IP Library › Granted Patent US 12,558,420
Granted Patent B2
US 12,558,420 · App. 18/063,981 · Granted Feb 24, 2026

Methods for treating inflammation using antibodies to kallidin and des-Arg

Inventors: Han Li (Yardley, PA); Dorothea Kominos (Millington, NJ); Jie Zhang (Cambridge, MA); Alla Pritsker (Cambridge, MA); Matthew Davison (Cambridge, MA); Nicolas Baurin (Arpajon, FR); Govindan Subramanian (Belle Mead, NJ); Xin Chen (Edison, NJ)
Assignee: SANOFI
A61K39/3955A61P29/00C07K16/26A61K2039/505C07K7/18C07K14/575C07K2317/24C07K2317/33C07K2317/34C07K2317/56C07K2317/565C07K2317/76C07K2317/92
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 12,558,420
App. No.
18/063,981
Granted
Feb 24, 2026
Kind
B2
Abstract

The invention provides antibodies that specifically bind to Kallidin or des-Arg10-Kallidin. The invention also provides pharmaceutical compositions, as well as nucleic acids encoding anti-Kallidin or des-Arg10-Kallidin antibodies, recombinant expression vectors and host cells for making such antibodies, or fragments thereof. Methods of using antibodies of the invention to modulate Kallidin or des-Arg10-Kallidin activity or detect Kallidin or des-Arg10-Kallidin or, either in vitro or in vivo, are also provided by the invention. The invention further provides methods of making antibodies that specifically bind to des-Arg 9 -Bradykinin and des-Arg 10 -Kallidin-like peptide.

Claims (122)

1 . A method for treating inflammation, the method comprising administering to a subject having inflammation a pharmaceutical composition comprising an isolated antibody or antigen binding fragment thereof that specifically binds to Kallidin or des-Arg 10 -Kallidin, but not to Bradykinin or des-Arg 9 -Bradykinin,

wherein the antibody or antigen binding fragment comprises:

i) a heavy chain variable domain comprising a heavy chain complementarity determining region 3 (HCDR3) amino acid sequence selected from the group consisting of:

a) SEQ ID NO: 7 [X 1 Y-X 2 -X 3 D-X 4 HAM-X 5 Y], wherein

X 1 is Y, F or H,

X 2 is R, D, A, V, L, I, M, F, Y or W,

X 3 is Y, F, W or H,

X 4 is D, E or Y, and,

X 5 is D or E;

b) SEQ ID NO: 63 [X 1 EYDGX 2 YX 3 X 4 LDX 5 ], wherein

X 1 is W or F,

X 2 is N or no amino acid;

X 3 is Y or S,

X 4 is D or P, and

X 5 is F or Y;

c) SEQ ID NO: 13;

d) SEQ ID NO: 32;

e) SEQ ID NO: 40;

f) SEQ ID NO: 47; and

g) SEQ ID NO: 55,

ii) a heavy chain variable domain comprising a heavy chain complementarity determining region 2 (HCDR2) amino acid sequence selected from the group consisting of:

h) SEQ ID NO: 8 [YFX 1 PX 2 NGNTGYNQKFRG], wherein

X 1 is D, R, A, V, L, I, M, F, Y or W, and

X 2 is Y, D, E, N, or Q;

i) SEQ ID NO: 64 [WX 1 DPENGDX 2 X 3 YAPKFQG], wherein

X 1 is I, or V,

X 2 is T, or S, and

X 3 is G, or D;

j) SEQ ID NO: 14

k) SEQ ID NO: 33;

l) SEQ ID NO: 41;

m) SEQ ID NO: 48; and

n) SEQ ID NO: 56,

iii) a heavy chain variable domain comprising a heavy chain complementarity determining region 1 (HCDR1) amino acid sequence selected from the group consisting of:

o) SEQ ID NO: 9 [GYSFTDYX 1 IY], wherein X 1 is N, W or Y;

p) SEQ ID NO: 65 [GFNIKDYYX 1 H], wherein X 1 is L, or M;

q) SEQ ID NO: 15;

r) SEQ ID NO: 34;

s) SEQ ID NO: 42;

t) SEQ ID NO: 49; and

u) SEQ ID NO: 57,

iv) a light chain variable domain comprising a light chain complementarity determining region 3 (LCDR3) amino acid sequence selected from the group consisting of:

v) SEQ ID NO: 10 [QQ-X 1 -X 2 S-X 3 P-X 4 T], wherein

X 1 is Y, F or H,

X 2 is Y, F, H or W,

X 3 is Y, F, T or H, and,

X 4 is W, Y, F, H or L;

w) SEQ ID NO: 66 [QX 1 X 2 X 3 SX 4 PX 5 T], wherein

X 1 is Q or N,

X2 is Y, F, D or H,

X3 is Y, F, H or W,

X4 is Y, F, T or H, and

X5 is W, Y, F, H or L;

x) SEQ ID NO: 69 [X 1 QGTHFPYT], wherein X 1 is L or M;

y) SEQ ID NO: 16;

z) SEQ ID NO: 35;

aa) SEQ ID NO: 43;

bb) SEQ ID NO: 50; and

cc) SEQ ID NO: 58, or

v) a light chain variable domain comprising a light chain complementarity determining region 2 (LCDR2) amino acid sequence selected from the group consisting of:

dd) SEQ ID NO: 11 [WASTRX 1 ], wherein X 1 is E, D, Q or N;

ee) SEQ ID NO: 67 [X 1 ASTRX 2 ], wherein

X 1 is W or G, and

X 2 is E, D, Q or N;

ff) SEQ ID NO: 17;

gg) SEQ ID NO: 36;

hh) SEQ ID NO: 51; and

ii) SEQ ID NO: 59, and

vi) a light chain variable domain comprising a light chain complementarity determining region 1 (LCDR1) amino acid sequence selected from the group consisting of:

jj) SEQ ID NO: 12 [KSSQSLL-X 1 SSNQKN-X 2 LA], wherein

X 1 is W, H, Y or F, and

X 2 is H or Y;

kk) SEQ ID NO: 68 [KSSCISLLX 1 X 2 SX 3 QX 4 NX 5 LA], wherein

X 1 is W, H, Y or F,

X 2 is S or G,

X 3 is N or D,

X 4 is K or R, and

X 5 is H or Y;

ll) SEQ ID NO: 70 [KSSQSLLYSNGX 1 TYLN], wherein X 1 is K or E;

mm) SEQ ID NO: 18;

nn) SEQ ID NO: 37;

oo) SEQ ID NO: 44;

pp) SEQ ID NO: 52; and

qq) SEQ ID NO: 60.

2 . The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises:

a) a heavy chain variable domain comprising the consensus HCDR3, HCDR2 and HCDR1 region amino sequences set forth in SEQ ID NOs: 7, 8, and 9, respectively; and

b) a light chain variable domain comprising the consensus LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID Nos: 10, 11, and 12, respectively.

3 . The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises:

a) a heavy chain variable domain comprising the HCDR3, HCDR2 and HCDR1 region amino sequences set forth in SEQ ID NOs: 13, 14, and 15, respectively; and

b) a light chain variable domain comprising the LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID Nos: 16, 17, and 18, respectively.

4 . The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises:

a) a heavy chain variable domain comprising the HCDR3, HCDR2 and HCDR1 region amino sequences set forth in SEQ ID NOs: 32, 33, and 34, respectively; and

b) a light chain variable domain comprising the LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID Nos: 35, 36, and 37, respectively.

5 . The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises:

a) a heavy chain variable domain comprising the HCDR3, HCDR2 and HCDR1 region amino sequences set forth in SEQ ID NOs: 40, 41 and 42, respectively; and

b) a light chain variable domain comprising the LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID Nos: 43, 17, and 44, respectively.

6 . The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises: a) a heavy chain variable domain comprising the HCDR3, HCDR2 and HCDR1 region amino sequences set forth in SEQ ID NOs: 47, 48, and 49, respectively; and

b) a light chain variable domain comprising the LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID Nos: 50, 51, and 52, respectively.

7 . The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises:

a) a heavy chain variable domain comprising the HCDR3, HCDR2 and HCDR1 region amino sequences set forth in SEQ ID NOs: 55, 56, and 57, respectively; and

b) a light chain variable domain comprising the LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID Nos: 58, 59, and 60, respectively.

8 . The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises:

a) a heavy chain variable domain comprising the HCDR3, HCDR2 and HCDR1 region amino sequences set forth in SEQ ID NOs: 13, 14, and 15, respectively, and one or more amino acid substitution at positions selected from the group consisting of H1, H5, H9, H11, H12, H16, H38, H40, H41, H43, H44, H66, H75, H79, H81, H82A, H83, H87, and H108, according to Kabat; and

b) a light chain variable domain comprising the LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID Nos: 16, 17, and 18, respectively, and one or more amino acid substitution at positions selected from the group consisting of L5, L9, L15, L18, L19, L21, L22, L43, L63, L78, L79, L83, L85, L100 and L104, according to Kabat.

9 . The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises the heavy chain and light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 24 and 30, respectively.

10 . The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises:

a) a heavy chain variable region domain comprising an amino acid sequence with at least 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 20, 21, 22, 24, 25, 38, 45, 53, and 61; and

b) a light chain variable domain comprising an amino acid sequence with at least 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 27, 28, 29, 30, 31, 39, 46, 54, and 62.

11 . The method of claim 1 , wherein the inflammation is chronic inflammation.

12 . The method of claim 1 , wherein the inflammation is associated with inflammatory pain.

13 . The method of claim 12 , wherein the antibody or antigen binding fragment:

a) specifically binds to kallidin or des-Arg 10 -kallidin with a K D of less than 1×10 −10 M;

b) specifically binds to kallidin or des-Arg 10 -kallidin with a K off of less than 1×10 4 s −1 ; and/or

c) specifically binds to kallidin or des-Arg 10 -kallidin and inhibits binding to the bradykinin B1 receptor.

14 . The method of claim 12 , wherein the antibody or antigen binding fragment:

a) binds to the N-terminal lysine residue of kallidin or des-Arg 10 -kallidin;

b) inhibits the binding of kallidin or des-Arg 10 -kallidin to a bradykinin-1 receptor; and/or

c) binds specifically to mouse kallidin-like peptide (KLP).

15 . The method of claim 12 , wherein the antibody or antigen binding fragment specifically binds to a conformational epitope of kallidin (KD) or desArg 10 -kallidin (DAKD) which adopts a Pro4 kink conformation comprising a type II tight turn at proline 4 of the KD or DAKD.

16 . The method of claim 15 , wherein the Pro4 kink conformation of KD or DAKD further comprises amino acid repeats of a sigmoid shape which align the hydrophobic side chains of the amino acids in a spatially stacking mode.

17 . A method for treating inflammation, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising an antibody or antigen binding fragment thereof that specifically binds to Kallidin or des-Arg10-Kallidin but not to Bradykinin or des-Arg9-Bradykinin, and one or more pharmaceutically acceptable carriers, wherein the antibody or antigen binding fragment thereof comprises the heavy chain and light chain variable domain amino acid sequences set forth in SEQ ID NOs: 24 and 30, respectively.

18 . A method for treating inflammation, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising an antibody or antigen binding fragment thereof that specifically binds to Kallidin or des-Arg 10 -Kallidin but not to Bradykinin or des-Arg 9 -Bradykinin, and one or more pharmaceutically acceptable carriers, wherein the antibody or antigen binding fragment thereof comprises: a) a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 20, 21, 22, 24, 25, 38, 45, 53, and 61; and b) a light chain variable domain amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 27, 28, 29, 30, 31, 39, 46, 54, and 62.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 16, 2024
From: LI, HAN; KOMINOS, DOROTHEA; ZHANG, JIE; PRITSKER, ALLA; DAVISON, MATTHEW; BAURIN, NICOLAS; SUBRAMANIAN, GOVINDAN; CHEN, XIN
To: SANOFI
Reel/Frame 068317/0692 →
CHANGE OF ADDRESS Recorded Jul 3, 2024
From: SANOFI
To: SANOFI
Reel/Frame 068105/0767 →
Priority Claims (1)
FR 1350953 · Feb 4, 2013 · national
Continuity (6)
Continuation 16580603 · Sep 24, 2019
Continuation 15844883 · Dec 18, 2017
Division 15163883 · May 25, 2016
Division 14382798
Provisional Application 61616845 · Mar 28, 2012
Related Publication 20230399388A1 · Dec 14, 2023
References Cited (160)
US 4741900A · Alvarez et al. · 1988 [cited by applicant]
US 4816397A · Boss et al. · 1989 [cited by applicant]
US 4816567A · Cabilly et al. · 1989 [cited by applicant]
US 5225539A · Winter · 1993 [cited by applicant]
US 5314995A · Fell, Jr. et al. · 1994 [cited by applicant]
US 5460785A · Rhodes et al. · 1995 [cited by applicant]
US 5530101A · Queen et al. · 1996 [cited by applicant]
US 5565332A · Hoogenboom et al. · 1996 [cited by applicant]
US 5585089A · Queen et al. · 1996 [cited by applicant]
US 5639641A · Pedersen et al. · 1997 [cited by applicant]
US 5648260A · Winter et al. · 1997 [cited by applicant]
US 5739277A · Presta et al. · 1998 [cited by applicant]
US 5807715A · Morrison et al. · 1998 [cited by applicant]
US 5834250A · Wells et al. · 1998 [cited by applicant]
US 5869046A · Presta et al. · 1999 [cited by applicant]
US 6096871A · Presta et al. · 2000 [cited by applicant]
US 6121022A · Presta et al. · 2000 [cited by applicant]
US 6193980B1 · Efstathiou et al. · 2001 [cited by applicant]
US 6194551B1 · Idusogie et al. · 2001 [cited by applicant]
US 6242195B1 · Idusogie et al. · 2001 [cited by applicant]
US 6277375B1 · Ward · 2001 [cited by applicant]
US 6528624B1 · Idusogie et al. · 2003 [cited by applicant]
US 6538124B1 · Idusogie et al. · 2003 [cited by applicant]
US 6737056B1 · Presta · 2004 [cited by applicant]
US 6821505B2 · Ward · 2004 [cited by applicant]
US 6998253B1 · Presta et al. · 2006 [cited by applicant]
US 7083784B2 · Dall'Acqua et al. · 2006 [cited by applicant]
US 9376494B2 · Li et al. · 2016 [cited by applicant]
US 9879079B2 · Li et al. · 2018 [cited by applicant]
US 9958572B2 · Chang et al. · 2018 [cited by applicant]
US 10465002B2 · Li et al. · 2019 [cited by applicant]
US 20020102208A1 · Chinn et al. · 2002 [cited by applicant]
US 20150050270A1 · Li et al. · 2015 [cited by applicant]
US 20160368976A1 · Li et al. · 2016 [cited by applicant]
US 20180222967A1 · Li et al. · 2018 [cited by applicant]
CA 2868353A1 · 2013 [cited by applicant]
EP 0239400A2 · 1987 [cited by applicant]
EP 0396387A2 · 1990 [cited by applicant]
EP 0519596A1 · 1992 [cited by applicant]
EP 0592106A1 · 1994 [cited by applicant]
EP 2831113A1 · 2015 [cited by applicant]
EP 3246339A1 · 2017 [cited by applicant]
JP 2008543810A · 2008 [cited by applicant]
JP 2015513903A · 2015 [cited by applicant]
WO WO1988007089A1 · 1988 [cited by applicant]
WO WO1989012624A2 · 1989 [cited by applicant]
WO WO1991009967A1 · 1991 [cited by applicant]
WO WO1991014438A1 · 1991 [cited by applicant]
WO WO1992008495A1 · 1992 [cited by applicant]
WO WO1996014339A1 · 1996 [cited by applicant]
WO WO1998005787A1 · 1998 [cited by applicant]
WO WO1998023289A1 · 1998 [cited by applicant]
WO WO1998052976A1 · 1998 [cited by applicant]
WO WO1999051642A1 · 1999 [cited by applicant]
WO WO2000009560A2 · 2000 [cited by applicant]
WO WO2000032767A1 · 2000 [cited by applicant]
WO WO2000034317A2 · 2000 [cited by applicant]
WO WO2000042072A2 · 2000 [cited by applicant]
WO WO2002044215A2 · 2002 [cited by applicant]
WO WO2002060919A2 · 2002 [cited by applicant]
WO WO2003074569A2 · 2003 [cited by applicant]
WO WO2004016750A2 · 2004 [cited by applicant]
WO WO2004029207A2 · 2004 [cited by applicant]
WO WO2004035752A2 · 2004 [cited by applicant]
WO WO2004063351A2 · 2004 [cited by applicant]
WO WO2004074455A2 · 2004 [cited by applicant]
WO WO2004099249A2 · 2004 [cited by applicant]
WO WO2005018572A2 · 2005 [cited by applicant]
WO WO2005040217A2 · 2005 [cited by applicant]
WO WO2005047327A2 · 2005 [cited by applicant]
WO WO2005070963A1 · 2005 [cited by applicant]
WO WO2005077981A2 · 2005 [cited by applicant]
WO WO2005092925A2 · 2005 [cited by applicant]
WO WO2005123780A2 · 2005 [cited by applicant]
WO WO2006019447A1 · 2006 [cited by applicant]
WO WO2006047350A2 · 2006 [cited by applicant]
WO WO2006085967A2 · 2006 [cited by applicant]
WO WO2006134125A9 · 2007 [cited by applicant]
WO WO2009032661A1 · 2009 [cited by applicant]
WO WO2013148296A1 · 2013 [cited by applicant]
Bedi, et al. (Sep. 27, 1985) “Monoclonal Antibodies to Bradykinin Inhibit Smooth Muscle Contractile Action of Bradykinin”, Biochimica et Biophysica Acta, vol. 842, No. 1, pp. 90-99. [cited by applicant]
Benjamini, et al. (1991) “Immunology: A Short Course”, 2nd edition, p. 40. [cited by applicant]
Bennett, et al. (Apr. 1998) “A Peripheral Mononeuropathy in Rat That Produces Disorders of Pain Sensation Like Those Seen in Man”, Pain, vol. 33, No. 1, pp. 87-107. [cited by applicant]
Berman, et al. (Jan. 1, 2000) “The Protein Data Bank”, Nucleic Acids Research, vol. 28, No. 1, pp. 235-242. [cited by applicant]
Brooks, et al. (1983) “CHARMM: A Program for Macromolecular Energy, Minimization, and Dynamics Calculations”, Journal of Computational Chemistry, vol. 4, Issue 2, pp. 187-217. [cited by applicant]
Brummell, et al. (1993) “Probing the Combining Site of an Anti-Carbohydrate Antibody by Saturation-Mutagenesis: Role of the Heavy-Chain CDR3 Residues”, Biochemistry, vol. 32, No. 4, pp. 1180-1187. [cited by applicant]
Burks, et al. (Jan. 21, 1997) “In Vitro Scanning Saturation Mutagenesis of an Antibody Binding Pocket”, Proceedings of the National Academy of Sciences of the United States of America, vol. 94, No. 2, pp. 412-417. [cited by applicant]
Campbell, et al. (1984) “General Properties and Applications of Monoclonal Antibodies”, Laboratory Techniques in Biochemistry and Molecular Biology, vol. 13, Chapter 1, pp. 1-33. [cited by applicant]
Carretero, et al. (Oct. 15, 1976) “Measurement of Urinary Kallikrein Activity by Kinin Radioimmunoassay”, Biochemical Pharmacology, vol. 25, No. 20, pp. 2265-2270. [cited by applicant]
Case, et al. (Dec. 2005) “The Amber Biomolecular Simulation Programs”, Journal of Computational Chemistry, vol. 26, No. 16, pp. 1668-1688. [cited by applicant]
Casset, et al. (Jul. 18, 2003) “A Peptide Mimetic of an Anti-CD4 Monoclonal Antibody by Rational Design”, Biochemical and Biophysical Research Communications, vol. 307, Issue 1, pp. 198-205. [cited by applicant]
Chapman, et al. (2002) “PEGylated Antibodies and Antibody Fragments for Improved Therapy: A Review”, Advanced Drug Delivery Reviews, vol. 54, No. 4, pp. 531-545. [cited by applicant]
Chen et al., “Targeting the bradykinin B1 receptor to reduce pain”, Expert Opin Ther Targets, 2007, 11(1): 21-35. [cited by applicant]
Chen, et al. (2010) “Nitric Oxide Synthase Modulates CFA-Induced Thermal Hyperalgesia Through Cytokine Regulation in Mice”, Molecular Pain, vol. 6, No. 13, 11 Pages. [cited by applicant]
Chen, et al. (Nov. 5, 1999) “Selection and Analysis of an Optimized Anti-VEGF Antibody: Crystal Structure of an Affinity-Matured Fab in Complex with Antigen”, Journal of Molecular Biology, vol. 293, No. 4, pp. 865-881. [cited by applicant]
Chothia, et al. (Aug. 20, 1987) “Canonical Structures for the Hypervariable Regions of Immunoglobulins”, Journal of Molecular Biology, vol. 196, No. 4, pp. 901-917. [cited by applicant]
Couture et al., “Kinin receptors in pain and inflammation”, European Journal of Pharmacology, 2001, 429: 161-176. [cited by applicant]
Debnath, et al. (2010) “Molecular Diagnostics: Promises and Possibilities”, Immunoassay, Chapter 11, pp. 171-180. [cited by applicant]
Duncan, et al. (Apr. 2000) “Kinins in Humans”, American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, vol. 278, No. 4, pp. R897-R904. [cited by applicant]
Extended European Search Report received for European Patent Application No. 17179380.5, mailed on Oct. 6, 2017, 7 Pages. [cited by applicant]
FErnández-Sánchez, et al. (Apr. 27, 2009) “Mouse Monoclonal Antibodies to Pneumococcal C-Polysaccharide Backbone Show Restricted Usage of VH-DH-JH Gene Segments and Share the Same Kappa Chain”, Immunology Letters, vol. … [cited by applicant]
Foote, et al. (Mar. 20, 1992) “Antibody Framework Residues Affecting the Conformation of the Hypervariable Loops”, Journal of Molecular Biology, vol. 224, No. 2, pp. 487-499. [cited by applicant]
Freedberg, et al. (1998) “Flexibility and Function in HIV Protease: Dynamics of the HIV-1 Protease Bound to the Asymmetric Inhibitor Kynostatin 272 (KNI-272)”, Journal of the American Chemical Society, vol. 120, No. 31,… [cited by applicant]
Gentz, et al. (1989) “Bioassay for Trans-Activation Using Purified Human Immunodeficiency Virus Tat-Encoded Protein: Trans-Activation Requires mRNA Synthesis”, Proceedings of the National Academy of Sciences, vol. 86, N… [cited by applicant]
Geppetti, et al. (May 17, 1991) “Kallidin Applied to the Human Nasal Mucosa Produces Algesic Response Not Blocked by Capsaicin Desensitization”, Regulatory Peptides, vol. 33, No. 3, pp. 321-329. [cited by applicant]
Gillies, S D., et al. (Dec. 20, 1989) “High Level Expression of Chimeric Antibodies using Adapted cDNA Variable Region Cassettes”, Journal of Immunological Methods, vol. 125, Issues 1-2, pp. 191-202. [cited by applicant]
Grünberg (Apr. 2006) “Flexibility and Conformational Entropy in Protein-Protein Binding”, Structure, vol. 14, Issue 7, pp. 683-693. [cited by applicant]
Haasemann (Dec. 1, 1991) “Anti-Idiotypic Antibodies Bearing the Internal Image of a Bradykinin Epitope. Production, Characterization, and Interaction with The Kinin Receptor”, The Journal of Immunology, vol. 147, No. 11… [cited by applicant]
Harris, et al. (Mar. 2004) “Commercial Manufacturing Scale Formulation and Analytical Characterization of Therapeutic Recombinant Antibodies”, Drug Development Research, vol. 61, Issue 3, pp. 137-154. [cited by applicant]
Hilgenfeldt, et al. (Jun. 1, 1995) “Strategy of Measuring Bradykinin and Kallidin and Their Concentration in Plasma and Urine”, Analytical Biochemistry, vol. 228, No. 1, pp. 35-41. [cited by applicant]
Holland et al., “Bradykinin Induces Superoxide Anion Release from Human Endothelial Cells”, Journal of Cellular Physiology, 1990, 143: 21-25. [cited by applicant]
Holm, et al. (Feb. 2007) “Functional Mapping and Single Chain Construction of the Anti-Cytokeratin 8 Monoclonal Antibody TS1”, Molecular Immunology, vol. 44, No. 6, pp. 1075-1084. [cited by applicant]
International Search Report and Written Opinion received for PCT Patent Application No. PCT/US2013/031836, mailed on Jun. 5, 2013, 10 Pages. [cited by applicant]
James, et al. (Feb. 28, 2003) “Antibody Multispecificity Mediated by Conformational Diversity”, Science, vol. 299, Issue 5611, pp. 1362-1367. [cited by applicant]
Jones, et al. (Jan. 1977) “Proteinase mutants of [cited by applicant]
Jones, et al. (May 29, 1986) “Replacing the Complementarity-Determining Regions in a Human Antibody with Those from a Mouse”, Nature, vol. 321, No. 6069, pp. 522-525. [cited by applicant]
Jönsson, et al. (2003) “Effect of Spatially Distributed Hydrophobic Surface Residues on Protein-Polymer Association”, The Journal of Physical Chemistry B, vol. 107, No. 23, pp. 5511-5518. [cited by applicant]
Kabat, et al. (Oct. 10, 1977) “Unusual Distributions of Amino Acids in Complementarity-Determining (Hypervariable) Segments of Heavy and Light Chains of Immunoglobulins and Their Possible Roles in Specificity of Antibod… [cited by applicant]
Kakoki et al., “Senescence-associated phenotypes in Akita diabetic mice are enhanced by absence of bradykinin B2 receptors”, The Journal of Clinical Investigation, 2006, 116(5): 1302-1309. [cited by applicant]
Kakoki et al., “The kallikrein-kinin system in health and in diseases of the kidney”, Kidney Int., 2009, 75(10): 1019-1030. [cited by applicant]
Kingsman, et al. (1979) “Replication in [cited by applicant]
Kobayashi, et al. (Oct. 1999) “Tryptophan H33 Plays an Important Role in Pyrimidine (6-4) Pyrimidone Photoproduct Binding by a High-Affinity Antibody”, Protein Engineering, Design and Selection, vol. 12, No. 10, pp. 879… [cited by applicant]
Kundu, et al. (Aug. 2002) “Dynamics of Proteins in Crystals: Comparison of Experiment with Simple Models”, Biophysical Journal, vol. 83, No. 2, pp. 723-732. [cited by applicant]
Leong, et al. (Nov. 2001) “Adapting Pharmacokinetic Properties of a Humanized Anti-Interleukin-8 Antibody for Therapeutic Applications Using Site-Specific Pegylation”, Cytokine, vol. 16, Issue 3, pp. 106-119. [cited by applicant]
Liu, et al. (Jun. 6, 2006) “Characterization of the Stability of a Fully Human Monoclonal IgG After Prolonged Incubation at Elevated Temperature”, Journal of Chromatography B, vol. 837, Issues 1-2, pp. 35-43. [cited by applicant]
Maccallum, et al. (Oct. 11, 1996) “Antibody-Antigen Interactions: Contact Analysis and Binding Site Topography”, Journal of molecular biology, vol. 262, No. 5, pp. 732-745. [cited by applicant]
Mackerell, et al. (1998) “The Encyclopedia of Computational Chemistry”, vol. 1, pp. 271-277. [cited by applicant]
Monsellier, et al. (2006) “Improving the Stability of an Antibody Variable Fragment by a Combination of Knowledge-based Approaches: Validation and Mechanisms”, Journal of Molecular Biology, vol. 362, pp. 580-593. [cited by applicant]
Monsellier, et al. (Aug. 2007) “Prevention of Amyloid-Like Aggregation as a Driving Force of Protein Evolution”, EMBO Reports, vol. 8, Issue 8, pp. 737-742. [cited by applicant]
Morrison, et al. (1984) “Chimeric Human Antibody Molecules: Mouse Antigen-Binding Domains with Human Constant Region Domains”, Proceedings of the National Academy of Sciences, vol. 81, No. 21, pp. 6851-6855. [cited by applicant]
Morrison, Sherie, L. (Sep. 20, 1985) “Transfectomas Provide Novel Chimeric Antibodies”, Science, vol. 229, No. 4719, pp. 1202-1207. [cited by applicant]
Neuberger, et al. (1984) “Recombinant Antibodies Possessing Novel Effector Functions”, Nature, vol. 312, No. 5995, pp. 604-608. [cited by applicant]
Noda et al., “Neuroprotective role of bradykinin because of the attenuation of pro-inflammatory cytokine release from activated microglia”, Journal of Neurochemistry, 2007, 101: 397-410. [cited by applicant]
Odya, et al. (Dec. 1993) “Immunoassays for Des-Arg9-Bradykinin”, Journal of Immunoassay and Immunochemistry, vol. 14, No. 4, pp. 227-240. [cited by applicant]
Odya, et al. (Jul. 15, 1990) “Enzyme-Linked Immunosorbent Assays for Kinins Using High-Affinity Monoclonal Kinin Antibodies”, Biochemical Pharmacology, vol. 40, No. 2, pp. 245-251. [cited by applicant]
Oi et al., “Chimeric Antibodies”, BioTechniques, 1986, vol. 4, pp. 214-221. [cited by applicant]
Padlan, Eduardo A. (Apr.-May 1991) “A Possible Procedure for Reducing the Immunogenicity of Antibody Variable Domains While Preserving Their Ligand Binding Properties”, Molecular Immunology, vol. 28, No. 4-5, pp. 489-49… [cited by applicant]
Paige et al, “The top 10 things nephrologists wish every primary care physician knew”, Mayo Clin Proc., Feb. 2009, 84(2): 180-186. [cited by applicant]
Pascalis, et al. (Sep. 15, 2002) “Grafting of “Abbreviated” Complementarity-Determining Regions Containing Specificity-Determining Residues Essential for Ligand Contact to Engineer A Less Immunogenic Humanized Monoclona… [cited by applicant]
Peters, et al. (Mar. 2005) “The Immune Epitope Database and Analysis Resource: From Vision to Blueprint”, PLoS Biology, vol. 3, No. 3, e91, pp. 0379-0381. [cited by applicant]
Pietersz, et al. (Apr. 1987) “The Use of Monoclonal Antibody Conjugates for The Diagnosis and Treatment of Cancer”, Immunology and Cell Biology, vol. 65, Pt 2, pp. 111-125. [cited by applicant]
Richardson, Jane S. (1981) “The Anatomy and Taxonomy of Protein Structure”, Advances in Protein Chemistry, vol. 34, pp. 167-339. [cited by applicant]
Ridgway, Anthony A.G. (1988) “Vectors A survey of Molecular cloning Vectors and Their Uses”, Mammalian Expression Vectors, Biotechnology, Reading, Mass, vol. 10, pp. 467-492. [cited by applicant]
Riechmann, et al. (Mar. 24, 1988) “Reshaping Human Antibodies for Therapy”, Nature, vol. 332, No. 6162, pp. 323-327. [cited by applicant]
Rizzo (2000) “Validation of a Model for the Complex of HIV-1 Reverse Transcriptase with Sustiva through Computation of Resistance Profiles”, Journal of the American Chemical Society, vol. 122, No. 51, pp. 12898-12900. [cited by applicant]
Roguska, et al. (Feb. 1, 1994) “Humanization of Murine Monoclonal Antibodies Through Variable Domain Resurfacing”, Proceedings of the National Academy of Sciences, vol. 91, No. 3, pp. 969-973. [cited by applicant]
Rudikoff, et al. (Mar. 1, 1982) “Single Amino Acid Substitution Altering Antigen-Binding Specificity”, Proceedings of the National Academy of Sciences of the United States of America, vol. 79, pp. 1979-1983. [cited by applicant]
Saddi, et al. (Dec. 15, 2000) “The Formalin Test in the Mouse: A Parametric Analysis of Scoring Properties”, Pain, vol. 89, No. 1, pp. 53-63. [cited by applicant]
Seco, et al. (Apr. 23, 2009) “Binding Site Detection and Druggability Index from First Principles”, Journal of Medicinal Chemistry, vol. 52, No. 8, pp. 2363-2371. [cited by applicant]
Steipe, et al. (Jul. 15, 1994) “Sequence Statistics Reliably Predict Stabilizing Mutations in a Protein Domain”, Journal of Molecular Biology, vol. 240, No. 3, pp. 188-192. [cited by applicant]
Stinchcomb, et al. (Nov. 1, 1979) “Isolation and Characterisation of a Yeast Chromosomal Replicator”, Nature, vol. 282, No. 5734, pp. 39-43. [cited by applicant]
Studnicka, et al. (Jun. 1, 1994) “Human-Engineered Monoclonal Antibodies Retain Full Specific Binding Activity by Preserving Non-CDR Complementarity-Modulating Residues”, Protein Engineering, vol. 7, No. 6, pp. 805-814. [cited by applicant]
Sundberg, et al. (Jul. 15, 2000) “Luxury Accommodations: The Expanding Role of Structural Plasticity in Protein-Protein Interactions”, Structure, vol. 8, No. 7, pp. R137-R142. [cited by applicant]
Takeda, et al. (1985) “Construction of Chimaeric Processed Immunoglobulin Genes Containing Mouse Variable and Human Constant Region Sequences”, Nature, vol. 314, No. 6010, pp. 452-454. [cited by applicant]
Tomita et al., “The kallikrein-kinin system in diabetic nephropathy”, Kidney Int., Apr. 2012, 81(8): 733-744, epublished Feb. 8, 2012. [cited by applicant]
Vajdos, et al. (Jul. 1, 2002) “Comprehensive Functional Maps of the Antigen-Binding Site of an Anti-ErbB2 Antibody Obtained with Shotgun Scanning Mutagenesis”, Journal of Molecular Biology, vol. 320, No. 2, pp. 415-428. [cited by applicant]
Vita, et al. (Jan. 1, 2010) “The Immune Epitope Database 2.0”, Nucleic Acids Research, vol. 38, Issue suppl_1, pp. D854-D862. [cited by applicant]
Weir, et al. (2002) “Formatting Antibody Fragments to Mediate Specific Therapeutic Functions”, Biochemical Society Transactions, vol. 30, pp. 512-516. [cited by applicant]
Wilson, et al. (1984) “The Structure of an Antigenic Determinant in a Protein”, Cell, vol. 37, No. 3, pp. 767-778. [cited by applicant]
Wu, et al. (Nov. 19, 1999) “Humanization of a Murine Monoclonal Antibody by Simultaneous Optimization of Framework and CDR Residues”, Journal of Molecular Biology, vol. 294, No. 1, pp. 151-162. [cited by applicant]