BC-007

Last updated

BC-007
INN: Rovunaptabin
BC-007.svg
Clinical data
Other names
  • ARC183, ARC-183
  • BC007, BC-007
  • GS522, GS-522
  • G15D
  • HD1
  • HTQ
  • ODN-1
  • TBA
  • d(GGTTGGTGTGGTTGG)
  • 5'-GGTTGGTGTGGTTGG-3'
Routes of
administration 		Infusion
Pharmacokinetic data
Elimination half-life 2.9-11 min
Identifiers
  • [(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-(hydroxymethyl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl] [(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3-phosphonooxyoxolan-2-yl]methyl hydrogen phosphate
CAS Number
PubChem CID
PubChemSID
DrugBank
ChEBI
Chemical and physical data
Formula C150H188N57O97P15
Molar mass 4806.062 g·mol−1
3D model (JSmol)
  • OC[C@H]1O[C@@H](N2C=3N=C(NC(C3N=C2)=O)N)C[C@@H]1OP(OC[C@H]4O[C@@H](N5C=6N=C(NC(C6N=C5)=O)N)C[C@@H]4OP(OC[C@H]7O[C@@H](N8C=C(C(NC8=O)=O)C)C[C@@H]7OP(OC[C@H]9O[C@@H](N%10C=C(C(NC%10=O)=O)C)C[C@@H]9OP(OC[C@H]%11O[C@@H](N%12C=%13N=C(NC(C%13N=C%12)=O)N)C[C@@H]%11OP(OC[C@H]%14O[C@@H](N%15C=%16N=C(NC(C%16N=C%15)=O)N)C[C@@H]%14OP(OC[C@H]%17O[C@@H](N%18C=C(C(NC%18=O)=O)C)C[C@@H]%17OP(OC[C@H]%19O[C@@H](N%20C=%21N=C(NC(C%21N=C%20)=O)N)C[C@@H]%19OP(OC[C@H]%22O[C@@H](N%23C=C(C(NC%23=O)=O)C)C[C@@H]%22OP(OC[C@H]%24O[C@@H](N%25C=%26N=C(NC(C%26N=C%25)=O)N)C[C@@H]%24OP(OC[C@H]%27O[C@@H](N%28C=%29N=C(NC(C%29N=C%28)=O)N)C[C@@H]%27OP(OC[C@H]%30O[C@@H](N%31C=C(C(NC%31=O)=O)C)C[C@@H]%30OP(OC[C@H]%32O[C@@H](N%33C=C(C(NC%33=O)=O)C)C[C@@H]%32OP(OC[C@H]%34O[C@@H](N%35C=%36N=C(NC(C%36N=C%35)=O)N)C[C@@H]%34OP(OC[C@H]%37O[C@@H](N%38C=%39N=C(NC(C%39N=C%38)=O)N)C[C@@H]%37OP(O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O
  • InChI=InChI=1S/C150H188N57O97P15/c1-52-22-193(145(224)187-121(52)209)88-9-60(77(278-88)32-265-314(249,250)299-66-15-96(201-45-162-105-114(201)171-138(153)180-129(105)217)283-81(66)36-262-306(233,234)291-58-7-94(275-73(58)28-208)199-43-160-103-112(199)169-136(151)178-127(103)215)292-308(237,238)264-31-76-63(12-91(277-76)196-25-55(4)124(212)190-148(196)227)295-311(243,244)271-39-84-71(20-101(286-84)206-50-167-110-119(206)176-143(158)185-134(110)222)303-318(257,258)274-42-87-70(19-100(289-87)205-49-166-109-118(205)175-142(157)184-133(109)221)302-317(255,256)268-35-80-64(13-92(281-80)197-26-56(5)125(213)191-149(197)228)296-312(245,246)270-38-83-68(17-98(285-83)203-47-164-107-116(203)173-140(155)182-131(107)219)300-315(251,252)267-34-79-65(14-93(280-79)198-27-57(6)126(214)192-150(198)229)297-313(247,248)272-40-85-72(21-102(287-85)207-51-168-111-120(207)177-144(159)186-135(111)223)304-319(259,260)273-41-86-69(18-99(288-86)204-48-165-108-117(204)174-141(156)183-132(108)220)301-316(253,254)266-33-78-61(10-89(279-78)194-23-53(2)122(210)188-146(194)225)293-309(239,240)263-30-75-62(11-90(276-75)195-24-54(3)123(211)189-147(195)226)294-310(241,242)269-37-82-67(16-97(284-82)202-46-163-106-115(202)172-139(154)181-130(106)218)298-307(235,236)261-29-74-59(290-305(230,231)232)8-95(282-74)200-44-161-104-113(200)170-137(152)179-128(104)216/h22-27,43-51,58-102,208H,7-21,28-42H2,1-6H3,(H,233,234)(H,235,236)(H,237,238)(H,239,240)(H,241,242)(H,243,244)(H,245,246)(H,247,248)(H,249,250)(H,251,252)(H,253,254)(H,255,256)(H,257,258)(H,259,260)(H,187,209,224)(H,188,210,225)(H,189,211,226)(H,190,212,227)(H,191,213,228)(H,192,214,229)(H2,230,231,232)(H3,151,169,178,215)(H3,152,170,179,216)(H3,153,171,180,217)(H3,154,172,181,218)(H3,155,173,182,219)(H3,156,174,183,220)(H3,157,175,184,221)(H3,158,176,185,222)(H3,159,177,186,223)/t58-,59-,60-,61-,62-,63-,64-,65-,66-,67-,68-,69-,70-,71-,72-,73+,74+,75+,76+,77+,78+,79+,80+,81+,82+,83+,84+,85+,86+,87+,88+,89+,90+,91+,92+,93+,94+,95+,96+,97+,98+,99+,100+,101+,102+/m0/s1 "CHEBI:140487 - 5'-GGTTGGTGTGGTTGG-3'". ChEBI. European Bioinformatics Institute. 2018-04-11. Retrieved 2023-05-31.
  • Key:LADFAOKPINUFBB-TWPNXFTKSA-N

BC-007, whose international nonproprietary name is Rovunaptabin, [1] is an oligonucleotide aptamer, a synthetic DNA compound designed to bind other chemicals. [2] BC-007 is in early-stage clinical trials as a lead compound intended for the potential treatment of heart failure or long COVID.

Contents

History

Since the 1990s, the binding of G protein coupled receptors to autoantibodies (GPCR-AABs) was investigated as a possible factor in the pathology of several diseases, including heart disease. [3] [4] In parallel, treatment strategies to remove GPCR-AABs were investigated, initially using proteins or peptides to bind the antibodies. [5] [6]

In 2012, scientists from the Max Delbrück Center and the Charité Heart Center obtained a patent in the United States for using aptamers as a therapy or diagnosis of autoimmune diseases. [7] Beginning in 2013, the research group focused on the treatment of dilated cardiomyopathy in people positive for beta-1 adrenergic receptor autoantibodies. [8] [9] In 2015–16, scientists reported that two aptamers might bind and inhibit GPCR-AABs. [10] [11]

The biotechnology company Berlin Cures pursued the development of the aptamer with the nucleotide sequence GGT TGG TGT GGT TGG under the codename BC-007 for the inhibition of autoantibodies in cardiomyopathy. [12]

Properties

BC-007 is a 15-nucleotide single-stranded DNA molecule consisting of nine unmodified deoxy-guanosines and six corresponding deoxythymidines with the sequence 5'-GGT TGG TGT GGT TGG-3'. [2] Its three-dimensional structure allows it to wrap around the target structure of G-protein-coupled receptor autoantibodies and neutralize their activity. [2]

BC-007 is synthetic, enabling it to be produced in high volumes quickly. [13] It is stable and suited for long-term storage. [13] It has shown no side effects in early clinical studies, and does not trigger immunological responses. [2] [13] As it is water soluble, it can be formulated as inhalation or as nasal spray. [13] In some human studies, it was given by intravenous infusion, displaying an in vivo half-life in blood of about 4 minutes. [2]

Research

Heart failure

The removal of pathogenic functional autoantibodies through a medical blood purification procedure, known as immunoadsorption, can stabilize heart function in people with dilated cardiomyopathy who are awaiting heart transplantation. [14] [15] In 2018, a Phase I clinical trial found that BC-007 was well-tolerated, with no serious adverse events reported. [2] [12] Phase IIa trials demonstrated that BC-007 could neutralize the activity of functional autoantibodies in most subjects treated. [16]

Long COVID

BC-007 is under investigation as a possible agent for treating disorders of long COVID. [17]

Related Research Articles

<span class="mw-page-title-main">G protein-coupled receptor</span> Class of cell surface receptors coupled to G-protein-associated intracellular signaling

G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. They are coupled with G proteins. They pass through the cell membrane seven times in the form of six loops of amino acid residues, which is why they are sometimes referred to as seven-transmembrane receptors. Ligands can bind either to the extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists, although a spontaneous auto-activation of an empty receptor has also been observed.

<span class="mw-page-title-main">Adrenergic receptor</span> Class of G protein-coupled receptors

The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta blockers, beta-2 (β2) agonists and alpha-2 (α2) agonists, which are used to treat high blood pressure and asthma, for example.

<span class="mw-page-title-main">Arrhythmogenic cardiomyopathy</span> Medical condition

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease.

<span class="mw-page-title-main">Dilated cardiomyopathy</span> Condition involving an enlarged, ineffective heart

Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. Complications can include heart failure, heart valve disease, or an irregular heartbeat.

<span class="mw-page-title-main">Carvedilol</span> Blood pressure medication

Carvedilol is a beta-blocker medication, that may be prescribed for the treatment of high blood pressure (hypertension) and chronic heart failure with reduced ejection fraction. Beta-blockers as a collective medication class are not recommended as routine first-line treatment of high blood pressure for all patients, due to evidence demonstrating less effective cardiovascular protection and a less favourable safety profile when compared to other classes of blood pressure-lowering medications.

<span class="mw-page-title-main">Penbutolol</span> Chemical compound

Penbutolol is a medication in the class of beta blockers, used in the treatment of high blood pressure. Penbutolol is able to bind to both beta-1 adrenergic receptors and beta-2 adrenergic receptors, thus making it a non-selective β blocker. Penbutolol is a sympathomimetic drug with properties allowing it to act as a partial agonist at β adrenergic receptors.

<span class="mw-page-title-main">Beta-1 adrenergic receptor</span> Protein-coding gene in the species Homo sapiens

The beta-1 adrenergic receptor, also known as ADRB1, can refer to either the protein-encoding gene or one of the four adrenergic receptors. It is a G-protein coupled receptor associated with the Gs heterotrimeric G-protein that is expressed predominantly in cardiac tissue. In addition to cardiac tissue, beta-1 adrenergic receptors are also expressed in the cerebral cortex.

<span class="mw-page-title-main">Beta-2 adrenergic receptor</span> Mammalian protein found in humans

The beta-2 adrenergic receptor, also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that binds epinephrine (adrenaline), a hormone and neurotransmitter whose signaling, via adenylate cyclase stimulation through trimeric Gs proteins, increases cAMP, and, via downstream L-type calcium channel interaction, mediates physiologic responses such as smooth muscle relaxation and bronchodilation.

<span class="mw-page-title-main">Nebivolol</span> Chemical compound

Nebivolol is a beta blocker used to treat high blood pressure and heart failure. As with other β-blockers, it is generally a less preferred treatment for high blood pressure. It may be used by itself or with other blood pressure medication. It is taken by mouth.

<span class="mw-page-title-main">G protein-coupled receptor kinase</span> Family of protein kinases

G protein-coupled receptor kinases are a family of protein kinases within the AGC group of kinases. Like all AGC kinases, GRKs use ATP to add phosphate to Serine and Threonine residues in specific locations of target proteins. In particular, GRKs phosphorylate intracellular domains of G protein-coupled receptors (GPCRs). GRKs function in tandem with arrestin proteins to regulate the sensitivity of GPCRs for stimulating downstream heterotrimeric G protein and G protein-independent signaling pathways.

<span class="mw-page-title-main">G protein-coupled receptor kinase 2</span> Enzyme

G-protein-coupled receptor kinase 2 (GRK2) is an enzyme that in humans is encoded by the ADRBK1 gene. GRK2 was initially called Beta-adrenergic receptor kinase, and is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases that is most highly similar to GRK3(βARK2).

<span class="mw-page-title-main">Diabetic cardiomyopathy</span> Medical condition

Diabetic cardiomyopathy is a disorder of the heart muscle in people with diabetes. It can lead to inability of the heart to circulate blood through the body effectively, a state known as heart failure(HF), with accumulation of fluid in the lungs or legs. Most heart failure in people with diabetes results from coronary artery disease, and diabetic cardiomyopathy is only said to exist if there is no coronary artery disease to explain the heart muscle disorder.

<span class="mw-page-title-main">Alpha blocker</span> Class of pharmacological agents

Alpha-blockers, also known as α-blockers or α-adrenoreceptor antagonists, are a class of pharmacological agents that act as antagonists on α-adrenergic receptors (α-adrenoceptors).

<span class="mw-page-title-main">G beta-gamma complex</span>

The G beta-gamma complex (Gβγ) is a tightly bound dimeric protein complex, composed of one Gβ and one Gγ subunit, and is a component of heterotrimeric G proteins. Heterotrimeric G proteins, also called guanine nucleotide-binding proteins, consist of three subunits, called alpha, beta, and gamma subunits, or Gα, Gβ, and Gγ. When a G protein-coupled receptor (GPCR) is activated, Gα dissociates from Gβγ, allowing both subunits to perform their respective downstream signaling effects. One of the major functions of Gβγ is the inhibition of the Gα subunit.

Heterologous desensitization is the term for the unresponsiveness of cells to one or more agonists to which they are normally responsive. Typically, desensitization is a receptor-based phenomenon in which one receptor type, when bound to its ligand, becomes unable to further influence the signalling pathways by which it regulates cells and, in the case of cell surface membrane receptors, may thereafter be internalized. The desensitized receptor is degraded or freed of its activating ligand and re-cycled to a state where it is again able to respond to cognate ligands by activating its signalling pathways.

Beta adrenergic receptor kinase carboxyl-terminus is a peptide composed of the last 194 amino acid residues of the carboxyl-terminus of beta adrenergic receptor kinase 1 (βARK1). It binds the βγ subunits of G proteins located in the plasma membrane of cells. It is currently an experimental gene therapy for the treatment of heart failure.

Coxsackieviruses-induced cardiomyopathy are positive-stranded RNA viruses in picornavirus family and the genus enterovirus, acute enterovirus infections such as Coxsackievirus B3 have been identified as the cause of virally induced acute myocarditis, resulting in dilated cardiomyopathy. Dilated cardiomyopathy in humans can be caused by multiple factors including hereditary defects in the cytoskeletal protein dystrophin in Duchenne muscular dystrophy (DMD) patients). A heart that undergoes dilated cardiomyopathy shows unique enlargement of ventricles, and thinning of the ventricular wall that may lead to heart failure. In addition to the genetic defects in dystrophin or other cytoskeletal proteins, a subset of dilated cardiomyopathy is linked to enteroviral infection in the heart, especially coxsackievirus B. Enterovirus infections are responsible for about 30% of the cases of acquired dilated cardiomyopathy in humans.

<span class="mw-page-title-main">Discovery and development of beta-blockers</span>

β adrenergic receptor antagonists were initially developed in the 1960s, for the treatment of angina pectoris but are now also used for hypertension, congestive heart failure and certain arrhythmias. In the 1950s, dichloroisoproterenol (DCI) was discovered to be a β-antagonist that blocked the effects of sympathomimetic amines on bronchodilation, uterine relaxation and heart stimulation. Although DCI had no clinical utility, a change in the compound did provide a clinical candidate, pronethalol, which was introduced in 1962.

<span class="mw-page-title-main">Adrenergic receptor autoantibodies</span>

Adrenergic receptor autoantibodies

Adrenergic blocking agents are a class of drugs that exhibit its pharmacological action through inhibiting the action of the sympathetic nervous system in the body. The sympathetic nervous system(SNS) is an autonomic nervous system that we cannot control by will. It triggers a series of responses after the body releases chemicals named noradrenaline and epinephrine. These chemicals will act on adrenergic receptors, with subtypes Alpha-1, Alpha-2, Beta-1, Beta-2, Beta-3, which ultimately allow the body to trigger a "fight-or-flight" response to handle external stress. These responses include vessel constriction in general vessels whereas there is vasodilation in vessels that supply skeletal muscles or in coronary vessels. Additionally, the heart rate and contractile force increase when SNS is activated, which may be harmful to cardiac function as it increases metabolic demand.

References

  1. ↑ "WHO Drug Information - International Nonproprietary Names for Pharmaceutical Substances (INN) - Recommended INN: List 91". INN and Classification of Medical Products (INN), World Health Organization. 2024-03-25. Archived from the original (PDF) on 2024-03-25. Retrieved 2024-04-03.
  2. 1 2 3 4 5 6 Kolter T (2023). "BC-007". In Böckler F, Dill B, Eisenbrand G, et al. (eds.). Römpp [Online]. Georg Thieme Verlag. Archived from the original on 2023-07-23.
  3. ↑ Matsui S, Fu ML (May 1998). "Myocardial injury due to G-protein coupled receptor-autoimmunity". Japanese Heart Journal. 39 (3): 261–274. doi: 10.1536/ihj.39.261 . PMID   9711178. S2CID   22133040.
  4. ↑ Bornholz B, Wallukat G, Roggenbuck D, Schimke I (2017-02-17). "Chapter 3 - Autoantibodies Directed Against G-Protein-Coupled Receptors in Cardiovascular Diseases: Basics and Diagnostics". In Nussinovitch U (ed.). The Heart in Rheumatic, Autoimmune and Inflammatory Diseases. Academic Press. pp. 49–63. doi:10.1016/B978-0-12-803267-1.00003-X. ISBN   978-0-12-803267-1.
  5. ↑ Wallukat G, Müller J, Hetzer R (November 2002). "Specific removal of beta1-adrenergic autoantibodies from patients with idiopathic dilated cardiomyopathy". The New England Journal of Medicine. 347 (22): 1806. doi: 10.1056/NEJM200211283472220 . PMID   12456865.
  6. ↑ Doesch AO, Konstandin M, Celik S, Kristen A, Frankenstein L, Hardt S, et al. (2009-07-09). "Effects of protein A immunoadsorption in patients with advanced chronic dilated cardiomyopathy". Journal of Clinical Apheresis. 24 (4): 141–149. doi:10.1002/jca.20204. PMID   19591221. S2CID   5566530.
  7. ↑ Büttner, Bettina (2012). "Technology offer - Aptamers for the Treatment and Diagnosis of Diseases Seropositive for Autoantibodies - Ref. No.: CH553" (PDF). Charité-Universitätsmedizin Berlin. Archived from the original (PDF) on 2023-04-23.
  8. ↑ Haberland A, Wallukat G, Schimke I (March 2013). "The patent situation concerning the treatment of diseases associated with autoantibodies directed against G-protein-coupled receptors". Pharmaceutical Patent Analyst. 2 (2): 231–248. doi:10.4155/ppa.12.88. PMID   24237028.
  9. ↑ Patel PA, Hernandez AF (July 2013). "Targeting anti-beta-1-adrenergic receptor antibodies for dilated cardiomyopathy". European Journal of Heart Failure. 15 (7): 724–729. doi:10.1093/eurjhf/hft065. PMC   3707431 . PMID   23639780.
  10. ↑ Haberland A, Holtzhauer M, Schlichtiger A, Bartel S, Schimke I, Müller J, et al. (October 2016). "Aptamer BC 007 - A broad spectrum neutralizer of pathogenic autoantibodies against G-protein-coupled receptors". European Journal of Pharmacology. 789: 37–45. doi:10.1016/j.ejphar.2016.06.061. PMID   27375076.
  11. ↑ Wallukat G, Müller J, Haberland A, Berg S, Schulz A, Freyse EJ, et al. (January 2016). "Aptamer BC007 for neutralization of pathogenic autoantibodies directed against G-protein coupled receptors: A vision of future treatment of patients with cardiomyopathies and positivity for those autoantibodies". Atherosclerosis. 244: 44–47. doi:10.1016/j.atherosclerosis.2015.11.001. PMID   26584137.
  12. 1 2 "Berlin Cures Announces Successful Completion of Phase 1 Study of BC 007 for the Treatment of Cardiomyopathy". BioSpace. 2018-08-22. Archived from the original on 2023-05-30. Retrieved 2023-05-30.
  13. 1 2 3 4 Lang, Carolin (2020-07-08). "Wirkstoff-Kandidat auf DNA Basis - Mit James Bond gegen Covid-19" [Drug candidate based on DNA - Fighting Covid-19 with James Bond]. Pharmazeutische Zeitung (PZ) - Die Zeitschrift der deutschen Apotheker (in German). Avoxa - Mediengruppe Deutscher Apotheker GmbH. ISSN   0031-7136. Archived from the original on 2020-07-08. Retrieved 2024-04-09.
  14. ↑ Werner S, Wallukat G, Becker NP, Wenzel K, Müller J, Schimke I, Wess G (June 2020). "The aptamer BC 007 for treatment of dilated cardiomyopathy: evaluation in Doberman Pinschers of efficacy and outcomes". ESC Heart Failure. 7 (3): 844–855. doi:10.1002/ehf2.12628. PMC   7261533 . PMID   32212256.
  15. ↑ Dandel M, Wallukat G, Englert A, Lehmkuhl HB, Knosalla C, Hetzer R (December 2012). "Long-term benefits of immunoadsorption in β(1)-adrenoceptor autoantibody-positive transplant candidates with dilated cardiomyopathy". European Journal of Heart Failure. 14 (12): 1374–1388. doi: 10.1093/eurjhf/hfs123 . PMID   22892122.
  16. ↑ Düngen HD, Dordevic A, Felix SB, Pieske B, Voors AA, McMurray JJ, Butler J (January 2020). "β1-Adrenoreceptor Autoantibodies in Heart Failure: Physiology and Therapeutic Implications". Circulation: Heart Failure. 13 (1): e006155. doi: 10.1161/CIRCHEARTFAILURE.119.006155 . PMID   31957469. S2CID   210831160.
  17. ↑ Becker NP, Haberland A, Wenzel K, Göttel P, Wallukat G, Davideit H, et al. (May 2020). "A Three-Part, Randomised Study to Investigate the Safety, Tolerability, Pharmacokinetics and Mode of Action of BC 007, Neutraliser of Pathogenic Autoantibodies Against G-Protein Coupled Receptors in Healthy, Young and Elderly Subjects". Clinical Drug Investigation. 40 (5): 433–447. doi:10.1007/s40261-020-00903-9. PMC   7181550 . PMID   32222912.
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