years in order to further investigate Kellems [11] . and clarify the receptor structures and, especially, the A G-protein-coupled receptor autoantibody against mechanisms of receptor action on a molecular level, in- the adrenergic system was first discovered by Craig Vencluding the autoantibody effects on the receptors [5] . It ter et al. in 1980, who described an autoantibody that has, as such, recently been published by Unal et al. [6] targeted the adrenergic b2-receptor from the serum of for the AT1-receptor that a conserved disulfide bound patients suffering from allergic asthma and rhinitis [12] . between the second extracellular loop and the third Shortly after, Borda et al. described an autoantibody transmembrane domain of the receptor is an essential against the adrenergic b2-receptor in Latin-American controlling element in agonist and antagonist action. patients suffering from Chagas’ cardiomyopathy [13] , These new aspects have not only been the basis for referring to the discovery of the agonistic activity of improved drug development, they also delivered a ret- chagastic sera described in 1976 by Sterin-Borda [14] . rospective explanation for older observations that oxi- A related type of cardiomyopathy in western indusdative processes interfered with the agonistic receptor trial countries – idiopathic dilated cardiomyopathy response in a biphasic manner [7] . While early oxida- (IDCM) – has also been reported to be accompanied tive processes resulted in receptor activation, contin- to a high level by autoantibodies targeting either the ued oxidative stress reduced the receptor response. The first or the second loop of the adrenergic b1-receptor crucial role of an oxidation-sensitive disulfide bond in- [15] . This all occurred at a time when the autoimmune volved in the receptor response to the ligand binding as origin of the Graves’ disease, the auto antibodies

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Treatment of diseases associated with autoantibodies directed against G-protein-coupled receptors

against the TSH receptor, had already been discovered and described [16] . The clear proof of the causal pathologic activity of the autoantibodies has been shown for the b1-receptor autoantibody using animal experiments, either inducing the autoantibody generation by immunizing rabbits or rats with the autoantibody epitope sequences (sequence of the second extracellular loop of the adrenergic b1-receptor) [17,18] , or by transferring such generated autoantibodies to healthy animals and observing under all such constellations, the development of cardiac disturbances [18] . The direct transfer of lymphocytes of immunized rabbits to SCID mice, which caused pathologic consequences, was another example of proof in animals [19,20] . However, the causal relationship has also been demonstrated in humans. The elimination of autoantibodies from the serum of IDCM patients using highly autoantibody-specific apheresis columns resulted in a long-lasting therapeutic benefit showing the dominant role of autoantibodies in the persistence of the disease [21] . Autoantibodies against the adrenergic b1-, b2-, a1-, and the muscarinic M2-receptor are often found in patients with diseases showing cardiovascular involvement, such as IDCM, Chagas’ cardiomyopathy, peripartum cardiomyopathy, malign hypertension and pulmonary hypertension [3,11] , but also for Type II diabetes [22] , glaucoma [301] and Alzheimer’s disease [23] . Other such G-protein-coupled receptor autoantibodies target the angiotensin II AT1-receptor, which has been found to be strongly connected to kidney allograph rejection and preeclampsia [24,25] . The endothelin receptor, as a target for autoantibodies, has more recently been observed in pulmonary hypertension [26] while the well investigated autoantibodies against the TSH receptor, causing the Graves’ disease, have been known for a long time [11] . The trigger of such autoantibody production remains largely unknown. Only in rare cases, such as Chagas’ cardiomyopathy, has the origin been detected, where a molecular mimicry to a former parasite infection (Trypanosoma cruzi, Chagas’ disease) may be the trigger of autoantibody formation [27] . The occurrence of distinct structural criteria on the extracellular loops of the receptors is discussed to be a possible prerequisite for the stimulation of autoimmunity [5] . Current treatment strategies ■■ The epitope-peptide treatment strategy

While studying G-protein-coupled receptor autoantibodies, their IgG-subtype origin was characterized by scientists and the exact epitopes on the receptors were identified using epitope-mapping peptide-libraries [28,29] . As a result, it is known today that, as usually


Patent Review

observed with autoimmune reacKey terms tions, the exact epitopes of the G-protein-coupled receptor: targeted receptors are not exactly Characterized by seven identical in different patient subtransmembrane domains and types. This also holds true for carthree extracellular loops, (which are the targets for the G-proteindiomyopathies. Here, although b1coupled receptor autoantibodies), autantibodies target, for example, and three intracellular loops inthe second extracellular loop of the cluding the binding site for adrenergic b1-receptor, on a moG-proteins (guanine lecular level the exact epitopes are nucleotide-binding proteins). not always identical, but sometimes Epitope: Also known as antigenic slightly shifted on the peptide-loop determinant and is the part of an with different cardiomyopathy antigen that is recognized by the subtypes [3] (Figure 1) . antibodies. Despite this knowledge, it was Autoimmunity: Failure of the the first and very logical strategy for body to recognize its own parts a possible therapeutic interference, (protein, cell or tissue) as ‘self’ and to exploit the epitope sequences consequently produces an imfor competition (neutralization by mune response against this part. application) or the elimination of specific G-protein-receptor auto antibodies. Rönspeck et al. were one of the first groups to file peptide-sequences occurring from the autoantibody epitope of b1-autoantibodies from IDCM patients to be used for therapeutic and diagnostic use in 1999 [101] (Table I [101–192] , Rönspeck et al. [101,104–108,109–112] and Ogino et al. [113–116]), although this principle had already been applied to autoantibodies against the nicotinic acetylcholine receptor in 1993 [30] (Table I Takamori et al. [101] and Okumura et al. [103]). For a possible therapeutic application, the epitope-sequence-peptides protected by Rönspeck et al. [101] were to be used in the linear, or cyclized form for stability reasons, and amino acids substitutions were also supposed to be exploitable. Moreover, such epitope sequences were supposed to be used to specify apheresis technology, as already done using the epitope peptides of the acetylcholine receptor autoantibodies [30] , as well as to develop diagnostic tools. While the first example was successfully applied as described above [21] , exploiting the patent-based b1-autoantibody-specific apheresis column Coraffin® (Affina Immuntechnik GmbH), the use of the epitope sequences for diagnostic purposes has not reached the commercial level yet, for whatever reason and despite intensive endeavors in order to develop an assay. In parallel with the order of the detection and description of new G-protein-coupled receptor autoantibodies, the list of new patents protecting peptides or proteins of the epitope sequences for therapeutic and diagnostic purposes has been growing, as shown in Table I for the adrenergic a1-receptor [136–139,168–171] , AT1-receptor [140–146] , PAR-receptor [147–151] , muscarinic M2-receptor [161–163] , adrenergic b2-receptor [161–164] , TSH-receptor [172–185] and endothelin-receptor autoantibodies [186–192] .

Pharm. Pat. Analyst (2013) 2(2)

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234

Title

Applicant

Number

Filing date

Publication date

Peptide

Okumura S, Komai K, Satake R and Takamori M

Kuraray Co, Takamori and Masaharu

Kuraray Co., Takamori and Masaharu


Adsorbents for DCM

Ogino E, Furuyoshi S, Hirai F and Nishimoto T

AAB: Autoantibody; DCM: Dilated cardiomyopathy.

Peptide for combating the autoantibodies that are responsible for DCM

Peptides against autoantibodies elecited by DCM

Rönspeck W, Kunze R, Wallukat G and Dierenfeld M

Rönspeck W, Kunze R and Wallukat G

WO0076662 A1

US0120946 A1

Ogino Eiji, Furuyoshi Shigeo, Hirai Fumiyasu and Nishimoto Takehiro Kaneka Corp., Ogino Eiji, Furuyoshi Shigeo, Hirai Fumiyasu and Nishimoto Takehiro

EP1270030 A4 EP1270030 A1 US7309488

Kaneka Corp.

WO0021660 A1

Affina Immuntechnik GmbH, Rönspeck W, Kunze R, Wallukat G and Dierenfeld M

JP286554 A

EP1214350 B1 US6994970 B1

Fresenius Medical Care Affina

Kanegafuchi Chemical Ind.

KR102002047177 A

DE19945211 A1 DE19945210 A1 EP1086955 A1 EP1214350 A1 EP1086955 A1 EP1086954 A1

JP4029999 A

JP4193897 A

Affina Immuntechnik GmbH


DCM (DCM, AABs against first and second loop of the adrenergic b1-receptor)

Peptide

Takamori M, Okumura S, Tanihara M and Oka K

9 April 2001

15 November 2002

9 April 2001 9 April 2001 15 November 2001

7 April 2000

21 September 2000

21 September 2000 21 June 2002

20 March 2002

21 September 1999 21 September 1999 28 March 2001 21 September 2000 21 September 1999 21 September 1999

23 May 1990

27 November 1990

18 October 2001

24 June 2004

27 April 2005 2 January 2003 18 December 2007

16 October 2001

29 March 2001

6 September 2006 7 February 2006

21 June 2002

29 March 2001 29 March 2001 29 March 2001 29 June 2002 28 March 2001 28 March 2001

31 January 1992

13 July 1992

Myasthenia gravis (acetylcholine receptor-AABs). First-time protection of the therapeutic principle at an autoantibody against a nicotinic receptor)

Inventor

Table 1. List of a patent familly-protecting epitope peptides and proteins, for the diagnosis and treatment of autoantibody-associated diseases (autoantibodies against the nicotinic receptor and, especially, autoantibodies against G-protein-coupled receptors).

[118]

[117]

[116]

[115]

[114]

[113]

[112]

[111]

[110]

[109]

[101]

[108]

[107]

[106]

[105]

[104]

[103]

[102]

Ref.

Patent Review Haberland, Wallukat & Schimke


Title

Applicant


Mutant double cyclized receptor peptides inhibiting b1adrenoceptor antibodies

Nikolaev V, Lohse M, Jahns R and Jahns V


Novel peptidehomologues for inhibiting b1adrenoceptor antibodies.

Peptides of the a1adrenergic receptor and their use for psoriasis


Wallukat G

Psoriasis (adrenergic a1-receptor AABs)

Jahns R, Jahns V, Lohse M and Rackwitz H-R

Jahns R, Jahns V, Mutant double Lohse M and Nicolaev V cyclized receptor peptides inhibiting b1adrenoceptor antibodies

Means fort he inhibition of anti-b1-adrenergic receptor antibodies

Jahns R, Jahns V, Lohse M and Palm D

WO0103101 A2

Julius Maximilians Uni Würzburg, Jahns R, Jahns V, Lohse MJ and Palm D

AU200185707 DE10041560 A1 WO0016431 A3 WO0016431 A2

Max-Delbrück-Centrum für molekulare Medizin Max-Delbrück-Centrum für Molekulare Medizin and G Wallukat

WO0086337 A1

Julius Maximilians Uni Würzburg, Jahns R. Jahns V, Lohse MJ and Rackwitz H-R

WO0027063 A3 WO0027063 A2

Jahns R, Jahns V, Lohse MJ and Nikolaev V and Julius Maximilians Uni Würzburg

MX007882 A EP2391637 A1

US0209445 A1

Jahns R, Jahns V, Lohse MJ and Nikolaev V

Julius Maximilians Uni Würzburg

CN101835793 A CA2697108 A1 EP2391637 A1 EP2197900 A2


AU291296 A1

WO0103101 A3

Julius Maximilians Uni Würzburg, Jahns R, Jahns V, Lohse MJ and Palm D


AU2006228664 A1 CA2602763 A1 EP1866335 A2 US0215675 A1

Number


Cardiomyopathy (second loop of adrenergic b1-receptor AABs)

Inventor

23 August 2001

23 August 2001 24 August 2000 23 August 2001

27 January 2010

26 July 2011 27 January 2010

22 August 2008 22 August 2008

22 August 2008

22 August 2008 22 August 2008 27 January 2010 22 August 2008

22 August 2008

31 March 2006

31 March 2006

31 March 2006 31 March 2006 31 March 2006 31 March 2006

Filing date

28 February 2002

4 March 2002 7 March 2002 18 July 2002

5 August 2010

4 November 2011 7 December 2011

23 July 2009 5 March 2009

19 August 2010

15 September 2010 5 March 2009 7 December 2011 23 June 2010

5 March 2009

5 October 2006

1 February 2007

5 October 2006 5 October 2006 19 December 2007 27 August 2009

Publication date

Table 1. List of a patent familly-protecting epitope peptides and proteins, for the diagnosis and treatment of autoantibody-associated diseases (autoantibodies against the nicotinic receptor and, especially, autoantibodies against G-protein-coupled receptors) (cont.).

[139]

[138]

[137]

[136]

[135]

[134]

[133]

[132

[131]

[130]

[129]

[128]

[127]

[126]

[125]

[124]

[123]

[122]

[121]

[120]

[119]

Ref.


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235

236

Title

Applicant

Peptide of the AT1 receptor and their use for preeclampsia and malign hypertension

DE19954305 A1 AU2429100 A CA2363999 A1 EP1141018 A2 WO0039154 A8 WO0039154 A2 WO0039154 A3

Homuth V, Luft F, Wallukat G, Max Delbrück Centrum für Molekulare Medizin




Method for prognosis of pulmonary hypertension by detecting anti-PAR2antibodies

Heidecke H and Schulze-Förster K

CellTrend GmbH Heidecke H, Schulze-Förster K

CellTrend GmbH (Germany), Heidecke H and Schulze-Förster K

Method for prognosis of pulmonary arterial hypertension by detecting anti-PAR1antibodies

US0026396 A1

Harrer T and Wallukat G

Heidecke H and Schulze-Förster K

WO0067549 A3

Harrer T, Wallukat G, Max-DelbrückCentrum für Molekulare Medizin

WO0015380 A1

WO0015381 A1

WO0151847 A1

EP1597271 A2

Max-Delbrück-Centrum für Molekulare Medizin, Univ Friedrich Alexander

Autoantibody binding Max-Delbrück-Centrum für Molekulare peptides and their use for Medizin, Deutsches Herzzentrum Berlin, the treatment of vascular Wallukat G, Harrer T and Dandel M diseases

DE10311106 B4 DE10311106 A1

Max-Delbrück-Centrum für molekulare Medizin

Wallukat G, Harrer T and Dandel M

Wallukat G and Harrer T Peptides directed against antibodies, which cause cold-intolerance, and the use thereof

Number

Max-Delbrück-Centrum für Molekulare Medizin

Cold-intolerance autoantibodies, pulmonary arterial hypertension (PAR-receptor AABs)

Wallukat G, Homuth V and Luft F

Preeclampsia and malign hypertension (AT1-receptor AABs)

Inventor

4 August 2010

4 August 2010

13 June 2008

29 January 2004

29 January 2004

29 January 2004

6 March 2003 6 March 2003

22 December 1999 22 December 1999

11 November 1999 22 December 1999 22 December 1999 22 December 1999 22 December 1999

Filing date

10 February 2011

10 February 2011

18 December 2008

1 February 2007

7 October 2004

23 November 2005

5 May 2011 12 August 2004

6 July 2000 21 Sepember 2000

29 June 2000 31 July 2000 6 July 2000 10 October 2001 15 February 2001

Publication date


[154]

[153]

[152]

[151]

[150]

[149]

[148]

[147]

[146]

[145]

[144]

[143]

[142]

[141]

[140]

Ref.


Title

Applicant


Method for predicting CellTrend GmbH the risk of transplantation rejection and immunological testkit

Schulz-Förster-K and Heidecke H

EP1393076 B1 US8110374 B2

WO0093171 A2

DE10123929 A1

Number

Determination of agonistic autoantibodies associated with humoral kidney rejection

Max-Delbrück-Centrum für Molekulare Medizin


Peptides against Autoantibodies associated with CRPS and use of these peptides

WO0069570 A3 WO0069570 A2

Max-Delbrück-Centrum für Molekulare Medizin, Univ. Giessen Justus Liebig, Wallukat G and Blaes F

Fresenius Medical Care GmbH, Habermann M, Jünemann A, Kunze R, Max-Delbrück-Centrum für Molekulare Medizin, Schlötzer U, Univ. Friedrich Alexander, Voll R and Wallukat G

WO0101732 A1

EP2001899 A1 EP1832600 A1

EP2199305 A1

EP1890150 A1 US0023662 A1

Max-Delbrück-Centrum für Molekulare Medizin and Univ. Giessen Justus Liebig

Peptides against Fresenius Medical Care GmbH, Maxautoantibodies Delbrück-Centrum für Molekulare associated with glaucom Medizin and Univ. Friedrich Alexander and use of these peptides


Hermann M, Jünemann A, Kunze R, Schlötzer U, Voll R and Wallukat G

Glaucom (adrenergic b2-receptor AABs)

Wallukat G and Blaes F

Complex regional pain syndrome (adrenergic b2-receptor AABs, muscarinic M2-receptor AABs)

Wallukat G

Humoral kidney rejection (AT1-receptor AABs, peptides or protein sequences for AAB diagnostic and therapy)

CellTrend GmbH, Dechend R, Dragun D, Schulze-Förster K, Heidecke H, Müller D and Wallukat G

Method for predicting the risk of transplant rejection and immunological testkit

Dechend R, Dragun D, Schulze-Förster K, Heidecke H, Müller D and Wallukat G

CellTrend GmbH

Predicting risk of transplant rejection, by detecting autoantibodies of the AT1-receptor, also immunological testkit

Schulze-Förster K, Heidecke H, Dechend R, Dragun D, Müller D and Wallukat G

Humoral kidney rejection (AT1-receptor AABs, peptides or protein sequences for AAB diagnostic)

Inventor

9 March 2007

9 March 2007 9 March 2006


18 December 2008

28 November 2003 30 November 2007

13 May 2002 24 May 2004

13 May 2002

11 May 2001

Filing date

13 September 2007

17 December 2008 12 September 2007

12 August 2010 24 June 2010

23 June 2010

20 February 2008 22 January 2009

15 June 2005 7 February 2012

21 November 2002

21 November 2002

Publication date


[166]

[165]

[164]

[163]

[162]

[161]

[160]

[159]

[158]

[157]

[156]

[155]

Ref.


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238

Title


Peptides having binding affinity to an antibody which recognizes an epitope on an A1 loop 2 or b2 loop 1 of an adrenoceptor


Parmentier M, Libert F, Methode zur Dumont J and Vassart G quantitativen Bestimmung von Thyrotropin (TSH) oder anti-ThyrothropinRezeptor Autoantikörper (anti-TSHR) unter Verwendung eines rekombinannten thyrotropin Rezeptor polypeptides und Kit

Peptide for TSH-receptor AABs

Kunze R, Wallukat G, Rosenthal P and Straube R

Alzheimer disease (adrenergic a1-receptor AABs)

Glaucom (adrenergic b2-receptor AABs)

Inventor

AT143375 E DE69028695 T2

WO0090227 A3 WO0090227 A2

Max-Delbrück-Centrum für Molekulare Medizin, Kunze R, Wallukat G, Rosenthal P and Straube R B.R.A.H.M.S Diagnostica GmbH

US0104226 A1

EP2244718 A2

US0220469 A1

Number

Kunze R, Rosenthal P, Straube R and Wallukat G

Max-Delbrück-Centrum für Molekulare Medizin and Kunze R

Fresenius Medical Care GmbH, MaxDelbrück-Centrum für Molekulare Medizin and Univ. Friedrich Alexander

Applicant


15 January 2009 15 January 2009

15 January 2009

15 January 2009

9 March 2007

Filing date

15 October 1996 20 February 1997

4 February 2010 23 July 2009

5 May 2011

3 November 2010

3 September 2009

Publication date


[173]

[172]

[171]

[170]

[169]

[168]

[167]

Ref.



Title



US6228597 B1 EP458940 A1 EP433509 B1 EP433509 A3 EP433509 A2 WO0009121 A3 WO0009121 A2

Henning Berlin GmbH B.R.A.H.M.S Diagnostica GmbH Henning Berlin GmbH Chemie- und Pharmawerk

CA2046917 C

Parmentier M, Libert F, Dumont J and Vassart G B.R.A.H.M.S Diagnostica GmbH

AU641209 B

Henning Berlin GmbH

CA2046917 A1

AU7038691 A

Parmentier M

Henning Berlin GmbH Chemie

DE68927461 T2

Method for diagnosis of a disease involving an anti-endothelin-receptor antibody


Schulze-Förster K and Heidecke H

Number

B.R.A.H.M.S Diagnostica GmbH

Applicant

EP1884776 A1 EP2352032 A1 EP2057470 B1 EP2057467 B1 EP1884775 B1 US0075348 A1 WO0015219 A1

CellTrend GmbH

CellTrend GmbH, Schulze-Förster K and Heidecke H

Endothelin-receptor AABs, peptides or protein sequences for AAB diagnostic and therapy

Parmentier M, Libert F, Polypeptides having Dumont J and Vassart G thyrothropin-receptor activity, nucleic acid sequences coding for such receptors and polypeptides, and appliations of these polypeptides

Peptide for TSH-receptor AABs

Inventor

31 July 2007

4 August 2006 31 July 2007 31 July 2007 31 July 2007 4 August 2006 31 July 2007

14 December 1989 14 December 1989 12 December 1990 12 December 1990

14 December 1989

12 December 1990

15 October 1991

12 December 1990

12 December 1990

12 December 1990

12 December 1990

14 December 1989

Filing date

7 February 2008

6 February 2008 3 August 2011 11 July 2012 17 July 2011 6 January 2010 25 March 2010

24 July 24 1991 26 June 1991 19 September 1991 27 June 1991

13 November 1996

4 December 1991

8 May 2001

15 June 1991

1 July 2003

16 September 2003

18 July 1991

20 March 1997

Publication date


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Patent Review


As a straightforward development from the results of Rönspeck et al. [101] , a second patent appeared in 2006, which protects a cyclized sequence of the second extracellular loop of the adrenergic b1-receptor [124] . Based on this patent, a straightforward development of the protected cyclized epitope sequence for therapeutic neutralization purposes followed, resulting in a successfully completed Phase I trial of the innocuousness when applied to humans [302,31] . The sequence, supposedly a for cure heart failure patients positive for autoantibodies against the second extracellular loop of the adrenergic b1-receptor is currently under efficacy testing in a Phase II clinial trial [303] (see also Table I, Jahns et al. [119–124,126–129] and Nicolaev et al. [125]). A different method using the same strategy is the exploitation of genetically engineered peptides or protein sequences, as is the case with the autoantibody-epitope sequences of the TSH-receptor. Here, Parmentier et al. [172–185] had particularly protected sequences in the first line for diagnostic purposes, which could have also been used for therapy. This principle has also been exploited for the development of a diagnostic test, detecting the AT1-receptor autoantibodies in patients suffering from kidney transplant rejection (Table I ; Schulze-Förster et al. [155,157,158] and Dechend et al. [156]). A different specific principle is the exploitation of receptor blockers for the treatment of the diseases accompanied with autoantibodies against G‑protein-coupled receptors [193] . For some of the listed diseases such as heart failure, breceptor blockers have been part of a standard therapy protocol for a long time besides diuretics, angiotensinconverting enzyme inhibitors or angiotensin-receptor blockers and sometimes digoxin [32] . For more recently described G-protein-coupled receptor-autoantibodyassociated diseases, receptor blockers do not, however, belong to their standard therapy protocols. With respect to the heart failure, receptor blockers such as the selective b1-receptor blockers or the nonselective b-receptor blockers are not neglectable from the therapy process, since they have proven their beneficial effects in many trials [32] . However, Aso et al. did not see any influence on b-receptor autoantibody levels in their study investigating the relationship between anti-b1-receptor autoantibodies and myocardial sympathetic nerve activity in chronic heart failure, when comparing patients treated with or without a nonselective b blocker [33] . Here Unal et al. [5] clearly recommended the future co mbination of ‘selective antagonist treatment in addition to removal of the antibody’ as an ‘optimal treatment strategy’. ■■ Strategy of general immunosuppressive therapy

A different strategy for IDCM treatment was the nonspecific elimination of the autoantibodies simply

240

by a general immunoglobulin removal [194] , which is, of course, an object of ongoing endeavors for specification and improvement, as can be seen from the above-mentioned patent applications. The vaguely nonspecific removal of antibodies or antibody subfractions in autoimmune conditions had, however, already been thought of, as can be seen from the patents regarding the nonspecific immunoglobulin removal listed in Table 2 [193–240] (e.g., protein A column [214–220] , anti-human-IgG-column [221] , and tryptophan and phenylalanine column [222–240]). This nonspecific immunoglobulin removal has also been proven to be beneficial for IDCM patients [21] . In contrast with nonspecific immunoglobulin removal, the application of nonspecific immunoglobulins is a different treatment strategy, as it has already proven its beneficial effect in a variety of autoimmune disorders. The improvement of the clinical situation of IDCM patients after immunoglobulin application has been reported, but without seeing an immunoglobulincaused neutralization of the b1-receptor autoantibodies via an anti-idiotypic antibody [34] . An overview of the immunoglobulin therapy for cardiovascular diseases is given by Nussinovitch and Schoenfeld [35] . G-protein-coupled receptor autoantibodies are supposed to be present in the low titer range. A general immunosupressive therapy is possible, with the application of this knowledge, even enabling the application of immunosuppressors at a dosage that favors the benefits over the risks. The application of rituximab in order to destroy activated B cells would be one possible strategy, especially since it has already shown proven benefits in the therapy of rheumatoid arthritis and many other autoimmune diseases, which was reviewed by Virgolini and Marzocchi [36] . However, as intensively discussed by Sanz [37] , not all autoimmune diseases would benefit from rituximab. By investigating the success and failure of the therapy, it seems that the involvement of B-cell regulatory cells in autoimmune disorders is a crucial point. A reduced role of the B-cell regulatory cells, as it is supposed to be the case with rheumatoid arthritis, is discussed as a possible prerequisite for the therapeutic success. However, the use of rituximab for diseases accompanied with autoantibodies against G-protein-coupled receptors has only been documented for Graves’ disease, to the best of our knowledge, and little is known regarding the process of B cell maturation in most of those diseases. Therefore, research in this field is required. This could also hold true for other more recent drug developments in this direction, such as abatazept, belimumab and/or epratuzumab. With corticosteroids the situation is a little different. Corticosteroids belong to the standard therapy of some diseases that are reported to be accompanied



Title

Applicant


Use of antagonists of E R D E AAK Diagnostik GmbH, Kunze R, G-protein-coupled receptors Bimmler M, Hempel P and Lemke B

Peptides the production and use thereof for binding immunogloblins


Reinke P, Brehme S, Baumann G, Koll R, MüllerDerlich J, Felix S and Späthe R

Treatment of cardiomyopathy by removal of autoantibodies

Apheresis for dilated cardiomyopathy patients

Egner R, Winkler D, Rönspeck W and Kunze R

DE69632476 T2 EP862444 B1 EP862444 A1 JP504831 A

Edwards Lifesciences Corp., Reinke P, Brehme S, Baumann G and Felix S Baxter Int., Reinke P, Brehme S, Baumann G and Felix S

WO0038592 A3 WO0038592 A2

Affina Immuntechnik GmbH, Egner R, Winkler D, Rönspeck W and Kunze R

AU731452 B CA2236598 C CA2236598 A1

US7205382 B2


Baxter Int., Baumann G, Felix S, Reinke P and Brehme S

US0087765 A1

Rönspeck W, Egner R, Winkler D and Kunze R

AU1054097 A

EP1332158 A2


Baxter Int., Reinke P, Brehme S and Baumann G

EP1332158 B1


AT266415 E

AU17010 A AU1701002 A


Edwards Lifesciences Corp., Reinke P, Brehme S, Baumann G and Felix S

AT368688 E

WO0007348 A2

Number


Nonspecific means. Peptides for binding of immunoglobulins

Kunze R, Bimmler M, Hempel P and Lemke B

Therapeutic use of antagonists (receptor blockers)

Inventor



15 November 1996 15 November 1996 15 November 1996

15 November 1996

15 November 1996


8 August 2003

8 August 2003

8 November 2001

8 November 2001


8 November 2001

7 July 2008

Filing date

09 September 1998 12 February 2002

12 May 2005 12 May 2004

29 March 2001 12 September 2006 22, May 1997

05 June 1997

15 May 2004

23 January 2003 16 May 2002

17 April 2007

6 May 2004

6 August 2003

1 August 2007

21 May 2002 21 May 2002

15 August 2007

15 January 2009

Publication date

Table 2. List of receptor-blockers or nonspecific means for treatment of diseases associated with the occurrence of G-protein-coupled receptor autoantibodies, directed towards the autoantibodies.

[212]

[211]

[210]

[209]

[208]

[207]

[206]

[205]

[204]

[203]

[202]

[201]

[200]

[199]

[198]

[197]

[196]

[195]

[193]

Ref.


Patent Review

241

242

Title

WO0028680 A3 WO0028680 A2

Fresenius Medical Care, Fresenius Biotech GmbH, Hepper M, Leinebach HP and Nocken F


Onodera H Filter medium having a and Yoshida M limited surface negative charge for treating a blood material Asahi Medical Co. Ltd

Asahi Medical Co. Ltd

Ameliorating immunological Plasmaselect GmbH Teterow rejection of allograft

Phenylalanin, Tryptophan column

MüllerDerlich J, Koll R, Böhm W, Bieber F and Spaethe R

Antihuman immunoglobulin column

EP561379 B1 EP561379 A1 JP600743 1A JP6007430 A JP6007429 A US5407581 A

DE69319471 T2

US6030614 A

DE102006042012 A1 EP2077870 A2 US0166742 A1

Fresenius Medical Care and Fresenius Biotech GmbH

Hepper M, Leinebach HP and Nocken F

Method for promoting immunotherapies

US5733254 A

Jones F, Method for treating patients Cypress Bioscience Inc. Balint JP Jr and suffering from immune Snyder HW Jr thrombocytopenic purpurea

WO0017980 A1

Baxter Int., Reinke P, Brehme S and Baumann G US5782792 A

Method for treatment of rheumatoid arthritis

US7022322 B2

Number

Edwards Lifesciences Corp.

Applicant

Cypress Bioscience Inc.

Jones F, Snyder HW Jr and Balint JP Jr

Protein A column

Apheresis for dilated cardiomyopathy patients

Inventor

17 March 1993 17 March 1993 17 March 1993 17 March 1993 17 March 1993 17 March 1993

17 March 1993

16 April 1996

7 September 2007 7 September 2007

7 September 2006 7 September 2007 7 September 2007

1 May 1995

12 December 1994

15 November 1996

19 November 2002

Filing date

8 July 1998 22 September 1993 18 Januaryuary 1994 18 January 1994 18 January 1994 18 April 1995

15 April 1999

29 February 2000

12 June 2008 13 March 2008

27 March 2008 15 July 2009 1 July 2010

31 March 1998

21 July 1998

22 May 1997

4 April 2006

Publication date

Table 2. List of receptor-blockers or nonspecific means for treatment of diseases associated with the occurrence of G-protein-coupled receptor autoantibodies, directed towards the autoantibodies (cont.).


[228]

[227]

[226]

[225]

[224]

[223]

[222]

[221]

[220]

[219]

[218]

[217]

[216]

[215]

[214]

[194]

[213]

Ref.


Title


An adsorber module for whole blood treatment and an adsorber apparatus containing the adsorber module

Asahi Medical Co. Ltd.

Applicant AU3237489 A AU622442 B CA1325770 C CA1325770 A DE68910175 T3 DE68910175 T2 EP341413 B1 EP341413 A3 EP341413 A2 JP2814399 B2 JP2029260 A US5286449 A

Number 3 April 1989 3 April 1989 3 April 1989 3 April 1989 4 April 1989 4 April 1989 4 April 1989 4 April 1989 4 April 1989 29 March 1989 29 March 1989 27 May 1992

Filing date 5 October 1989 9 April 1992 4 January 1994 4 January 1994 1 March 2001 17 February 1994 27 October 1993 25 July 1990 15 November 1989 22 October 1998 31 January 1990 15 February 1994

Publication date

Title

Applicant


Aptamers that inhibit interaction between antibody and 2nd extracellular loop of human b1-adrenergic receptor

EP2402016 A1

WO0000889 A1

AptaRes AG, CharitéUniversitätsmedizin, Dahmen C, Haberland A, Kage A, Max Delbrück Centrum, Schimke I and Wallukat G

Schimke I, Haberland A and Wallukat G

Use of aptamers in therapy and/or diagnosis of autoimmune diseases

Number

AptaRes AG, CharitéUniversitätsmedizin and Max Delbrück Centrum

EP2497828 A1

WO0119938 A2

Charité-Universitätsmedizin and Max Delbrück Centrum

Charité-Universitätsmedizin, Haberland A, Max Delbrück Centrum, Schimke I and Wallukat G

Aptamers against G-protein coupled receptor-autoantibody-associated diseases

Dahmen C, Haberland A, Kage A, Schimke I and Wallukat G

Aptamers against b1-receptor autoantibody-associated diseases

Inventor

2 March 2012

7 March 2011

23 June 2011

29 June 2010

Filing date

13 September 2012

13 September 2012

5 January 2012

4 January 2012

Publication date

[244]

[243]

[242]

[241]

Ref.

[240]

[239]

[238]

[237]

[236]

[235]

[234]

[233]

[232]

[231]

[230]

[229]

Ref.

Table 3. List of a patent family protecting aptamers for the diagnosis and treatment of autoantibody-associated diseases (autoantibodies against the G-protein-coupled receptors).

Kuroda T and Tohma N

Phenylalanin, Tryptophan column

Inventor

Table 2. List of receptor-blockers or nonspecific means for treatment of diseases associated with the occurrence of G-protein-coupled receptor autoantibodies, directed towards the autoantibodies (cont.).


Patent Review

243

Patent Review


by G-protein-coupled receptor autoantibodies, as is Aptamers: Oligonucleotide the case with, for example, aptamers are short empirically psoriasis or scleroderma, alidentified oligonucleotide though this is often limited sequences that specifically bind to the inflammatory phases to their target molecules. in order to limit unwanted effects. In addition, success of the therapy is often below expectations. With respect to cardiomyopathies, Mason et al. tested the effect of immunosuppressive therapy (prednisone and azathioprime) on clinical outcome of myocarditis-caused dilated cardiomyopathy patients (DCM) in a controlled ‘Multicenter Myocarditis treatment trial’ [38] . These authors did not observe any benefit for the DCM patients from the immunosuppressive therapy. The different efforts in the investigation of the effects of glucocorticoids in the therapy of heart disease have recently been collated and have been discussed by Nussinovitch et al. [39] , without neglecting the view of the benefit–risk ratio. Key term

■■ The aptamer-based treatment strategy A recently published study suggests that a ptamers that

bind and neutralize G-protein-coupled receptor autoantibodies could offer a new treatment strategy for patients who are positive for these autoantibodies [40] . Aptamers, a new class of molecules that bind single molecules and ions, as well as more complex compounds such as peptides, proteins, subcellular structures and cells, are single- or double-stranded oligonucleotides. In vitro identified aptamers were first described in 1990 by Ellington and Szostak [41] and Tuerk and Gold [42] and soon became an interesting new tool in the biotech world as a result of their qualities with potential use as chemical binders (chemical antibodies). Soon after their detection, Lee and Sullenger selected aptamers that were able to bind and neutralize the activity of pathogenic autoantibodies, against the insulin receptor and against the acetylcholine receptor [43,44] . With these studies, the technology has been proven to be exploitable for autoantibodies. With respect to the G-protein-coupled receptor autoantibodies involved in cardiovascular diseases (patents listed in Table 3 [241–244]), we first detected and patented: a highly specific aptamer (aptamer 111), which was only able to specifically bind and neutralize b1autoantibodies against the second loop found in DCM patients; and a second aptamer (aptamer 110), showing a wider efficacy. Aptamer 110 is able to neutralize b1-autoantibodies from DCM, Chagas’ cardiomyopathy and peripartum cardiomyopathy patients, even though the b1-autoantibodies of the different medical conditions recognize different epitopes on the second

244

extracellular loop (see also Figure 1). However, Aptamer 110 did not affect other b1-autoantibodies directed against the first extracellular loop of the b1-receptor or completely different G-protein-coupled receptor autoantibodies [242] . With the discovery of an aptamer, which, without knowing its exact binding, can actually bind and neutralize all of the G-protein-coupled receptor autoantibodies that have been tested to date [244] , and showing a lower affinity to a pool fraction of IgG3 and IgG4 and no affinity to IgG2 and IgG1 [243] , the concept of aptamers for the treatment of diseases positive for G-protein-coupled receptor autoantibodies has been opened for a future in vivo validation. In this context, aptamers can be used as antibodyspecific binders in apheresis technology which has already been tested in a ‘proof-of-concept study’ u sing G-protein-coupled receptor autoantibodypositive rats [45] and also for the in vivo neutralization of the autoantibodies. With respect to this, the so far described aptamers present a clearly individual treatment profile. The aptamers 110 and 111 are directed exclusively to b1-autoantibodies and, therefore, consequently for treatment of patients who are predominantly affected by those autoantibodies, such as those with DCM and peripartum cardiomyopathy. In contrast, an aptamer which can bind and neutralize the class of pathogen G-protein-coupled receptor autoantibodies should find its indication in patients suffering from diseases associated with a pool of different G-protein-coupled receptor autoantibodies, as it is the case with Chagas’ cardiomyopathy [46] or pulmonary hypertension [26] . Furthermore, this multipotent aptamer offers a treatment strategy of ‘one aptamer for different diseases with different G-protein-coupled receptor autoantibodies’, which could be preferred for the commercialization of aptamer-based treatments in diseases presenting with pathogenic autoantibodies directed against G‑protein‑coupled receptors. Future perspective

The steadily growing evidence of the pathogenic role of G-protein-coupled receptor autoantibodies in the pathogenesis of a variety of severe diseases is the basis of increasing endeavors and activities at the treatment level, including different approach strategies. Different treatment strategies are necessary due to the different phenotypic appearances of diseases such as Chagas’ cadiomyopathy or peripartum cardiomyopathy, affecting either adults or pregnant women, or in kidney allograft rejection, which is a very special clinical condition, just to demonstrate a few. The current line of general treatment strategies includes the in vivo neutralization or elimination of




autoantibodies via apheresis technology. While the first is still in the process of development referring to different neutralization molecules (peptides or aptamers), the second strategy, elimination, has already been introduced into clinics, although its use has been limited, despite its success. Here, again, a specification of the apheresis columns via peptides or aptamers is a future target for further developments. Presently, at such early state of specific drug and therapy development for diseases accompanied with G-protein-coupled receptor autoantibodies, nothing can be said about the general outcome, as of yet.

Patent Review

Financial & competing interests disclosure The authors acknowledge support from the ‘European Regional Development Fund’ (10141685, Berlin, Germany) and the ‘Deutsche Gesellschaft für Klinische Chemie und Laboratoriumsmedizin’ (48/2011). A Haberland, G Wallukat and I Schimke do research in this field in public research institutions and are inventors of some of the listed patents. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Executive summary A brief overview of the history & function of G-protein-coupled receptor autoantibodies & their corresponding diseases The identification of the involvement of pathogenic autoantibodies against receptors of the G-protein signal cascade (G-proteinreceptors) in cardiomypathies and allergic asthma was implemented in the 1980’s, discovering the autoantibodies against the adrenergic b1- b2 and the muscarinic M2 receptor, already knowing the autoantibodies against the thyroid stimulating hormone receptor, causing the Graves’ disease. Since then, numerous other G-protein-coupled receptor autoantibodies in different diseases have been detected and described. The pathogenic significance of such autoantibodies has been proven at the animal level, exploiting different models but also with humans. Current treatment strategies Strategy of general immunosuppressive therapy The specific removal of b1-autoantibodies by apheresis therapy (also called immunoadsorption) in dilated cardiomyopathy patients caused a very long-lasting beneficial effect. In order to circumvent specificity bottlenecks with respect to the great number of autoantibodies of this class, alternative developments (e.g., the general immunosupression) are also under testing. The epitope–peptide treatment strategy In order to develop easy applicable therapeutic alternatives to the apheresis therapy for the neutralization of the autoantibody activity, specific epitope competing peptides are under development – one such peptide, Cor-1, currently in Phase II clinical trials. The aptamer-based treatment strategy More specific than general immunosupression but not as specific as the epitope peptide might be the exploitation of a new class of binding molecules, the aptamers, being the basis for the development of binding molecules recognizing autoantibodies of the same group, showing epitope variability. Out of this aptamer-binder molecule class, one molecule has recently been identified that binds all presently tested autoantibodies against G-protein-coupled receptors. Future in vivo therapeutic experiments will evaluate its curative potential. target family. ChemMedChem. 1 (8), 760–782 (2006).

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Discovery of pathogenic autoantibodies against G-protein-coupled receptors.

23 Karczewski P, Hempel P, Kunze R, Bimmler M. Agonistic autoantibodies to the a(1) -adrenergic receptor and the b(2) -adrenergic receptor in Alzheimer’s and vascular dementia. Scand. J. Immunol. 75(5), 524–530 (2012).

n n

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Proof of the pathogenic activity of autoantibodies against G-protein-receptors, while inducing the autoantibodies and with it the disease in animals.

18 Jahns R, Boivin V, Hein L et al. Direct evidence for a beta 1-adrenergic receptordirected autoimmune attack as a cause of idiopathic dilated cardiomyopathy. J. Clin. Invest. 113(10), 1419–1429 (2004). 19 Matsui S, Fu M, Hayase M et al. Transfer of immune components from rabbit autoimmune cardiomyopathy into severe combined immunodeficiency (SCID) mice induces cardiomyopathic changes. Autoimmunity 39(2), 121–128 (2006). 20 Matsui S, Fu M, Hayase M et al. Transfer of rabbit autoimmune cardiomyopathy into severe combined immunodeficiency mice. J. Cardiovasc. Pharmacol. 42(Suppl. 1), S99–103 (2003). 21 Dandel M, Wallukat G, Englert A, Lehmkuhl HB, Knosalla C, Hetzer R. Long-term benefits of immunoadsorption in β1-adrenoceptor autoantibody-positive transplant candidates with dilated cardiomyopathy. Eur. J. Heart Fail. 14. [Epub ahead of print] (2012). n n

Valuable retrospective study on the impact of the autoantibody removal on patients condition.

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24 Dragun D, Philippe A, Catar R, Hegener B. Autoimmune mediated G-protein receptor activities in cardiovascular and renal pathologies. Thromb. Haemost. 101(4), 643–648 (2009). 25 Wallukat G, Homuth V, Fischer T et al. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J. Clin. Invest. 103(7), 945–952 (1999). 26 Dandel M, Wallukat G, Lehmkul HB, Englert A, Hetzer R. Autoantibodies against endothelin-1 receptors are involved in the pathogenesis of pulmonary arterial hypertension. Circulation 120(18, Suppl. 2), S1134 (2009). 27 Ferrari I, Levin MJ, Wallukat G et al. Molecular mimicry between the immunodominant ribosomal protein P0 of Trypanosoma cruzi and a functional epitope on the human beta 1-adrenergic receptor. J. Exp. Med. 182(1), 59–65 (1995). 28 Magnusson Y, Marullo S, Hoyer S et al. Mapping of a functional autoimmune epitope on the beta 1-adrenergic receptor in patients with idiopathic dilated cardiomyopathy. J. Clin. Invest. 86(5), 1658–1663 (1990). 29 Wallukat G, Wollenberger A, Morwinski R, Pitschner HF. Anti-beta 1-adrenoceptor autoantibodies with chronotropic activity from the serum of patients with dilated cardiomyopathy: mapping of epitopes in the first and second extracellular loops. J. Mol. Cell. Cardiol. 27(1), 397–406 (1995). 30 Nakaji S, Oka K, Tanihara M, Takakura K, Takamori M. Development of a specific immunoadsorbent containing immobilized synthetic peptide of acetylcholine receptor for treatment of myasthenia gravis. Ther. Apher. 4(2), 124–126 (2000). 31 Münch G, Boivin-Jahns V, Holthoff HP et al. Administration of the cyclic peptide COR-1 in humans (Phase I study): ex vivo measurements of anti- b1-adrenergic receptor antibody neutralization and of immune parameters. Eur. J. Heart Fail. 14(11), 1230– 1239 (2012). 32 Hunt SA, Abraham WT, Chin MH et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice


Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 119(14), e391–e479 (2009). 33 Aso S, Yazaki Y, Kasai H et al. Anti-beta 1-adrenoreceptor autoantibodies and myocardial sympathetic nerve activity in chronic heart failure. Int. J. Cardiol. 131(2), 240–245 (2009). 34 Larsson L, Mobini R, Aukrust P et al. Beneficial effect on cardiac function by intravenous immunoglobulin treatment in patients with dilated cardiomyopathy is not due to neutralization of anti-receptor autoantibody. Autoimmunity 37(6–7), 489–493 (2004). 35 Nussinovitch U, Shoenfeld Y. Intravenous immunoglobulin - indications and mechanisms in cardiovascular diseases. Autoimmun. Rev. (6), 445–452 (2008). 36 Viirgolini L, Marzocchi V. Rituximab in autoimmune diseases. Biomed. Pharmacotherapy 58(5), 299–309 (2004). n

Comprehensive review on the use of Rituximab in autoimmune diseases.

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Valuable review on the current knowledge of Rituximab action in autoimmune diseases.

38 Mason JW, O’Connell JB, Herskowitz A et al. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N. Engl. J. Med. 333(5), 269–275 (1995). 39 Nussinovitch U, de Carvalho JF, Pereira RM, Shoenfeld Y. Glucocorticoids and the cardiovascular system: state of the art. Curr. Pharm. Des. 16(32), 3574–3585 (2010). 40 Haberland A, Wallukat G, Dahmen C, Kage A, Schimke I. Aptamer neutralization of beta1adrenergic receptor autoantibodies isolated from patients with cardiomyopathies. Cir. Res. 109(9), 986–992 (2011). 41 Ellington AD, Szostak JW. In vitro selection of RNA molecules that bind specific ligands. Nature 346(6287), 818–822 (1990). 42 Tuerk C, Gold L. Systemic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249(4968), 505–510 (1990). 43 Lee SW, Sullenger BA. Isolation of a nucleaseresistant decoy RNA that selectively blocks autoantibody binding to insulin receptors on human lymphocytes. J. Exp. Med. 184(2), 315–324 (1996). n

One of the first selections of an aptamer against an autoantibody.

44 Lee SW, Sullenger BA. Isolation of a nucleaseresistant decoy RNA that can protect human acetylcholine receptors from myasthenic antibodies. Nat. Biotechnol. 15(1), 41–45 (1997).



45 Wallukat G, Haberland A, Berg S et al. The first aptamer-apheresis column specifically for clearing blood of β1-receptor autoantibodies. Circ. J. 76(10), 2449–2455 (2012). 46 Wallukat G, Muñoz Saravia SG, Haberland A et al. Distinct patterns of autoantibodies against G-protein-coupled receptors in Chagas’ cardiomyopathy and megacolon. Their potential impact for early risk assessment in asymptomatic Chagas’ patients. J. Am. Coll. Cardiol. 55(5), 463–468 (2010).

■■ Patents 101 Affina Immuntechnik GmbH: EP1086954 A1 (2001). n

The first use of the therapeutic principle of autoantibody-epitope petides for the therapy of autoimmune-associated dilated cardiomyopathy.

102 Kuraray Co, Takamori M:JP4193897 A (1992). 103 Kuraray Co, Takamori M:JP4029999 A (1992). 104 Affina Immuntechnik GmbH: DE19945211 A1 (2001). 105 Affina Immuntechnik GmbH: DE19945210 A1 (2001). 106 Affina Immuntechnik GmbH: EP1086955 A1 (2001).

123 Julius Maximilians Uni Würzburg, Jahns R, Jahns V, Lohse MJ, Palm D: WO0010310 A3 (2006).

149 Max-Delbrück-Centrum für molekulare Medizin, Univ Friedrich Alexander: EP1597271 A2 (2005).

124 Jahns R, Jahns V, Lohse MJ. Palm D, Julius Maximilians Uni Würzburg: WO0103101 A2 (2006).

150 Harrer T, Wallukat G, Max-DelbrückCentrum für Molekulare Medizin: WO0067549 A3 (2004).

125 Julius Maximilians Uni Würzburg: AU291296 A1(2009).

151 Harrer T, Wallukat G: US0026396 A1 (2007).

126 Julius Maximilians Uni Würzburg: CN101835793 A (2010). 127 Julius Maximilians Uni Würzburg: CA2697108 A1 (2009).

152 Max-Delbrück-Centrum für Molekulare Medizin, Deutsches Herzzentrum Berlin, Wallukat G, Harrer T, Dandel M: WO0151847 A1 (2008).

128 Julius Maximilians Uni Würzburg: EP2391637 A1 (2011).

153 CellTrend GmbH, Heidecke H, SchulzeFörster K: WO0015381 A1 (2011).


154 CellTrend GmbH, Heidecke H, SchulzeFörster K: WO0015380 A1 (2011).

130 Jahns R, Jahns V, Lohse MJ, Nikolaev V: US0209445 A1 (2010).

155 CellTrend GmbH: DE10123929 A1 (2002).

131 Jahns R, Jahns V, Lohse MJ,Nikolaev V, Julius Maximilians Uni Würzburg : WO0027063 A3 (2009).

133 Julius Maximilians Uni Würzburg: MX007882 A (2011).

160 Max-Delbrück-Centrum für Molekulare Medizin: US0023662 A1 (2009).


161 Max-Delbrück-Centrum für Molekulare Medizin, Univ. Giessen Justus Liebig: EP2199305 A1 (2010).

108 Affina Immuntechnik GmbH: EP1086955 A1 (2001).

136 Max-Delbrück-Centrum für molekulare Medizin: AU85707 (2001).

109 Affina Immuntechnik GmbH: KR102002047177 A (2002).

137 Max-Delbrück-Centrum für molekulare Medizin: DE10041560 A1 (2002).

110 Fresenius Medical Care Affina: EP1214350 (2006).

138 Max-Delbrück-Centrum für molekulare Medizin: WO0016431 A3 (2002).

111 Fresenius Medical Care Affina: US6994970 (2006).

139 Max-Delbrück-Centrum für molekulare Medizin, Wallukat G: WO0016431 A2 (2002).

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Patent Review

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