US2019056393A1PendingUtilityA1
Method of detecting auto-antibodies from patients suffering from rheumatoid arthritis, a peptide and assay kit
Assignee: STICHTING TECHNISCHE WETENSCHAPPENPriority: Dec 11, 2001Filed: Nov 2, 2018Published: Feb 21, 2019
Est. expiryDec 11, 2021(expired)· nominal 20-yr term from priority
Inventors:Waltherus Jacobus Wilhelmus Van VenrooijJan Wouter DrijfhoutMartinus Adrianus Maria Van BoekelGerardus Jozef Maria Pruijn
Y10S435/975Y10S530/806C07K 7/08G01N 2800/102C07K 14/4713G01N 33/564C07K 7/64G01N 2410/00Y10S435/973C07K 7/52G01N 33/6878C40B 30/04
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Claims
Abstract
Peptides useful in determining the presence of autoantibodies in patients suffering from rheumatoid arthritis are disclosed.
Claims
exact text as granted — not AI-modified1 . A method to detect the presence or absence of autoantibodies associated with rheumatoid arthritis (RA), which method comprises contacting a sample suspected of containing said antibodies with at least two peptide units for a time sufficiently long to allow a complex to be formed between the at least one of said peptide units and any said autoantibodies, and
detecting the presence or absence of the complex peptide unit wherein at least one peptide unit comprises the motif XG, and at least one peptide unit comprises the motif XnonG, wherein X is a citrulline residue or an analog thereof, G is the amino acid glycine and nonG is an amino acid other than glycine.
2 . The method of claim 1 , wherein nonG is an amino acid selected from H, I, W, S, R, K, Y, M, F, V, P, Cit or an analog thereof.
3 . The method of claim 1 , wherein at least one of the peptide units is a cyclic peptide unit.
4 . The method of claim 1 , wherein the peptide unit with XG motif and the peptide unit with XnonG motif are portions of a single peptide.
5 . The method of claim 1 , wherein the XnonG peptide unit is not derived from (pro)fillaggrin, fibrin, fibrinogen, vimentin, cytokeratin 1 or cytokeratin 9.
6 . The method of claim 1 , wherein the XG peptide unit is selected from the group consisting of:
(SEQ ID NO: 1)
0002-27
H Q K R G Cit G W S R A A
(SEQ ID NO: 2)
0002-29
H Q R R V Cit G W S R A A
(SEQ ID NO: 3)
0002-31
H Q R R I Cit G G S R A A
(SEQ ID NO: 4)
0002-32
H Q R K W Cit G A S R A A
(SEQ ID NO: 5)
0002-36
H Q F R F Cit G Cit S R A A
(SEQ ID NO: 6)
0002-37
H Q K W R Cit G R S Cit A A
and
(SEQ ID NO: 7)
0002-63
H Q F R F Cit G W S R A A
and the XnonG peptide unit is selected from the group consisting of:
(SEQ ID NO: 8)
0107-32
K P Y T V Cit K F M R R P
(SEQ ID NO: 9)
0107-35
A R F Q M Cit H Cit R L I R
(SEQ ID NO: 10)
0107-45
Y S F V W Cit S H A R P R
(SEQ ID NO: 11)
0113-30
A R F Q M R H Cit R L I R
and
(SEQ ID NO: 12)
0218-36
R N L R L Cit R E R N H A
7 . A peptide comprising a sequence with the formula (II):
(A1-A2-A3-A4-A5)-Cit-(A6)-(A7-A8-A9-A10-A11) (II)
wherein
A1-A2-A3-A4-A5 is an amino acid sequence selected from the group consisting of:
(SEQ ID NO: 13)
RHGRQ
(SEQ ID NO: 14)
IRCitYK
(SEQ ID NO: 15)
HGRQCit
(SEQ ID NO: 16)
GRQCitCit
(SEQ ID NO: 17)
FQMCitH
(SEQ ID NO: 18)
CitWRGM
(SEQ ID NO: 19)
ARFQM
(SEQ ID NO: 20)
QCitYKW
(SEQ ID NO: 21)
KPYTV
(SEQ ID NO: 22)
NRLRL
(SEQ ID NO: 23)
RRRCitY
(SEQ ID NO: 24)
RFKSN
(SEQ ID NO: 25)
RGKSN
(SEQ ID NO: 26)
RWVSQ
(SEQ ID NO: 27)
MKPRY
(SEQ ID NO: 28)
KSFVW
(SEQ ID NO: 29)
YSFVW
(SEQ ID NO: 30)
FQMRH
(SEQ ID NO: 31)
RNMNR
and
(SEQ ID NO: 32)
RMGRP
and sequences homologous thereto;
A6 represents an amino acid other than glycine;
A7-A8-A9-A10-A11 represents an amino acid sequence selected from the group consisting of:
(SEQ ID NO: 33)
KYIIY
(SEQ ID NO: 34)
TNRKF
(SEQ ID NO: 35)
KWCitKI
(SEQ ID NO: 36)
CitRAVI
(SEQ ID NO: 37)
RCitGHS
(SEQ ID NO: 38)
CitGRSR
(SEQ ID NO: 39)
CitYIIY
(SEQ ID NO: 40)
CitRLIR
(SEQ ID NO: 41)
IERKR
(SEQ ID NO: 42)
FMRKP
(SEQ ID NO: 43)
FMRRP
(SEQ ID NO: 44)
ERNHA
(SEQ ID NO: 45)
AVITA
(SEQ ID NO: 46)
TPNRW
(SEQ ID NO: 47)
TYNRW
(SEQ ID NO: 48)
RTPTR
(SEQ ID NO: 49)
RIVVV
(SEQ ID NO: 50)
HARPR
(SEQ ID NO: 51)
RGMCitR
and
(SEQ ID NO: 52)
IRFPV
and sequences homologous thereto.
8 . A peptide comprising a sequence with the formula (III):
(B1-B2-B3-B4-B5-B6)-Cit-(B7)-(B8-B9-B10-B11) (III)
wherein
B1-B2-B3-B4-B5-B6 is an amino acid sequence selected from the group consisting of:
(SEQ ID NO: 53)
INCitRAS
(SEQ ID NO: 54)
ICitKRLY
(SEQ ID NO: 55)
KCitCitYNI
(SEQ ID NO: 56)
RLYFICit
(SEQ ID NO: 57)
IRQGAR
(SEQ ID NO: 58)
CitERCitVQ
(SEQ ID NO: 59)
CitHQRIT
(SEQ ID NO: 60)
RICitRVCit
(SEQ ID NO: 61)
GRNQRY
(SEQ ID NO: 62)
RCitRQHP
(SEQ ID NO: 63)
CitCitRCitVA
(SEQ ID NO: 64)
RPKQHV
(SEQ ID NO: 65)
RKCitGCitR
(SEQ ID NO: 66)
RCitCitRNT
(SEQ ID NO: 67)
RCitQCitFT
(SEQ ID NO: 68)
QLVYLQ
(SEQ ID NO: 69)
QYNRFK
(SEQ ID NO: 70)
CitLRHIR
(SEQ ID NO: 71)
PRCitCitCitK
(SEQ ID NO: 72)
RCitQVRY
(SEQ ID NO: 73)
GRCitHAH
(SEQ ID NO: 74)
ARHVIR
(SEQ ID NO: 75)
RCitGHMF
(SEQ ID NO: 76)
GRNIRV
(SEQ ID NO: 77)
QIFYLCit
(SEQ ID NO: 78)
RQGPIA
(SEQ ID NO: 79)
GVYLVR
(SEQ ID NO: 80)
NCitCitRRV
(SEQ ID NO: 81)
KCitRLCitY
(SEQ ID NO: 82)
GRRCitCitL
and
(SEQ ID NO: 83
RMPHCitH
and sequences homologous thereto;
B7 represents an amino acid other than glycine;
B8-B9-B10-B11 represents an amino acid sequence selected from the group consisting of:
(SEQ ID NO: 84)
CitHRR
(SEQ ID NO: 85)
CitIRR
(SEQ ID NO: 86)
FRRN
(SEQ ID NO: 87)
AQTT
(SEQ ID NO: 88)
GYPK
(SEQ ID NO: 89)
RPPQ
(SEQ ID NO: 90)
GCitRK
(SEQ ID NO: 91)
PIPR
(SEQ ID NO: 92)
YTIH
(SEQ ID NO: 93)
RIKA
(SEQ ID NO: 94)
CitRVR
(SEQ ID NO: 95)
TRRP
(SEQ ID NO: 96)
TIRP
(SEQ ID NO: 97)
IKCitR
(SEQ ID NO: 98)
RNVV
(SEQ ID NO: 99)
CitRRy
(SEQ ID NO: 100)
CitRPR
(SEQ ID NO: 101)
TRCitCit
(SEQ ID NO: 102)
CitCitGR
(SEQ ID NO: 103)
LCitRCit
(SEQ ID NO: 104)
RVRCit
(SEQ ID NO: 105)
VPRT
(SEQ ID NO: 106)
YCitFR
(SEQ ID NO: 107)
ARCitCit
(SEQ ID NO: 108)
RQCitR
(SEQ ID NO: 109)
HIRR
(SEQ ID NO: 110)
CitMMR
(SEQ ID NO: 111)
CitRICit
(SEQ ID NO: 112)
VRKS
(SEQ ID NO: 113)
PCitCitR
and
(SEQ ID NO: 114)
CitRRK
and sequences homologous thereto.
9 . The peptide of claim 7 , wherein A6 is selected from the group consisting of Cit, H, I, K, R, S, W, Y, M, F, V and P.
10 . The peptide of claim 7 , wherein the peptide is a cyclic peptide comprising a ring of at least 8 amino acids.
11 . The peptide of claim 10 , wherein the ring comprises at least 11 amino acids.
12 . The peptide of claim 7 which comprises the peptide sequence
(SEQ ID NO: 115)
R H G R Q Cit Cit K Y I I Y
(SEQ ID NO: 116)
I R Cit Y K Cit I T N R K F
(SEQ ID NO: 117)
R H G R Q Cit Cit Cit Y I I Y
(SEQ ID NO: 118)
A R F Q M Cit H Cit R L I R
(SEQ ID NO: 119)
Q Cit Y K W Cit K I E R K R
(SEQ ID NO: 120)
K P Y T V Cit K F M R K P
(SEQ ID NO: 121)
K P Y T V Cit K F M R R P
(SEQ ID NO: 122)
R N L R L Cit R E R N H A
(SEQ ID NO: 123)
R R R Cit Y Cit R A V I T A
(SEQ ID NO: 124)
R F K S N Cit R I P N R W
(SEQ ID NO: 125)
R G K S N Cit R T Y N R W
(SEQ ID NO: 126)
R F K S N Cit R T Y N R W
(SEQ ID NO: 127)
R G K S N Cit R I P N R W
(SEQ ID NO: 128)
R W V S Q Cit R R I P I R
(SEQ ID NO: 129)
M K P R Y Cit R R I V V V
(SEQ ID NO: 130)
K S F V W Cit S H A R P R
(SEQ ID NO: 131)
Y S F V W Cit S H A R P R
(SEQ ID NO: 132)
R N M N R Cit W R G M Cit R ,
or
(SEQ ID NO: 133)
R M G R P Cit W I R F P V
or an analog thereof.
13 . The peptide of claim 8 , which comprises a peptide sequence selected from
(SEQ ID NO: 134)
I N Cit R A S Cit K Cit H R R
(SEQ ID NO: 135)
I Cit K R L Y Cit M Cit I R R
(SEQ ID NO: 136)
K Cit Cit Y N I Cit Cit F R R N
(SEQ ID NO: 137)
R L Y F I Cit Cit R A Q T T
(SEQ ID NO: 138)
I R Q G A R Cit R G Y P K
(SEQ ID NO: 139)
Cit E R Cit V Q Cit R R P P Q
(SEQ ID NO: 140)
Cit H Q R I T Cit V G Cit R K
(SEQ ID NO: 141)
R I Cit R V Cit Cit T P I P R
(SEQ ID NO: 142)
G R N Q R Y Cit L Y T I H
(SEQ ID NO: 143)
R Cit R Q H P Cit H R I K A
(SEQ ID NO: 144)
Cit Cit R Cit V A Cit F Cit R V R
(SEQ ID NO: 145)
R P K Q H V Cit H T R R P
(SEQ ID NO: 146)
R K Cit G Cit R Cit Cit T I R P
(SEQ ID NO: 147)
R Cit Cit R N T Cit H I K Cit R
(SEQ ID NO: 148)
R Cit Q Cit F T Cit Cit R N V V
(SEQ ID NO: 149)
Q L V Y L Q Cit Cit Cit R R Y
(SEQ ID NO: 150)
Q Y N R F K Cit Cit Cit R P R
(SEQ ID NO: 151)
Cit L R H I R Cit Q T R Cit Cit
(SEQ ID NO: 152)
P R Cit Cit Cit K Cit R Cit Cit G R
(SEQ ID NO: 153)
R Cit Q V R Y Cit Cit L Cit R Cit
(SEQ ID NO: 154)
G R Cit H A H Cit P R V R Cit
(SEQ ID NO: 155)
A R H V I R Cit Cit V P R T
(SEQ ID NO: 156)
R Cit G H M F Cit V Y Cit F R
(SEQ ID NO: 157)
G R N I R V Cit Cit A R Cit Cit
(SEQ ID NO: 158)
Q I F Y L Cit Cit H R Q Cit R
(SEQ ID NO: 159)
R Q G P I A Cit L H I R R
(SEQ ID NO: 160)
G V Y L V R Cit L Cit M M R
(SEQ ID NO: 161)
N Cit Cit R R V Cit M Cit R I Cit
(SEQ ID NO: 162)
K Cit R L Cit Y Cit P V R K S
(SEQ ID NO: 163)
G R R Cit Cit L Cit R P Cit Cit R
or
(SEQ IS NO: l61)
R M P H Cit H Cit S Cit R R K
or an analog thereof.
14 . A peptide comprising a sequence with the formula (IV)
(C1-C2)-(C3-C4-C5)-X-G-C6-(C7-C8-C9-C10) (IV)
wherein C1-C2 is HQ, GF, EG or GV; C3-C4-05 represents 3 amino acids of which at least 1 is basic, aromatic or V; C6 is a basic or aromatic amino acid, or is A, G, E, P, V, S or Cit or analog thereof; and C7-C8-C9-C10 is SRAA (SEQ ID NO:208), SCitAA (SEQ ID NO:209), RPLD (SEQ ID NO:210), RVVE (SEQ ID NO:211) or PGLD (SEQ ID NO:212); and analogs of the peptide with the formula (IV).
15 . The peptide of claim 14 , which is a cyclic peptide comprising a ring of at least 8 amino acids.
16 . The peptide of claim 15 , wherein the ring comprises at least 11 amino acids.
17 . The peptide of claim 14 , which is
(SEQ ID NO: 165)
H Q R K W Cit G A S R A A
(SEQ ID NO: 166)
H Q H W R Cit G A S R A A
(SEQ ID NO: 167)
H Q F R F Cit G Cit S R A A
(SEQ ID NO: 168)
H Q E R R Cit G E S R A A
(SEQ ID NO: 169)
H Q K W R Cit G F S R A A
(SEQ ID NO: 170)
H Q R W K Cit G G S R A A
(SEQ ID NO: 171)
H Q R R T Cit G G S R A A
(SEQ ID NO: 172)
H Q R R G Cit G G S R A A
(SEQ ID NO: 173)
H Q Cit F R Cit G H S R A A
(SEQ ID NO: 174)
G F F S A Cit G H R P L D
(SEQ ID NO: 175)
H Q E R G Cit G K S R A A
(SEQ ID NO: 176)
H Q E K R Cit G K S R A A
(SEQ ID NO: 177)
H Q R W L Cit G K S R A A
(SEQ ID NO: 178)
H Q K R N Cit G K S R A A
(SEQ ID NO: 179)
E G G G V Cit G P R V V E
(SEQ ID NO: 180)
H Q W R H Cit G R S Cit A A
(SEQ ID NO: 181)
H Q K W N Cit G R S R A A
(SEQ ID NO: 182)
H Q K F W Cit G R S R A A
(SEQ ID NO: 183)
H Q K Cit K Cit G R S R A A
(SEQ ID NO: 184)
H Q K W R Cit G R S Cit A A
(SEQ ID NO: 185)
H Q A W R Cit G R S Cit A A
(SEQ ID NO: 186)
H Q N Q W Cit G R S R A A
(SEQ ID NO: 187)
H Q N S K Cit G R S R A A
(SEQ ID NO: 188)
H Q K R R Cit G R S R A A
(SEQ ID NO: 189)
H Q K R F Cit G R S R A A
(SEQ ID NO: 190)
H Q K R Y Cit G R S R A A
(SEQ ID NO: 191)
H Q K R H Cit G R S R A A
(SEQ ID NO: 192)
H Q E R A Cit G S S R A A
(SEQ ID NO: 193)
H Q E K M Cit G V S R A A
(SEQ ID NO: 194)
H Q K R G Cit G W S R A A
(SEQ ID NO: 195)
H Q R R V Cit G W S R A A
(SEQ ID NO: 196)
H Q W N R Cit G W S R A A
(SEQ ID NO: 197)
H Q Q R M Cit G W S R A A
(SEQ ID NO: 198)
H Q S H R Cit G W S R A A
(SEQ ID NO: 199)
H Q F R F Cit G W S R A A
(SEQ ID NO: 200)
H Q K R R Cit G W S R A A
or
(SEQ ID NO: 201)
G V K G H Cit G Y P G L D
or an analog thereof.
18 . A peptide comprising
(a) a peptide unit with the formula (II) or (III) or analogs thereof and (b) a peptide with the formula (IV) or an analog thereof
wherein each peptide unit may be linear or cyclic.
19 . A diagnostic test kit for determining the presence or absence of autoantibodies to rheumatoid arthritis, comprising a peptide according to any of claim 7 , 8 , 14 or 18 or mixtures thereof, together with at least one further reagent.
20 . A method to select a peptide for diagnosis of RA, which comprises screening a peptide library with antibodies obtained from patients with RA and wherein the peptide library is selected from a group consisting of:
Lib (1):
(SEQ ID NO: 202)
H Q E X X Cit X X S R A A
Wherein X =any amino acid except cysteine and tryptophan;
Lib (2):
(SEQ ID NOS: 203-204)
H Q X X X Cit G X S R/Cit A A
Wherein X =any amino acid except cysteine but including Citrulline;
Lib (3):
(SEQ ID NOS: 205-206)
H Q E X X Cit X X S R/Cit A A
Wherein X =any amino acid except cysteine but including Citrulline; and
Lib (4):
(SEQ ID NO: 207)
X X X X X X Cit X X X X X
Wherein X =any amino acid except cysteine but including Citrulline or equivalents thereof.
21 . A peptide obtainable by the method of claim 20 .
22 . The peptide of claim 8 , wherein A6 is selected from the group consisting of Cit, H, I, K, R, S, W, Y, M, F, V and P.
23 . The peptide of claim 22 , wherein the peptide is a cyclic peptide comprising a ring of at least 8 amino acids.
24 . The peptide of claim 23 , wherein the ring comprises at least 11 amino acids.
25 . The method of claim 1 wherein said peptide comprising the motif XG and the peptide comprising the motif XnonG are separate peptides.Join the waitlist — get patent alerts
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