IP Library › Granted Patent US 12,390,508
Granted Patent B2
US 12,390,508 · App. 17/046,648 · Granted Aug 19, 2025

Brain natriuretic peptide engrafted antibodies

Inventors: Damian Brockschnieder (Haan, DE); Jan Tebbe (Cologne, DE); Andreas Wilmen (Cologne, DE); Frank Wunder (Wuppertal, DE)
Assignee: BOEHRINGER INGELHEIM INTERNATIONAL GMBH
A61K38/00A61P9/12C07K14/58C07K16/00A61K2039/505A61P9/04C07K2317/21C07K2317/24C07K2317/565C07K2317/94C07K2318/10C07K2319/31
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,390,508
App. No.
17/046,648
Granted
Aug 19, 2025
Kind
B2
Abstract

The present invention relates to an antibody or a fragment thereof comprising at least one heterologous amino acid sequence incorporated within at least one CDR region of said antibody or fragment thereof, wherein said at least one heterologous amino acid sequence comprises an N-terminal linker sequence (Ntls), a Brain Natriuretic Peptide (BNP) and a C-terminal linker sequence (Ctls). Optionally, at least a portion of said at least one CDR region is replaced by said at least one heterologous amino acid sequence incorporated therein. The present invention further relates to such antibody or fragment thereof for use in a method for treatment, a composition comprising such antibody or fragment thereof, a nucleic acid or a mixture of nucleic acids encoding such antibody or fragment thereof, a host cell comprising such nucleic acid or such mixture of nucleic acids and to a process for producing such antibody or fragment thereof.

Claims (92)

1. An antibody or a fragment thereof comprising a heterologous amino acid sequence incorporated within a CDR region of said antibody or fragment thereof,

wherein said heterologous amino acid sequence comprises an N-terminal linker sequence (Ntls), a Brain Natriuretic Peptide (BNP), and a C-terminal linker sequence (Ctls),

wherein the Ntls comprises at least 12 amino acid residues and the Ctls comprises at least 9 amino acid residues,

wherein:

(i) in case of incorporation of said heterologous amino acid sequence within CDRH1, the Ntls is present between amino acid residue HC res25 according to Kabat and the first amino acid residue of said BNP, and the Ctls is present between the last amino acid residue of said BNP and amino acid residue HC res35a according to Kabat, or

(ii) in case of incorporation of said heterologous amino acid sequence within CDRH2, the Ntls is present between amino acid residue HC res51 according to Kabat and the first amino acid residue of said BNP, and the Ctls is present between amino acid residue HC res57 according to Kabat, or

(iii) in case of incorporation of said heterologous amino acid sequence within CDRH3, the Ntls is present between amino acid residue HC res92 according to Kabat and the first amino acid residue of said BNP, and the Ctls is present between amino acid residue HC res106 according to Kabat, or

(iv) in case of incorporation of said heterologous amino acid sequence within CDRL1, the Ntls is present between amino acid residue LC res26 according to Kabat, and the Ctls is present between amino acid residue LC res 32 according to Kabat, or

(v) in case of incorporation of said heterologous amino acid sequence within CDRL2, the Ntls is present between amino acid residue LC res49 according to Kabat and the first amino acid residue of said BNP, and the Ctls is present between amino acid residue LC res57 according to Kabat, or

(vi) in case of incorporation of said heterologous amino acid sequence within CDRL3, the Ntls is present between amino acid residue LC res88 according to Kabat and the first amino acid residue of said BNP, and the Ctls is present between amino acid residue LC res98 according to Kabat, and

wherein:

(i) said Ntls and said Ctls each comprise a GS linker sequence, or

(ii) said Ntls and said Ctls each comprise a PN linker sequence, or

(iii) said Ntls comprises the sequence of any one of SEQ ID NOs: 1, 2, or 4 and said Ctls comprises the sequence of any one of SEQ ID NOs: 1, 3, or 5, or

(iv) said Ntls and said Ctls each comprise the sequence of SEQ ID NO: 6, or

(v) said Ntls comprises the sequence of SEQ ID NO: 7 and said Ctls comprises the sequence of SEQ ID NO: 8, or

(vi) said Ntls comprises the sequence of SEQ ID NO: 9 and said Ctls comprises the sequence of SEQ ID NO: 10, or

(vii) said Ntls comprises the sequence of SEQ ID NO: 11 and said Ctls comprises the sequence of SEQ ID NO: 12, or

(viii) said Ntls comprises the sequence of SEQ ID NO: 13 and said Ctls comprises the sequence of SEQ ID NO: 14, or

(ix) said Ntls and said Ctls each comprise the sequence of SEQ ID NO: 15; or

(x) said Ntls comprises the sequence of SEQ ID NO: 9 and said Ctls comprises the sequence of SEQ ID NO: 20, or

(xi) said Ntls comprises the sequence of SEQ ID NO: 21 and said Ctls comprises the sequence of SEQ ID NO: 22, and

wherein said antibody or fragment thereof is of the class IgG.

2. The antibody or fragment thereof according to claim 1 , wherein said BNP is a human BNP comprising the sequence of SEQ ID NO: 24 or a BNP comprising at least 95% sequence identity therewith.

3. The antibody or fragment thereof according to claim 1 , wherein said Ntls further comprises an anchoring element A1 at its C terminal end and/or said Ctls further comprises an anchoring element A2 at its N terminal end, and wherein at least 60% of the amino acid residues of A1 and/or A2, when present, are selected from glycine and serine residues.

4. The antibody or fragment thereof according to claim 1 , wherein: the amino acid stretch present between

(i) amino acid residue HC res25 according to Kabat and the first amino acid residue of the BNP in case of an incorporation of said heterologous amino acid sequence within CDRH1; or

(ii) amino acid residue HC res51 according to Kabat and the first amino acid residue of the BNP in case of an incorporation of said heterologous amino acid sequence within CDRH2; or

(iii) amino acid residue HC res92 according to Kabat and the first amino acid residue of the BNP in case of an incorporation of said heterologous amino acid sequence within CDRH3; or

(iv) amino acid residue LC res26 according to Kabat and the first amino acid residue of the BNP in case of an incorporation of said heterologous amino acid sequence within CDRL1; or

(v) amino acid residue LC res49 according to Kabat and the first amino acid residue of the BNP in case of an incorporation of said heterologous amino acid sequence within CDRL2; or

(vi) amino acid residue LC res88 according to Kabat and the first amino acid residue of the BNP in case of an incorporation of said heterologous amino acid sequence within CDRL3 comprises the sequence of any one of SEQ ID NOs: 26 to 38; and

wherein the amino acid stretch present between the last amino acid residue of said BNP and

(i) amino acid residue HC res35a according to Kabat in case of an incorporation of said heterologous amino acid sequence within CDRH1; or

(ii) amino acid residue HC res57 according to Kabat in case of an incorporation of said heterologous amino acid sequence within CDRH2; or

(iii) amino acid residue HC res106 according to Kabat in case of an incorporation of said heterologous amino acid sequence within CDRH3; or

(iv) amino acid residue LC res 32 according to Kabat in case of an incorporation of said heterologous amino acid sequence within CDRL1; or

(v) amino acid residue LC res57 according to Kabat in case of an incorporation of said heterologous amino acid sequence within CDRL2; or

(vi) amino acid residue LC res98 according to Kabat in case of an incorporation of said heterologous amino acid sequence within CDRL3 comprises the sequence of any one of SEQ ID NOs: 39 to 51.

5. The antibody or fragment thereof according to claim 1 , wherein the amino acid stretch present between

(i) amino acid residue HC res25 according to Kabat and amino acid residue HC res35a according to Kabat in case of an incorporation of said heterologous amino acid sequence within CDRH1; or

(ii) amino acid residue HC res51 according to Kabat and amino acid residue HC res57 according to Kabat in case of an incorporation of said heterologous amino acid sequence within CDRH2; or

(iii) amino acid residue HC res92 according to Kabat and amino acid residue HC res 106 according to Kabat in case of an incorporation of said heterologous amino acid sequence within CDRH3; or

(iv) amino acid residue LC res26 according to Kabat and amino acid residue LC res 32 according to Kabat in case of an incorporation of said heterologous amino acid sequence within CDRL1; or

(v) amino acid residue LC res49 according to Kabat and amino acid residue LC res57 according to Kabat in case of an incorporation of said heterologous amino acid sequence within CDRL2; or

(vi) amino acid residue LC res88 according to Kabat and amino acid residue LC res98 according to Kabat in case of an incorporation of said heterologous amino acid sequence within CDRL3

comprises the sequence of any one of SEQ ID NOs: 52 to 64.

6. The antibody or fragment thereof according to claim 1 , further comprising at least one further natriuretic peptide, wherein said BNP and said at least one further natriuretic peptide are incorporated within at least two separate CDR regions, and wherein said at least one further natriuretic peptide is selected from ANP and CNP.

7. The antibody or fragment thereof according to claim 1 , wherein the light chain comprises or consists of the amino acid sequence of SEQ ID NO: 66 and the heavy chain comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 442 to 444.

8. The antibody or fragment thereof according to claim 1 , wherein said antibody fragment is selected from the group consisting of Fab, Fab′, Fab′-SH, F(ab′)2, Fv fragments, diabodies, single domain antibodies (Dabs), linear antibodies, single-chain antibody molecules (scFv), and disulfide-stabilized Fv antibody fragments (dsFv).

9. A composition comprising the antibody or fragment thereof according to claim 1 and a pharmaceutically acceptable carrier.

10. The antibody or fragment thereof according to claim 7 , wherein the light chain comprises the amino acid sequence of SEQ ID NO: 66 and the heavy chain comprises the amino acid sequence of SEQ ID NO: 442.

11. The antibody or fragment thereof according to claim 7 , wherein the light chain comprises the amino acid sequence of SEQ ID NO: 66 and the heavy chain comprises the amino acid sequence of SEQ ID NO: 443.

12. The antibody or fragment thereof according to claim 7 , wherein the light chain comprises the amino acid sequence of SEQ ID NO: 66 and the heavy chain comprises the amino acid sequence of SEQ ID NO: 444.

13. The antibody or fragment thereof according to claim 1 , wherein at least a portion of said CDR region is replaced by said heterologous amino acid sequence incorporated therein.

14. The antibody or fragment thereof according to claim 1 , wherein:

(i) the Ntls comprises the amino acid sequence of SEQ ID NO: 268 and the Ctls comprises the amino acid sequence of SEQ ID NO: 252; or

(ii) the Ntls comprises the amino acid sequence of SEQ ID NO: 430 and the Ctls comprises the amino acid sequence of SEQ ID NO: 431; or

(iii) the Ntls comprises the amino acid sequence of SEQ ID NO: 268 and the Ctls comprises the amino acid sequence of SEQ ID NO: 252; or

(iv) the Ntls comprises the amino acid sequence of SEQ ID NO: 259 and the Ctls comprises the amino acid sequence of SEQ ID NO: 432; or

(v) the Ntls comprises the amino acid sequence of SEQ ID NO: 189 and the Ctls comprises the amino acid sequence of SEQ ID NO: 190; or

(vi) the Ntls comprises the amino acid sequence of SEQ ID NO: 105 and the Ctls comprises the amino acid sequence of SEQ ID NO: 106; or

(vii) the Ntls comprises the amino acid sequence of SEQ ID NO: 211 and the Ctls comprises the amino acid sequence of SEQ ID NO: 212; or

(viii) the Ntls comprises the amino acid sequence of SEQ ID NO: 236 and the Ctls comprises the amino acid sequence of SEQ ID NO: 237; or

(ix) the Ntls comprises the amino acid sequence of SEQ ID NO: 281 and the Ctls comprises the amino acid sequence of SEQ ID NO: 282; or

(x) the Ntls comprises the amino acid sequence of SEQ ID NO: 402 and the Ctls comprises the amino acid sequence of SEQ ID NO: 403.

15. A nucleic acid or a mixture of nucleic acids encoding an antibody or fragment thereof,

wherein the antibody or the fragment thereof comprises at least one a heterologous amino acid sequence incorporated within a CDR region of said antibody or the fragment thereof,

wherein said heterologous amino acid sequence comprises an N-terminal linker sequence (Ntls), a Brain Natriuretic Peptide (BNP), and a C-terminal linker sequence (Ctls),

wherein the Ntls comprises at least 12 amino acid residues and the Ctls comprises at least 9 amino acid residues,

wherein:

(i) in case of an incorporation of said heterologous amino acid sequence within CDRH1, the Ntls is present between amino acid residue HC res25 according to Kabat and the first amino acid residue of said BNP, and the Ctls is present between the last amino acid residue of said BNP and amino acid residue HC res35a according to Kabat, or

(ii) in case of an incorporation of said heterologous amino acid sequence within CDRH2, the Ntls is present between amino acid residue HC res51 according to Kabat and the first amino acid residue of said BNP, and the Ctls is present between amino acid residue HC res57 according to Kabat, or

(iii) in case of an incorporation of said heterologous amino acid sequence within CDRH3, the Ntls is present between amino acid residue HC res92 according to Kabat and the first amino acid residue of said BNP, and the Ctls is present between amino acid residue HC res106 according to Kabat, or

(iv) in case of an incorporation of said heterologous amino acid sequence within CDRL1, the Ntls is present between amino acid residue LC res26 according to Kabat, and the Ctls is present between amino acid residue LC res 32 according to Kabat, or

(v) in case of an incorporation of said heterologous amino acid sequence within CDRL2, the Ntls is present between amino acid residue LC res49 according to Kabat and the first amino acid residue of said BNP, and the Ctls is present between amino acid residue LC res57 according to Kabat, or

(vi) in case of an incorporation of said heterologous amino acid sequence within CDRL3, the Ntls is present between amino acid residue LC res88 according to Kabat and the first amino acid residue of said BNP, and the Ctls is present between amino acid residue LC res98 according to Kabat;

wherein:

(i) said Ntls and said Ctls each comprise a GS linker sequence, or

(ii) said Ntls and said Ctls each comprise a PN linker sequence, or

(iii) said Ntls comprises the sequence of any one of SEQ ID NOs: 1, 2, or 4 and said Ctls comprises the sequence of any one of SEQ ID NOs: 1, 3, or 5, or

(iv) said Ntls and said Ctls each comprise the sequence of SEQ ID NO: 6, or

(v) said Ntls comprises the sequence of SEQ ID NO: 7 and said Ctls comprises the sequence of SEQ ID NO: 8, or

(vi) said Ntls comprises the sequence of SEQ ID NO: 9 and said Ctls comprises the sequence of SEQ ID NO: 10, or

(vii) said Ntls comprises the sequence of SEQ ID NO: 11 and said Ctls comprises the sequence of SEQ ID NO: 12, or

(viii) said Ntls comprises the sequence of SEQ ID NO: 13 and said Ctls comprises the sequence of SEQ ID NO: 14, or

(ix) said Ntls and said Ctls each comprise the sequence of SEQ ID NO: 15; or

(x) said Ntls comprises the sequence of SEQ ID NO: 9 and said Ctls comprises the sequence of SEQ ID NO: 20, or

xi) said Ntls comprises the sequence of SEQ ID NO: 21 and said Ctls comprises the sequence of SEQ ID NO: 22, and

wherein said antibody or fragment thereof is of the class IgG.

16. A host cell comprising the nucleic acid or the mixture of nucleic acids according to claim 15 .

17. A process for producing an antibody or fragment thereof, comprising culturing the host cell according to claim 16 under conditions suitable for expression of the antibody or fragment thereof.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 25, 2025
From: BAYER AKTIENGESELLSCHAFT
To: BOEHRINGER INGELHEIM INTERNATIONAL GMBH
Reel/Frame 071061/0978 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 19, 2020
From: BROCKSCHNIEDER, DAMIAN; TEBBE, JAN; WILMEN, ANDREAS; WUNDER, FRANK
To: BAYER AKTIENGESELLSCHAFT
Reel/Frame 054099/0484 →
Priority Claims (1)
EP 18167106 · Apr 12, 2018 · regional
Continuity (1)
Related Publication 20210147504A1 · May 20, 2021
References Cited (104)
US 4399216A · Axel · 1983 [cited by applicant]
US 4510245A · Cousens · 1985 [cited by applicant]
US 4634665A · Axel · 1987 [cited by applicant]
US 4816397A · Boss · 1989 [cited by applicant]
US 4968615A · Koszinowski · 1990 [cited by applicant]
US 5168062A · Stinski · 1992 [cited by applicant]
US 5179017A · Axel · 1993 [cited by applicant]
US 5288931A · Chang · 1994 [cited by applicant]
US 7112660B1 · Domingues · 2006 [cited by applicant]
US 7521424B2 · Rosen · 2009 [cited by applicant]
US 7705043B2 · Alonso-alija et al. · 2010 [cited by applicant]
US 7781470B2 · Alonso-alija et al. · 2010 [cited by applicant]
US 8796324B2 · Bruggemeier et al. · 2014 [cited by applicant]
US 9193777B2 · Burnett, Jr. · 2015 [cited by applicant]
US 9687476B2 · Fürstner et al. · 2017 [cited by applicant]
US 9993476B2 · Follmann et al. · 2018 [cited by applicant]
US 20030045474A1 · Sailer · 2003 [cited by applicant]
US 20040253242A1 · Bowdish · 2004 [cited by applicant]
US 20070292411A1 · Salcedo · 2007 [cited by applicant]
US 20100310561A1 · Canada · 2010 [cited by applicant]
US 20120114659A1 · Waterman · 2012 [cited by applicant]
US 20140148390A1 · Haupts · 2014 [cited by applicant]
US 20140154743A1 · Levy · 2014 [cited by applicant]
US 20210079056A1 · Brockschnieder · 2021 [cited by applicant]
US 20210139555A1 · Mayer-Bartschmid et al. · 2021 [cited by applicant]
CN 103087191A · 2013 [cited by applicant]
CN 103649116A · 2014 [cited by applicant]
EP 2432489B1 · 2016 [cited by applicant]
WO 0006568A1 · 2000 [cited by applicant]
WO 0006569A1 · 2000 [cited by applicant]
WO 0119355A2 · 2001 [cited by applicant]
WO 0119776A2 · 2001 [cited by applicant]
WO 0119778A1 · 2001 [cited by applicant]
WO 0119780A2 · 2001 [cited by applicant]
WO 0119780A3 · 2001 [cited by applicant]
WO 0119776A3 · 2001 [cited by applicant]
WO 0242301A1 · 2002 [cited by applicant]
WO 02070462A1 · 2002 [cited by applicant]
WO 02070510A2 · 2002 [cited by applicant]
WO 02078612A2 · 2002 [cited by applicant]
WO 02070510A3 · 2003 [cited by applicant]
WO 03095451A1 · 2003 [cited by applicant]
WO 2005060642A2 · 2005 [cited by applicant]
WO 2005082004A2 · 2005 [cited by applicant]
WO 2005060642A3 · 2005 [cited by applicant]
WO 2006107124A1 · 2006 [cited by applicant]
WO 2008079995A2 · 2008 [cited by applicant]
WO 2008079995A3 · 2008 [cited by applicant]
WO 2005082004A3 · 2008 [cited by applicant]
WO 2008136611A1 · 2008 [cited by applicant]
WO 2008154226A1 · 2008 [cited by applicant]
WO 2009033094A2 · 2009 [cited by applicant]
WO 2010054007A1 · 2010 [cited by applicant]
WO 2010105770A1 · 2010 [cited by applicant]
WO 2010117760A2 · 2010 [cited by applicant]
WO 2010117760A3 · 2010 [cited by applicant]
WO 2010135541A2 · 2010 [cited by applicant]
WO 2011104322A1 · 2011 [cited by applicant]
WO 2011147809A1 · 2011 [cited by applicant]
WO 2012004258A1 · 2012 [cited by applicant]
WO 2012028647A1 · 2012 [cited by applicant]
WO 2012059549A1 · 2012 [cited by applicant]
WO 2015006337A2 · 2015 [cited by applicant]
WO 2016071212A1 · 2016 [cited by applicant]
Mezo, A.R., et al. (2012). “Atrial Natriuretic Peptide-Fc, ANP-Fc, Fusion Proteins: Semisynthesis, In Vitro Activity and Pharmacokinetics in Rats,” American Chemical Society, 23: 518-526. [cited by applicant]
Peng, J., et al. (Apr. 25, 2018). “Preparation of anti hCG single domain antibodies using antigen binding peptide engrafted antibody technology,” Chinese Journal of Biotechnology, 34(4): 569-577. English translation of … [cited by applicant]
Anand-Srivastava, M.B. (Jun. 2005). “Natriuretic peptide receptor-C signaling and regulation,” Peptides 26(6): 1044-1059. [cited by applicant]
Anker, S.D. et al. (Mar. 21, 2015). “Ularitide for the treatment of acute decompensated heart failure: from preclinical to clinical studies,” Eur Heart J. 36 (12): 715-723. [cited by applicant]
Baliga, R.S. et al. (Jul. 2014). “Intrinsic defence capacity and therapeutic potential of natriuretic peptides in pulmonary hypertension associated with lung fibrosis,” British Journal of Pharmacology 171(14): 3463-3475. [cited by applicant]
Buglioni, A. et al. (2016). “New Pharmacological Strategies to Increase cGMP,” Annu Rev .Med. 67: 229-243. [cited by applicant]
Dahrouj, M. et al. (Jan. 2013). “C-Type Natriuretic Peptide Protects the Retinal Pigment Epithelium against Advanced Glycation End Product-Induced Barrier Dysfunction.” J Pharmacol Exp Ther. 344 (1): 96-102. [cited by applicant]
Edelson, J.D. et al. (Apr. 2013). “In vitro and in vivo pharmacological profile of PL-3994, a novel cyclic peptide Hept-cyclo(Cys-His-Phe-D-Ala-Gly-Arg-D-Nle-Asp-Arg-Ile-Ser-Cys)-Tyr-[Argmimetic]-NH2) natriuretic peptid… [cited by applicant]
Hunt, P.J. et al. (1994). “Bioactivity and Metabolism of C-Type Natriuretic Peptide in Normal Man*” Journal of Clinical Endocrinology and Metabolism, 78(6):1428-1435. [cited by applicant]
International Search Report mailed Oct. 17, 2019 for PCT International Application No. PCT/EP2019/059101, filed Apr. 10, 2019, 4 pages. [cited by applicant]
Kimura, K. et al. (2007). “ANP is cleared much faster than BNP in patients with congestive heart failure,” Eur J Clin Pharmacol, 63:699-702. [cited by applicant]
Kimura, T. et al. (2016). “C-type natriuretic peptide ameliorates pulmonary fibrosis by acting on lung fibroblasts in mice,” Respiratory Research, 17(19):1-17. [cited by applicant]
Knowles, J.W. et al. (2001). “Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice,” J.Clin. Invest. 107(8): 975-984. [cited by applicant]
Lee, C. et al. (2007). “Pharmacokinetic and pharmacodynamic study of a novel chimeric natriuretic peptide, CD-NP, in the normal dog,” BMC Pharmacology 7 (Suppl I): P38. [cited by applicant]
Lumsden, N.G. et al. (2010). “C-type Natriuretic Peptide (CNP): Cardiovascular Roles and Potential as a Therapeutic Target,” Current Pharmaceutical Design, 16:4080-4088. [cited by applicant]
McKie, P. et al. (2010) “CD-NP: An Innovative Designer Natriuretic Peptide Activator of Particulate Guanylyl Cyclase Receptors for Cardiorenal Disease,” Curr Heart Fail Rep, 7:93-99. [cited by applicant]
McKie, P.M. et al. (Dec. 2010). “A Novel Atrial Natriuretic Peptide Based Therapeutic in Experimental Angiotensin II Mediated Acute Hypertension,” Hypertension 56 (6): 1152-1159. [cited by applicant]
Mitaka, C. et al. (2014) “Effects of atrial natriuretic peptide on inter-organ crosstalk among the kidney, lung, and heart in a rat model of renal ischemia-reperfusion injury,” Intensive Care Medicine Experimental, 2(28… [cited by applicant]
Moyes, A.J. et al. (2014), “Endothelial C-type natriuretic peptide maintains vascular homeostasis,” The Journal of Clinical Investigation, 124(9):4039-4051. [cited by applicant]
Pan, S. et al. (Jul. 7, 2009). “Biodesign of a renal-protective peptide based on alternative splicing of B-type natriuretic peptide,” PNAS 106 (27): 11282-11287. [cited by applicant]
Potter, L. et al. (2009) “Natriuretic Peptides: Their Structures, Receptors, Physiologic Functions and Therapeutic Applications,” Handb Exp Pharmacol., 191:341-66. [cited by applicant]
Wang, W. et al. (Nov. 2004). “AlbuBNP, a Recombinant B-TypeNatriuretic Peptide and Human Serum Albumin Fusion Hormone, asa Long-Term Therapy of Congestive Heart Failure,” Pharmaceutical Research, Springer 21(11):2105-21… [cited by applicant]
Wendt, D. J. et al. (Apr. 2015). “Neutral Endopeptidase-Resistant C-Type Natriuretic Peptide Variant Represents a New Therapeutic Approach for Treatment of Fibroblast Growth Factor Receptor 3-Related Dwarfism,” J. Pharm… [cited by applicant]
Werner, F. et al. (2016) “Endothelial actions of atrial natriuretic peptide prevent pulmonary hypertension in mice,” Basic Res Cardiol 111(22):1-16. [cited by applicant]
Woods, R. (2004) “Cardioprotective Functions of Atrial Natriuretic Peptide and B-Type Natriuretic Peptide: A Brief Review,” Clinical and Experimental Pharmacology and Physiology, 31:791-794. [cited by applicant]
Yasoda, A. et al. (2009). “Effects of natriuretic peptides on endochondral bone growth,” Clinical Calcium, 17(7):103-108. English Abstract. [cited by applicant]
Fillippovic O. B. et al., Biochemical basis for human life activity. Textbook for for college-level.—M.: Vlados, 2005.—407 p. il.; see p. 49-50 and 70. (Partial English Translation only.). [cited by applicant]
Roitt A. et al. (2000), Immunology. Translation from English—M.: Mir, 2000.—592 p. ill.; p. 150. (Partial English Translation only.). [cited by applicant]
Šarošina I. A. et al. (2003). “The role of natriuretic peptides for the diagnosis of heart failure,” Russian Journal of Cardiology, N 2(40): 81-86. [cited by applicant]
Alaoui-Ismaili, M.H. et al. (2009). “Design of Second Generation Therapeutic Recombinant Bone Morphogenetic Proteins,” Cytokine Growth Factor Rev. 20:501-507. [cited by applicant]
Bernier, V. et al. (2004, e-pub. Aug. 23, 2004). “Pharmacological Chaperone Action on G-protein-coupled Receptors,” Curr. Opin. Pharmacol. 4:528-533. [cited by applicant]
Bhattacharya, R. et al. (Mar. 15, 2017). “Impact of Genetic Variations on Three Dimensional Structure and Function of Proteins,” PLoS ONE 12(3):e0171355, 22 pages. [cited by applicant]
Fenton, A. W. et al. (2020, e-pub. Jun. 7, 2020). “Rheostat Positions: A New Classification of Protein Positions Relevant to Pharmacogenomics,” Medicinal Chemistry Research 29:1133-1146. [cited by applicant]
Guo, H. H. et al. (Jun. 22, 2004). “Protein Tolerance to Random Amino Acid Change,” PNAS 101(25):9205-9210. [cited by applicant]
International Search Report and Written Opinion, mailed May 17, 2019, for PCT Application No. PCT/EP2019/059101, filed Apr. 10, 2019, 10 pages. [cited by applicant]
International Search Report and Written Opinion, mailed May 20, 2019, for PCT Application No. PCT/EP2019/059103, filed Apr. 10, 2019, 11 pages. [cited by applicant]
Teng, S. et al. (2010, e-pub. Feb. 4, 2011). “Structural Assessment of the Effects of Amino Acid Substitutions on Protein Stability and Protein-Protein Interaction,” Int J Comput Biol Drug Des. 3(4):334-349. [cited by applicant]
Tobi, D. et al. (Dec. 14, 2005). “Structural Changes Involved in Protein Binding Correlate with Intrinsic Motions of Proteins in the Unbound State,” PNAS 102(52):18908-18913. [cited by applicant]
Tokuriki, N. et al. (2009, e-pub. Sep. 16, 2009). “Stability Effects of Mutations and Protein Evolvability,” Curr. Opin. Struc. Biol. 19:596-604. [cited by applicant]
Ulloa-Aguirre, A. et al. (2004). “Pharmacologic Rescue of Conformationally-Defective Proteins: Implications for the Treatment of Human Disease,” Traffic 5:821-837. [cited by applicant]