IP Library › Granted Patent US 12,448,464
Granted Patent B2
US 12,448,464 · App. 17/933,229 · Granted Oct 21, 2025

Anti-PAD4 antibody

Inventors: Mamoru Sato (Yokohama, JP); Michiyuki Yamada (Yokohama, JP); Satoshi Kanazawa (Nagoya, JP); Masayoshi Toyoura (Kyoto, JP); Yuji Shoya (Kyoto, JP); Kenji Saito (Kyoto, JP); Chihiro Yamazaki (Kyoto, JP)
Assignees: PUBLIC UNIVERSITY CORPORATION YOKOHAMA CITY UNIVERSITY; PUBLIC UNIVERSITY CORPORATION NAGOYA CITY UNIVERSITY; PHARMA FOODS INTERNATIONAL CO., LTD.
C07K16/40A61K39/395A61K39/3955C12N9/99C12N15/09C12N15/63C12Y305/03015A61K2039/505C07K2317/24C07K2317/33C07K2317/34C07K2317/56C07K2317/565C07K2317/622C07K2317/76C07K2317/92
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Quick Facts
Patent No.
US 12,448,464
App. No.
17/933,229
Granted
Oct 21, 2025
Kind
B2
Abstract

Provided are anti-PAD4 antibodies having excellent properties and an excellent method for treatment of RA. Used are anti-PAD4 antibodies that specifically bind to an epitope containing positions 345, 347, and 348 of PAD4. These anti-PAD4 antibodies may inhibit the citrullination activity of PAD4. In addition, these anti-PAD4 antibodies may have a KD (M) of 9.0×10 −9 or less. Optionally, the anti-PAD4 antibody and a TNFα inhibitor are used in combination.

Claims (16)

1. A method of treating rheumatoid arthritis (RA) or arthritis comprising administering to a patient in need thereof an anti-PAD4 (peptidylarginine deiminase 4) antibody in combination with a TNFα inhibitor, wherein the antibody specifically binds to positions 345, 347, and 348 of human PAD4.

2. The method according to claim 1 , wherein the patient has already received the TNFα inhibitor.

3. The method according to claim 1 , wherein the antibody is a humanized antibody.

4. The method according to claim 1 , wherein the TNFα inhibitor is an anti-TNFα antibody, a TNF receptor-fusion protein, a dominant negative TNFα mutant, an RNAi molecule against TNFα, a miRNA molecule against TNFα, an antisense nucleic acid against TNFα, a polynucleotide encoding an RNAi molecule against TNFα, or a polynucleotide encoding an miRNA molecule against TNFα.

5. The method according to claim 1 , wherein the TNFα inhibitor is an anti-TNFα antibody or a TNF receptor-fusion protein.

6. A method of treating arthritis, comprising administering to a patient in need thereof an anti-PAD4 (peptidylarginine deiminase 4) antibody which specifically binds to an epitope containing positions 345, 347, and 348 of human PAD4.

7. The method according to claim 6 , wherein the antibody inhibits citrullination activity of PAD4.

8. The method according to claim 6 , wherein the antibody binds human PAD4 with a KD (M) of 9.0×10 −9 or less.

9. The method according to claim 6 , wherein the epitope is identified by alanine scan in which a single amino acid is replaced.

10. The method according to claim 6 , wherein the antibody is a monoclonal antibody.

11. The method according to claim 6 , wherein the antibody is a humanized antibody.

12. An anti-human PAD4 antibody which binds to a peptide, the amino acid sequence of which is set forth in SEQ ID NO: 1, but cannot bind to a peptide, the amino acid sequence of which is set forth in SEQ ID NO: 32, 34, or 35.

13. The anti-human PAD4 antibody according to claim 12 , wherein the antibody inhibits citrullination activity of PAD4.

14. The anti-human PAD4 antibody according to claim 12 , wherein the antibody binds human PAD4 with a KD (M) of 9.0×10 −9 or less.

15. The anti-human PAD4 antibody according to claim 12 , wherein the antibody is a humanized antibody.

16. A method of treating rheumatoid arthritis or arthritis, comprising administering to a patient in need thereof the anti-human PAD4 antibody according to claim 12 .

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 3, 2022
From: SATO, MAMORU; YAMADA, MICHIYUKI; KANAZAWA, SATOSHI; TOYOURA, MASAYOSHI; SHOYA, YUJI; SAITO, KENJI; YAMAZAKI, CHIHIRO
To: PUBLIC UNIVERSITY CORPORATION YOKOHAMA CITY UNIVERSITY; PUBLIC UNIVERSITY CORPORATION NAGOYA CITY UNIVERSITY; PHARMA FOODS INTERNATIONAL CO., LTD.
Reel/Frame 061291/0556 →
Priority Claims (1)
JP 2015-044518 · Mar 6, 2015 · national
Continuity (2)
Continuation 15555808
Related Publication 20230192890A1 · Jun 22, 2023
References Cited (37)
US 11447569B2 · Sato et al. · 2022 [cited by applicant]
US 20130101611A1 · Andrade et al. · 2013 [cited by applicant]
US 20150153356A1 · Meng et al. · 2015 [cited by applicant]
US 20180044434A1 · Sato et al. · 2018 [cited by applicant]
JP 2009156615A · 2009 [cited by applicant]
WO WO2012026309A1 · 2012 [cited by applicant]
WO WO2013143026A1 · 2013 [cited by applicant]
WO WO2016155745A1 · 2016 [cited by applicant]
English translation of WO 2012/026309 (Mar. 1, 2012). [cited by examiner]
Foulquier et al. Peptidyl Arginine Deiminase Type 2 (PAD-2) and PAD-4 but Not PAD-1, PAD-3, and PAD-6 Are Expressed in Rheumatoid Arthritis Synovium in Close Association With Tissue Inflammation. Arth Rheum 56(11): 3541… [cited by examiner]
Kinloch et al. Synovial Fluid Is a Site of Citrullination of Autoantigens in Inflammatory Arthritis. Arth Rheum 58(8): 2287-2295, 2008. [cited by examiner]
Koushik et al. PAD4: pathophysiology, current therapeutics and future perspective in rheumatoid arthritis. Exp Opin Ther Targets 21(4): 433-447, 2017. [cited by examiner]
Ma et al. TNF inhibitor therapy for rheumatoid arthritis (Review). Biomed Reports 1: 177-184, 2013. [cited by examiner]
Savelieff et al. Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis in the Last Decade. Chem Rev 119: 1221-1322, … [cited by examiner]
Abbott et al., “Current approaches to fine mapping of antigen-antibody interactions,” Immunology. 142(4):526-35 (2014). [cited by applicant]
Abcam datasheet for anti-PAD4 antibody “ab96758”, Jul. 15, 2019 (3 pages). [cited by applicant]
Andrade et al., “Autocitrullination of human peptidyl arginine deiminase type 4 regulates protein citrullination during cell activation,” Arthritis Rheum. 62(6):1630-40 (2010). [cited by applicant]
Arita et al., “Structural basis for Ca(2+)-induced activation of human PAD4,” Nat Struct Mol Biol. 11(8):777-83 (2004). [cited by applicant]
Bardelli et al., “Epitope Mapping by Solution NMR Spectroscopy,” J Mol Recognit. 28(6):393-400 (Jun. 2015). [cited by applicant]
Communication Pursuant to Article 94(3) EPC for European Application No. 16761721.6, dated Apr. 17, 2020 (11 pages). [cited by applicant]
Extended European Search Report dated Dec. 20, 2017 for European Patent Application No. 16761721.6, Sato et al., “Novel Anti-PAD4 Antibody,” filed Mar. 7, 2016 (13 pages). [cited by applicant]
International Search Report for International Application No. PCT/JP2016/057030, filed Mar. 7, 2016, Sato et al., “Novel Anti-PAD4 Antibody,” mailed Jun. 7, 2016 (6 pages). [cited by applicant]
Ishigami et al., “Two novel sandwich ELISAs identify PAD4 levels and PAD4 autoantibodies in patients with rheumatoid arthritis,” Mod Rheumatol. 23(4):794-803 (2013). [cited by applicant]
Kolodziej et al., “PADI4 acts as a coactivator of Tal1 by counteracting repressive histone arginine methylation,” Nat Commun 5:3995 (2014). [cited by applicant]
Lipman et al., “Monoclonal Versus Polyclonal Antibodies: Distinguishing Characteristics, Applications, and Information Resources,” ILAR J 46(3):258-68 (2005). [cited by applicant]
Lloyd et al., “Modelling the human immune response: performance of a 10 [cited by applicant]
Office Action dated May 13, 2019 for European Patent Application No. 16761721.6, Sato et al., “Novel Anti-PAD4 Antibody,” filed Mar. 7, 2016 (8 pages). [cited by applicant]
Paul, Chapter 9: Structure and Function of Immunoglobulins. Fundamental Immunology, Third Edition. Raven Press, 292-295 (1993) (6 pages). [cited by applicant]
Reineke, “Antibody epitope mapping using arrays of synthetic peptides,” DNA Repair Protocols. Methods in Molecular Biology. Humana Press. 248:443-63 (2004). [cited by applicant]
Rohrbach et al., “Activation of PAD4 in NET formation,” Front Immunol. 3:360. doi: 10.3389/fimmu.2012.00360 (2012) (10 pages). [cited by applicant]
Rudikoff et al., “Single amino acid substitution altering antigen-binding specificity,” Proc Natl Acad Sci USA. 79:1979-1983 (1982) (5 pages). [cited by applicant]
Shelef et al., “Peptidylarginine deiminase 4 contributes to tumor necrosis factor alpha-induced inflammatory arthritis,” Arthritis Rheumatol. 66(6):1482-91 (2014). [cited by applicant]
Simonyan et al., “Conformational Epitope Mapping by Cross-link Mass Spectrometry: Analysis of Ipilimumab, Nivolumab and Pembrolizumab,” https://covalx.com/pdf/171113-CovalX-XLMS%20Xray%20Comparions-PEGSEU17.pdf, dated N… [cited by applicant]
Stave et al., “Antibody and antigen contact residues define epitope and paratope size and structure,” J Immunol. 191(3):1428-35 (2013). [cited by applicant]
Summons to attend oral proceedings pursuant to Rule 115(1) EPC dated Apr. 7, 2022 for European Application No. 16761721.6, Sato et al., “Novel ANTI-PAD4 Antibody,” filed Mar. 7, 2016 (13 pages). [cited by applicant]
Suzuki et al., “Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis,” Nat Genet. 34(4):395-402 (2003). [cited by applicant]
Wu et al., “Humanization of a murine monoclonal antibody by simultaneous optimization of framework and CDR residues,” J Mol Biol. 294(1):151-62 (1999). [cited by applicant]