IL-17A Antagonists
AssigneeJanssen Biotech, Inc.
InventorsJuan Carlos Almagro, Daniela Della Ducata, Merle Elloso, Jinquan Luo, Thomas Malia, Michael Naso, Galina Obmolova, Robert Rauchenberger, Mark Rutz, Raymond Sweet, Susann Taudte, Bingyuan Wu, Sheng-Jiun Wu
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Abstract
Interleukin-17A (IL-17A) antibody antagonists, polynucleotides encoding IL-17A antibody antagonists or fragments thereof, and methods of making and using the foregoing are disclosed.
Claims48
An isolated antibody or fragment thereof, wherein the antibody binds specifically to human IL-17A having the sequence shown in SEQ ID NO:
- 105 at amino acid residues 56-68 (SEQ ID NO:
- 157) and 100-116 (SEQ ID NO:
- 158);
- or at residues L26, R55, E57, P59, E60, R61, Y62, S64, V65, W67, R101, E102, P103 and F110.
An isolated antibody or fragment thereof, wherein the antibody binds specifically to a P2 pocket cavity on human IL-17A, the P2 pocket cavity comprising amino acid residues V22, V24, L26, 128, Y62, L99, R101, F110, and L112 of SEQ ID NO:
- 105.
An isolated antibody or fragment that binds specifically to human IL-17A that competes for human IL-17A binding with a monoclonal antibody comprising the heavy chain CDR 1, 2 and 3 (HCDR1, HCDR2 and HCDR3) amino acid sequences as shown in SEQ ID NOs:
- 25, 43 and 60, respectively, and the light chain CDR 1, 2 and 3 (LCDR1, LCDR2 and LCDR3) amino acid sequences as shown in SEQ ID NOs:
- 3, 6 and 18, respectively.
An isolated antibody or fragment that binds specifically to human IL-17A, comprising heavy chain variable region paratope amino acid residues that interact with residues of human IL-17A having the amino acid sequence shown in SEQ ID NO:
- 105, comprising:
- a. a first threonine residue that interacts with R55 or E57 of human IL-17A;
- b. a glutamine residue that interacts with R55 or E57 of human IL-17A;
- c. a lysine residue that interacts with E57 of human IL-17A;
- d. a tyrosine residue that interacts with P59, E60 or R101 of human IL-17A;
- e. a phenylalanine residue that interacts with E60, R101, E102 or P103 of human IL-17A;
- f. a serine residue that interacts with E60 of human IL-17A;
- and
- g. a second threonine residue that interacts with E60 of human IL-17A.
An isolated antibody or fragment that binds specifically to human IL-17A, comprising light chain variable region paratope amino acid residues that interact with residues of human IL-17A having the amino acid sequence shown in SEQ ID NO:
- 105, comprising:
- a. a first phenylalanine residue that interacts with L26 of human IL-17A;
- b. an aspartic acid residue that interacts with R55 or W67 of human IL-17A;
- c. a first tyrosine residue that interacts with P59, S64 or R101 of human IL-17A;
- d. a second phenylalanine residue that interacts with P59, E60, R61, Y62, R101 or F110 of human IL-17A;
- and
- e. a second tyrosine residue that interacts with V65 of human IL-17A.
An isolated antibody or fragment that binds specifically to human IL-17A, comprising a heavy chain variable region and a light chain variable region, wherein the antibody comprises:
- a. a heavy chain variable region paratope selected from Chothia residues S51, T53, F56, Y58, Q95, L96 and T97;
- or
- b. a light chain variable region paratope selected from Chothia residues Y32, D50, Y91, F93 and F94;
- or
- c. a heavy chain variable region paratope selected from Chothia residues S51, T53, F56, Y58, Q95, L96 and T97 and
- d. a light chain variable region paratope selected from Chothia residues Y32, D50, Y91, F93 and F94.
An isolated antibody or fragment that binds specifically to human IL-17A, comprising heavy chain variable region paratope amino acid residues and light chain variable region paratope amino acid residues that interact with residues of human IL-17A having the amino acid sequence shown in SEQ ID NO:
- 105, comprising:
- a. a tyrosine residue in the heavy chain variable region that interacts with R101 of human IL-17A;
- b. a phenylalanine residue in the heavy chain variable region that interacts with R101 of human IL-17A;
- c. a first phenylalanine residue in the light chain variable region that interacts with Y62 and R101 of human IL-17A;
- d. a second phenylalanine residue in the light chain variable region that interacts with L26 and F110 of human IL-17A;
- and
- e. a tyrosine residue in the light chain variable region that interacts with R101 of human IL-17A.
An isolated antibody or fragment that binds specifically to human IL-17A, comprising a heavy chain variable region and a light chain variable region, wherein the antibody comprises:
- a. a heavy chain variable region paratope selected from Chothia residues F56 and Y58;
- and
- b. a light chain variable region paratope selected from Chothia residues Y91, F93 and F94.
An isolated antibody or fragment thereof that binds specifically to human IL-17A, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the antibody comprises:
- a. the heavy chain complementarity determining region (CDR) 1, 2 and 3 (HCDR1, HCDR2, HCDR3) amino acid sequences as shown in SEQ ID NOs:
- 23, 35 and 52, respectively, wherein the HCDR2 of SEQ ID NO:
- 35 is further defined as shown in Formula (I):
- Xaa1-I-I-P-W-F-G-Xaa2-T-Xaa3-Y-A-Q-K-F-Q-G, (I)
- wherein
- Xaa1 may be His, Met, Arg, Ser or Tyr;
- Xaa2 may be Trp, Thr or Tyr;
- and
- Xaa3 may be Tyr, Phe, Ser or Asp;
- or
- b. the HCDR1, HCDR2, and HCDR3 amino acid sequences as shown in SEQ ID NOs:
- 23, 35 and 52, respectively, wherein the HCDR2 of SEQ ID NO:
- 35 is further defined as shown in Formula (I):
- Xaa1-I-I-P-W-F-G-Xaa2-T-Xaa3-Y-A-Q-K-F-Q-G, (I)
- wherein
- Xaa1 may be His, Met, Arg, Ser or Tyr;
- Xaa2 may be Trp, Thr or Tyr;
- and
- Xaa3 may be Tyr, Phe, Ser or Asp;
- and
- the light chain complementarity determining reigon (CDR) 1, 2 and 3 (LCDR1, LCDR2, LCDR3) amino acid sequences as shown in SEQ ID NOs:
- 1, 4 and 7, respectively;
- or
- c. the LCDR1, LCDR2, and LCDR3 amino acid sequences as shown in SEQ ID NOs:
- 2, 5 and 11, respectively, wherein the LCDR3 of SEQ ID NO:
- 11 is further defined as shown in Formula (II):
- Xaa4-Q-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa010 (II)
- wherein
- Xaa4 may be His or Gln;
- Xaa5 may be Phe or Gly;
- Xaa6 may be Thr, Val or Asn;
- Xaa7 may be Ile, Thr or Tyr;
- Xaa8 may be Pro or Arg;
- Xaa9 may be Ser or Pro;
- and
- Xaa10 may be His, Phe or Leu;
- or
- d. the LCDR1, LCDR2, and LCDR3 amino acid sequences as shown in SEQ ID NOs:
- 2, 5 and 11, respectively, wherein the LCDR3 of SEQ ID NO:
- 11 is further defined as shown in Formula (II):
- Xaa4-Q-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10, (II)
- wherein
- Xaa4 may be His or Gln;
- Xaa5 may be Phe or Gly;
- Xaa6 may be Thr, Val or Asn;
- Xaa7 may be Ile, Thr or Tyr;
- Xaa8 may be Pro or Arg;
- Xaa9 may be Ser or Pro;
- and
- Xaa10 may be His, Phe or Leu;
- and
- the HCDR1, HCDR2, and HCDR3 amino acid sequences as shown in SEQ ID NOs:
- 24, 36 and 53, respectively;
- or
- e. the HCDR1, HCDR2, and HCDR3 amino acid sequences as shown in SEQ ID NOs:
- 24, 36 and 57, respectively, wherein the HCDR3 of SEQ ID NO:
- 57 is further defined as shown in Formula (IV):
- E-V-D-S-Xaa19-Y-Y-S-Y-F-D-I, (IV)
- wherein
- Xaa19 is Met, Ile, Leu or Thr;
- or
- f. the LCDR1, LCDR2, and LCDR3 amino acid sequences as shown in SEQ ID NOs:
- 2, 5 and 17, respectively, wherein the LCDR3 of SEQ ID NO:
- 17 is further defined as shown in Formula (III):
- Xaa11-Q-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Xaa18-T, (III)
- wherein
- Xaa11 may be Gln or Thr;
- Xaa12 may be Ser or Tyr;
- Xaa13 may be Asn, Arg, Val or Tyr;
- Xaa14 may be His or Ser;
- Xaa15 may be Ile, Thr, Leu, Ala or Ser;
- Xaa16 may be Pro, Leu or Ser;
- Xaa17 may be Pro, Ser, Phe or Leu;
- and
- Xaa18 may be Ala, Leu or Asp;
- or
- g. the HCDR1, HCDR2 and HCDR3 amino acid sequences as shown in SEQ ID NOs:
- 24, 36 and 57, respectively, wherein the HCDR3 of SEQ ID NO:
- 57 is further defined as shown in Formula (IV):
- E-V-D-S-Xaa19-Y-Y-S-Y-F-D-I, (IV)
- wherein
- Xaa19 is Met, Ile, Leu or Thr;
- and
- the LCDR1, LCDR2, and LCDR3 amino acid sequences as shown in SEQ ID NOs:
- 2, 5 and 17, respectively, wherein the LCDR3 of SEQ ID NO:
- 17 is further defined as shown in Formula (III):
- Xaa11-Q-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Xaa18-T, (III)
- wherein
- Xaa11 may be Gln or Thr;
- Xaa12 may be Ser or Tyr;
- Xaa13 may be Asn, Arg, Val or Tyr;
- Xaa14 may be His or Ser;
- Xaa15 may be Ile, Thr, Leu, Ala or Ser;
- Xaa16 may be Pro, Leu or Ser;
- Xaa17 may be Pro, Ser, Phe or Leu;
- and
- Xaa18 may be Ala, Leu or Asp;
- or
- h. the HCDR1, HCDR2 and HCDR3 amino acid sequences as shown in SEQ ID NOs:
- 25, 46 and 61, respectively, wherein the HCDR2 of SEQ ID NO:
- 46 is further defined as shown in Formula (VI):
- Xaa21-I-Xaa22-Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Xaa28-Xaa29-Y-A-D-S-V-K-G, (VI)
- wherein
- Xaa21 may be Ala, Gly, Thr or Val;
- Xaa22 may be Asn or Ser;
- Xaa23 may be Gly, Met, Lys, Ile, Leu or His;
- Xaa24 may be Leu, Asp, Ala, His, Thr, Gly or Ser;
- Xaa25 may be Gly or Ser;
- Xaa26 may be Thr, Gly, Tyr or Asp;
- Xaa27 may be His, Trp, Tyr or Phe;
- Xaa28 may be Lys, Thr or Ile;
- and
- Xaa29 may be Tyr, Phe or Asn;
- and
- the HCDR3 of SEQ ID NO:
- 61 is further defined as shown in Formula (VII):
- Q-L-Xaa30-L-D-V, (VII)
- wherein
- Xaa30 may be Met, Leu or Thr;
- or
- i. the LCDR1, LCDR2, and LCDR3 amino acid sequences as shown in SEQ ID NOs:
- 3, 6 and 22, respectively, wherein the LCDR3 of SEQ ID NO:
- 22 is further defined as shown in Formula (V):
- G-S-Y-D-F-F-L-G-Xaa20-I-V, (V)
- wherein
- Xaa20 is Met, Leu, Thr or Tyr;
- or
- j. the HCDR1, HCDR2 and HCDR3 amino acid sequences as shown in SEQ ID NOs:
- 25, 46 and 61, respectively, wherein the HCDR2 of SEQ ID NO:
- 46 is further defined as shown in Formula (VI):
- Xaa21-I-Xaa22-Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Xaa28-Xaa29-Y-A-D-S-V-K-G, (VI)
- wherein
- Xaa21 may be Ala, Gly, Thr or Val;
- Xaa22 may be Asn or Ser;
- Xaa23 may be Gly, Met, Lys, Ile, Leu or His;
- Xaa24 may be Leu, Asp, Ala, His, Thr, Gly or Ser;
- Xaa25 may be Gly or Ser;
- Xaa26 may be Thr, Gly, Tyr or Asp;
- Xaa27 may be His, Trp, Tyr or Phe;
- Xaa28 may be Lys, Thr or Ile;
- and
- Xaa29 may be Tyr, Phe or Asn;
- and
- the HCDR3 of SEQ ID NO:
- 61 is further defined as shown in Formula (VII):
- Q-L-Xaa30-L-D-V, (VII)
- wherein
- Xaa30 may be Met, Leu or Thr;
- and
- the LCDR1, LCDR2, and LCDR3 amino acid sequences as shown in SEQ ID NOs:
- 3, 6 and 22, respectively, wherein the LCDR3 of SEQ ID NO:
- 22 is further defined as shown in Formula (V):
- G-S-Y-D-F-F-L-G-Xaa20-I-V, (V)
- wherein
- Xaa20 is Met, Leu, Thr or Tyr;
- or
- k. the HCDR1, HCDR2 and HCDR3 amino acid sequences as shown in SEQ ID NOs:
- 25, 51 and 58, respectively, wherein the HCDR2 of SEQ ID NO:
- 51 is further defined as shown in Formula (VIII):
- V-T-S-Xaa31-Xaa32-Xaa33-Xaa34-T-Y-Y-A-Xaa35-S-V-K-G, (VIII)
- wherein
- Xaa31 may be Ala, Lys, Met or His;
- Xaa32 may be Asn, Met, Thr or Arg;
- Xaa33 may be Gly or Asp;
- Xaa34 may be Arg, His or Asn;
- and
- Xaa35 may be Asp or Gly;
- or
- l. the HCDR1, HCDR2 and HCDR3 amino acid sequences as shown in SEQ ID NOs:
- 25, 51 and 58, respectively, wherein the HCDR2 of SEQ ID NO:
- 51 is further defined as shown in Formula (VIII):
- V-T-S-Xaa31-Xaa32-Xaa33-Xaa34-T-Y-Y-A-Xaa35-S-V-K-G, (VIII)
- wherein
- Xaa31 may be Ala, Lys, Met or His;
- Xaa32 may be Asn, Met, Thr or Arg;
- Xaa33 may be Gly or Asp;
- Xaa34 may be Arg, His or Asn;
- and
- Xaa35 may be Asp or Gly;
- and
- the LCDR1, LCDR2, and LCDR3 amino acid sequences as shown in SEQ ID NOs:
- 3, 6 and 18, respectively.
An isolated antibody or fragment thereof that binds specifically to human IL-17A, comprising a VH and a VL region, wherein the antibody comprises the HCDR1, HCDR2 and HCDR3 amino acid sequences as shown in
- a. SEQ ID NOs:
- 23, 26 and 52, respectively;
- b. SEQ ID NOs:
- 23, 27 and 52, respectively;
- c. SEQ ID NOs:
- 23, 28 and 52, respectively;
- d. SEQ ID NOs:
- 23, 29 and 52, respectively;
- e. SEQ ID NOs:
- 23, 30 and 52, respectively;
- f. SEQ ID NOs:
- 23, 31 and 52, respectively;
- g. SEQ ID NOs:
- 23, 32 and 52, respectively;
- h. SEQ ID NOs:
- 23, 33 and 52, respectively;
- or
- i. SEQ ID NOs:
- 23, 34 and 52, respectively.
An isolated antibody or fragment that binds specifically to human IL-17A, comprising a VH and a VL, wherein in the antibody comprises the LCDR1, LCDR2, and LCDR3 amino acid sequences as shown in SEQ ID NOs:
- 1, 4 and 7, respectively.
An isolated antibody or fragment binds specifically to human IL-17A, comprising a Vh and a VL, wherein the antibody comprises the LCDR1, LCDR2, and LCDR3 amino acid sequences as shown in:
- a. SEQ ID NOs:
- 2, 5 and 8, respectively;
- b. SEQ ID NOs:
- 2, 5 and 9, respectively;
- or
- c. SEQ ID NOs:
- 2, 5 and 10, respectively.
An isolated antibody or fragment that binds specifically to human IL-17A, comprising a VH and a VL, wherein the antibody comprises the HCDR1, HCDR2 and HCDR3 amino acid sequences as shown in:
- a. SEQ ID NOs:
- 24, 36 and 53, respectively;
- b. SEQ ID NOs:
- 24, 36 and 54, respectively;
- c. SEQ ID NOs:
- 24, 36 and 55, respectively;
- or
- d. SEQ ID NOs:
- 24, 36 and 56, respectively.
An isolated antibody or fragment that binds specifically to human IL-17A, comprising a VH and a VL, wherein the antibody comprises the LCDR1, LCDR2, and LCDR3 amino acid sequences as shown in:
- a. SEQ ID NOs:
- 2, 5 and 12, respectively;
- b. SEQ ID NOs:
- 2, 5 and 13, respectively;
- c. SEQ ID NOs:
- 2, 5 and 14, respectively;
- d. SEQ ID NOs:
- 2, 5 and 15, respectively;
- e. SEQ ID NOs:
- 2, 5 and 16, respectively.
An isolated antibody or fragment binds specifically to human IL-17A, comprising a VH and a VL, wherein the antibody comprises the HCDR1, HCDR2 and HCDR3 amino acid sequences as shown in:
- a. SEQ ID NOs:
- 25, 37 and 58, respectively;
- b. SEQ ID NOs:
- 25, 38 and 58, respectively;
- c. SEQ ID NOs:
- 25, 39 and 58, respectively;
- d. SEQ ID NOs:
- 25, 40 and 58, respectively;
- e. SEQ ID NOs:
- 25, 41 and 58, respectively;
- f. SEQ ID NOs:
- 25, 42 and 58, respectively;
- g. SEQ ID NOs:
- 25, 43 and 58, respectively;
- h. SEQ ID NOs:
- 25, 41 and 59, respectively;
- i. SEQ ID NOs:
- 25, 41 and 60, respectively;
- j. SEQ ID NOs:
- 25, 43 and 60, respectively;
- k. SEQ ID NOs:
- 25, 44 and 58, respectively;
- or
- l. SEQ ID NOs:
- 25, 45 and 58, respectively.
An isolated antibody or fragment binds specifically to human IL-17A, comprising a VH and a VL, wherein the antibody comprises the LCDR1, LCDR2, and LCDR3 amino acid sequences as shown in:
- a. SEQ ID NOs:
- 3, 6 and 18, respectively;
- b. SEQ ID NOs:
- 3, 6 and 19, respectively;
- c. SEQ ID NOs:
- 3, 6 and 20, respectively;
- or
- d. SEQ ID NOs:
- 3, 6 and 21, respectively.
An isolated antibody or fragment that binds specifically to human IL-17A, comprising a VH and a VL, wherein the antibody comprises the HCDR1, HCDR2 and HCDR3 amino acid sequences as shown in::
- a. SEQ ID NOs:
- 25, 47 and 58, respectively;
- b. SEQ ID NOs:
- 25, 48 and 58, respectively;
- c. SEQ ID NOs:
- 25, 49 and 58, respectively;
- or
- d. SEQ ID NOs:
- 25, 50 and 58, respectively.
An isolated antibody or fragment that binds specifically to human IL-17A comprising a VH and a VL, wherein the antibody comprises:
- a. the HCDR1, HCDR2 and HCDR3 amino acid sequences as shown in SEQ ID NOs:
- 25, 43 and 60, respectively;
- or
- b. the LCDR1, LCDR2, and LCDR3 amino acid sequences as shown in SEQ ID NOs:
- 3, 6 and 18, respectively;
- or
- c. the HCDR1, HCDR2 and HCDR3 amino acid sequences as shown in SEQ ID NOs:
- 25, 43 and 60, respectively and the LCDR1, LCDR2, and LCDR3 amino acid sequences as shown in SEQ ID NOs:
- 3, 6 and 18, respectively;
- or
- d. the VH of SEQ ID NO:
- 86;
- or
- e. the VL of SEQ ID NO:
- 79;
- or
- f. the VH of SEQ ID NO:
- 86 and the VL of SEQ ID NO:
- 79.
An isolated antibody or fragment that binds specifically to human IL-17A, comprising a VH and a VL, wherein the antibody comprises the VH having an amino acid sequence shown in SEQ ID NOs:
- 67, 68, 69, 81, 82, 83, 84, 85, or 86.
An isolated antibody or fragment that binds specifically to human IL-17A, comprising a VH and a VL, wherein the antibody comprises the VL having an amino acid sequence shown in SEQ ID NOs:
- 76, 77, 78, 79, or 80.
An isolated antibody or fragment that binds specifically to human IL-17A, comprising a VH and a VL, wherein the antibody comprises the VH which is at least 90% identical to the VH having an amino acid sequence shown in SEQ ID NOs:
- 67, 68, 69, 81, 82, 83, 84, 85, or 86.
An isolated antibody or fragment that binds specifically to human IL-17A, comprising a VH and a VL, wherein the antibody comprises the VL which is at least 90% identical to the variable region having an amino acid sequence shown in SEQ ID NOs:
- 76, 77, 78, 79, or 80.
An isolated antibody or fragment that binds specifically to human IL-17A, comprising an antibody heavy chain having an amino acid sequence shown in SEQ ID NOs:
- 92, 93, 94, 95, 96, 97, 98, 99, or 100.
An isolated antibody or fragment that binds specifically to IL-17A, comprising an antibody light chain having an amino acid sequence shown in SEQ ID NOs:
- 87, 88, 89, 90, or 91.
An isolated antibody heavy chain comprising the amino acid sequence shown in SEQ ID NOs:
- 67, 68, 69, 81, 82, 83, 84, 85, 86, 92, 93, 94, 95, 96, 97, 98, 99, or 100.
An isolated antibody light chain comprising the amino acid sequence shown in SEQ ID NOs:
- 76, 77, 78, 79, 80, 87, 88, 89, 90, or 91.
An isolated polynucleotide encoding an antibody heavy chain comprising the amino acid sequence shown in SEQ ID NO:
- 67, 68, 69, 81, 82, 83, 84, 85, 86, 92, 93, 94, 95, 96, 97, 98, 99, or 100.
An isolated polynucleotide encoding an antibody light chain comprising the amino acid sequence shown in SEQ ID NO:
- 76, 77, 78, 79, 80, 87, 88, 89, 90, or 91.
A method of inhibiting interaction of human IL-17A with IL-17RA comprising:
- a. providing human IL-17A and IL-17RA;
- and
- b. contacting human IL-17A with an antagonist that binds human IL-17A at at least one amino acid residue selected from the group consisting of V22, V24, L26, 128, Y62, L99, R101, F110, and L112.
A method of inhibiting IL-17A biological activity, comprising:
- a. providing human IL17-A and IL-17RA;
- and
- b. contacting human IL-17A with an antagonist that binds human IL-17A at at least one amino acid residue selected from the group consisting of V22, V24, L26, 128, Y62, L99, R101, F110, and L112.
Dependencies are inferred from the claim text.