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CN-122003442-A - Anti-IL-4 Rα/TSLP antibodies and uses thereof

CN122003442ACN 122003442 ACN122003442 ACN 122003442ACN-122003442-A

Abstract

Anti-IL-4 Rα antibodies or antigen-binding fragments thereof, anti-TSLP antibodies or antigen-binding fragments thereof, antigen-binding protein constructs (e.g., multi-specific or bispecific antibodies capable of specifically binding IL-4Rα and TSLP) are provided. Polynucleotides encoding the antibodies or antigen binding protein constructs, and expression vectors and host cells comprising the same are provided. Immunoconjugates, pharmaceutical compositions and medicaments are also provided, as well as their use for treating immune disorders (e.g., type II or mixed allergic diseases).

Inventors

  • XIONG YAO
  • LI LI
  • ZHOU SHUAIXIANG
  • ZHU MENGZHU
  • FU JIE

Assignees

  • 信达生物制药(苏州)有限公司

Dates

Publication Date
20260508
Application Date
20241011
Priority Date
20231012

Claims (20)

  1. 1. An antigen binding protein construct comprising a first antigen binding domain that specifically binds IL-4rα and a second antigen binding domain that specifically binds TSLP.
  2. 2. The antigen-binding protein construct of claim 2, wherein the first antigen-binding domain comprises a first heavy chain variable region (VH 1) and a first light chain variable region (VL 1), and The second antigen-binding domain comprises a second heavy chain variable region (VH 2) and a second light chain variable region (VL 2).
  3. 3. The antigen binding protein construct of claim 2, wherein The first heavy chain variable region (VH 1) comprising Complementarity Determining Regions (CDRs) 1,2 and 3, wherein the VH1 CDR1 region comprises an amino acid sequence at least 80% identical to the selected VH1 CDR1 amino acid sequence, the VH1 CDR2 region comprises an amino acid sequence at least 80% identical to the selected VH1 CDR2 amino acid sequence, and the VH1 CDR3 region comprises an amino acid sequence at least 80% identical to the selected VH1 CDR3 amino acid sequence, and The first light chain variable region (VL 1) comprises a CDR1, a CDR2 and a CDR3, wherein the VL1 CDR1 region comprises an amino acid sequence that is at least 80% identical to the selected VL1 CDR1 amino acid sequence, the VL1 CDR2 region comprises an amino acid sequence that is at least 80% identical to the selected VL1 CDR2 amino acid sequence, and the VL1 CDR3 region comprises an amino acid sequence that is at least 80% identical to the selected VL1 CDR3 amino acid sequence, Wherein the selected VH1 CDR1, VH1 CDR2, and VH1 CDR3 amino acid sequences, the selected VL1 CDR1, VL1 CDR2, and VL1 CDR3 amino acid sequences are one of the following: (1) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown in SEQ ID NOs 1, 2 and 3, respectively, and selected VL1 CDR1, VL1 CDR2 and VL1 CDR3 amino acid sequences are shown in SEQ ID NOs 4, 5 and 6, respectively; (2) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown in SEQ ID NOs 11, 12, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown in SEQ ID NOs 13, 14, 15, respectively; (3) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown in SEQ ID NOs 18, 19, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown in SEQ ID NOs 20, 21, 22, respectively; (4) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown in SEQ ID NOs 25, 26, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown in SEQ ID NOs 27, 28, 29, respectively; (5) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown in SEQ ID NOs 32, 19, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown in SEQ ID NOs 33, 34, 6, respectively; (6) The selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID NO 84, 2, 3, respectively, and the selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID NO 4, 5,6, respectively; (7) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown in SEQ ID NOs 85, 12, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown in SEQ ID NOs 13, 14, 15, respectively; (8) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown in SEQ ID NOs 85, 19, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown in SEQ ID NOs 20, 21, 22, respectively; (9) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown in SEQ ID NOs 85, 26, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown in SEQ ID NOs 27, 28, 29, respectively; (10) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown in SEQ ID nos. 85, 19, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown in SEQ ID nos. 33, 34, 6, respectively; (11) The selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown in SEQ ID NOs 87, 88, 89, respectively, and the selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown in SEQ ID NOs 90, 91, 92, respectively; (12) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID NOs 93, 94, 95, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID NOs 96, 97, 98, respectively; (13) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID NOs 99, 100, 101, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID NOs 102, 103, 104, respectively; (14) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID NOs 105, 106, 107, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID NOs 108, 109, 110, respectively; (15) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID NOs 111, 112, 113, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID NOs 114, 115, 116, respectively; (16) The selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as GFTFX 1 X 2 NAMN（SEQ ID NO:57）、RIRTKX 3 X 4 X 5 YATYHADSVKD（SEQ ID NO:59） and DVGRGFAY (SEQ ID NO: 3), respectively, wherein X 1 = N, E, K or D, X 2 = I or M, X 3 = S, G or T, X 4 = N, A or S, X 5 = N, K or D, wherein the selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as RASKSVSX 6 X 7 X 8 X 9 SYX 10 H（SEQ ID NO:60）、LX 11 X 12 X 13 LQS（SEQ ID NO:61） and QHSX 14 EX 15 PX 16 T (SEQ ID NO: 62), respectively, wherein X 6 =T, a sequence of amino acids, F. h or Y, X 7 = S, G, R or H, X 8 = G or E, X 9 = Y or F, X 10 = M or L, X 11 = a or G, X 12 = S, t or R, X 13 = N, Y, F or H, X 14 = R or T, X 15 = L or I, X 16 = L or I; (17) The selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as GFTFX 1 MNAMN（SEQ ID NO:58）、RIRTKX 3 X 4 X 5 YATYHADSVKD (SEQ ID NO: 59) and DVGRGFAY (SEQ ID NO: 3), respectively, wherein X 1 = N, E, K or D, X 3 = S, G or T, X 4 = N, A or S, X 5 = N, K or D, wherein the selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as RASKSVSX 6 X 7 X 8 X 9 SYX 10 H（SEQ ID NO:60）、LX 11 X 12 X 13 LQS（SEQ ID NO:61） and QHSX 14 EX 15 PX 16 T (SEQ ID NO: 62), respectively, wherein X 6 =T, a sequence of amino acids, F. h or Y, X 7 = S, G, R or H, X 8 = G or E, X 9 = Y or F, X 10 = M or L, X 11 = a or G, X 12 = S, t or R, X 13 = N, Y, F or H, X 14 = R or T, X 15 = L or I, X 16 = L or I; (18) Selected VH1 CDR1, VH1 CDR2, The VH1 CDR3 amino acid sequences are shown as X 2 NAMN（SEQ ID NO:123）、RIRTKX 3 X 4 X 5 YATYHADSVKD (SEQ ID NO: 59) and DVGRGFAY (SEQ ID NO: 3), respectively, where X 2 =I or M, X 3 =S, G or T, X 4 = N, A or S, X 5 = N, K or D, wherein the selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as RASKSVSX 6 X 7 X 8 X 9 SYX 10 H（SEQ ID NO:60）、LX 11 X 12 X 13 LQS（SEQ ID NO:61） and QHSX 14 EX 15 PX 16 T (SEQ ID NO: 62), respectively, wherein X 6 =T, a sequence of amino acids, F. h or Y, X 7 = S, G, R or H, X 8 = G or E, X 9 = Y or F, X 10 = M or L, X 11 = a or G, X 12 = S, t or R, X 13 = N, Y, F or H, X 14 = R or T, X 15 = L or I, X 16 = L or I; (19) The selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as MNAMN (SEQ ID NO: 85), RIRTKX 3 X 4 X 5 YATYHADSVKD (SEQ ID NO: 59) and DVGRGFAY (SEQ ID NO: 3), respectively, wherein X 3 = S, G or T, X 4 = N, A or S, X 5 = N, K or D, wherein the selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as RASKSVSX 6 X 7 X 8 X 9 SYX 10 H（SEQ ID NO:60）、LX 11 X 12 X 13 LQS（SEQ ID NO:61） and QHSX 14 EX 15 PX 16 T (SEQ ID NO: 62), respectively, wherein X 6 =T, a sequence of amino acids, F. h or Y, X 7 = S, G, R or H, X 8 = G or E, X 9 = Y or F, X 10 = M or L, X 11 = a or G, X 12 = S, t or R, X 13 = N, Y, F or H, X 14 = R or T, X 15 = L or I, X 16 = L or I; (20) The selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown in GFTFX 1 X 2 N（SEQ ID NO:124）、RTKX 3 X 4 X 5 YA (SEQ ID NO: 125) and DVGRGFAY (SEQ ID NO: 3), respectively, wherein X 1 = N, E, K or D, X 2 = I or M, X 3 = S, G or T, X 4 = N, A or S, X 5 = N, K or D, wherein the selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as RASKSVSX 6 X 7 X 8 X 9 SYX 10 H（SEQ ID NO:60）、LX 11 X 12 X 13 LQS（SEQ ID NO:61） and QHSX 14 EX 15 PX 16 T (SEQ ID NO: 62), respectively, wherein X 6 =T, a sequence of amino acids, F. h or Y, X 7 = S, G, R or H, X 8 = G or E, X 9 = Y or F, X 10 = M or L, X 11 = a or G, X 12 = S, T or R, X 13 = N, Y, F or H, X 14 = R or T, X 15 = L or I, X 16 = L or I, and (21) The selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as GFTFX 1 MN（SEQ ID NO:126）、RTKX 3 X 4 X 5 YA (SEQ ID NO: 125) and DVGRGFAY (SEQ ID NO: 3), respectively, wherein X 1 = N, E, K or D, X 3 = S, G or T, X 4 = N, A or S, X 5 = N, K or D, wherein the selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as RASKSVSX 6 X 7 X 8 X 9 SYX 10 H（SEQ ID NO:60）、LX 11 X 12 X 13 LQS（SEQ ID NO:61） and QHSX 14 EX 15 PX 16 T (SEQ ID NO: 62), respectively, wherein X 6 =T, a sequence of amino acids, F. h or Y, X 7 = S, G, R or H, X 8 = G or E, X 9 = Y or F, X 10 = M or L, X 11 = a or G, X 12 = S, T or R, X 13 = N, Y, F or H, X 14 =r or T, X 15 =l or I, X 16 =l or I.
  4. 4. The antigen binding protein construct of claim 2 or 3, wherein The second heavy chain variable region (VH 2) comprising CDR1, CDR2 and CDR3, wherein the VH2 CDR1 region comprises an amino acid sequence at least 80% identical to the selected VH2 CDR1 amino acid sequence, the VH2 CDR2 region comprises an amino acid sequence at least 80% identical to the selected VH2 CDR2 amino acid sequence and the VH2 CDR3 region comprises an amino acid sequence at least 80% identical to the selected VH2 CDR3 amino acid sequence, and The second light chain variable region (VL 2) comprises CDR1, CDR2, and CDR3, wherein the VL2 CDR1 region comprises an amino acid sequence that is at least 80% identical to the selected VL2 CDR1 amino acid sequence, the VL2 CDR2 region comprises an amino acid sequence that is at least 80% identical to the selected VL2 CDR2 amino acid sequence, and the VL2 CDR3 region comprises an amino acid sequence that is at least 80% identical to the selected VL2 CDR3 amino acid sequence; Wherein the selected VH2 CDR1, VH2 CDR2, and VH2 CDR3 amino acid sequences, and the selected VL2 CDR1, VL2 CDR2, and VL2 CDR3 amino acid sequences are one of: (1) Selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID NOs 37, 38, 39, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID NOs 40, 41, 42, respectively; (2) Selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID NO 86, 38, 39, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID NO 40, 41, 42, respectively, and (3) The selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID NOs 117, 118, 119, respectively, and the selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID NOs 120, 121, 122, respectively.
  5. 5. The antigen binding protein construct of any one of claims 2-4, wherein (1) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID nos. 1, 2, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID nos. 4, 5, 6, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID nos. 37, 38, 39, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID nos. 40, 41, 42, respectively; (2) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID nos. 11,12, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID nos. 13, 14, 15, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID nos. 37, 38, 39, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID nos. 40, 41, 42, respectively; (3) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID nos. 18, 19, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID nos. 20, 21, 22, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID nos. 37, 38, 39, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID nos. 40, 41, 42, respectively; (4) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID nos. 25, 26, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID nos. 27, 28, 29, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID nos. 37, 38, 39, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID nos. 40, 41, 42, respectively; (5) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID nos. 32, 19, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID nos. 33, 34, 6, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID nos. 37, 38, 39, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID nos. 40, 41, 42, respectively; (6) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID nos. 84, 2, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID nos. 4, 5, 6, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID nos. 86, 38, 39, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID nos. 40, 41, 42, respectively; (7) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID nos. 85, 12, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID nos. 13, 14, 15, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID nos. 86, 38, 39, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID nos. 40, 41, 42, respectively; (8) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID nos. 85, 19, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID nos. 20, 21, 22, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID nos. 86, 38, 39, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID nos. 40, 41, 42, respectively; (9) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID nos. 85, 26, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID nos. 27, 28, 29, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID nos. 86, 38, 39, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID nos. 40, 41, 42, respectively; (10) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID nos. 85, 19, 3, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID nos. 33, 34, 6, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID nos. 86, 38, 39, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID nos. 40, 41, 42, respectively; (11) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID nos. 87, 88, 89, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID nos. 90, 91, 92, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID nos. 117, 118, 119, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID nos. 120, 121, 122, respectively; (12) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID nos. 93, 94, 95, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID nos. 96, 97, 98, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID nos. 117, 118, 119, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID nos. 120, 121, 122, respectively; (13) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID NOs 99, 100, 101, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID NOs 102, 103, 104, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID NOs 117, 118, 119, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID NOs 120, 121, 122, respectively; (14) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID NO:105, 106, 107, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID NO:108, 109, 110, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID NO:117, 118, 119, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID NO:120, 121, 122, respectively, or (15) Selected VH1 CDR1, VH1 CDR2, VH1 CDR3 amino acid sequences are shown as SEQ ID nos. 111, 112, 113, respectively, and selected VL1 CDR1, VL1 CDR2, VL1 CDR3 amino acid sequences are shown as SEQ ID nos. 114, 115, 116, respectively, and selected VH2 CDR1, VH2 CDR2, VH2 CDR3 amino acid sequences are shown as SEQ ID nos. 117, 118, 119, respectively, and selected VL2 CDR1, VL2 CDR2, VL2 CDR3 amino acid sequences are shown as SEQ ID nos. 120, 121, 122, respectively.
  6. 6. The antigen binding protein construct of claim 5, wherein the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 7, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 8, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 43, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 44.
  7. 7. The antigen binding protein construct of claim 5, wherein the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 9, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 10, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 43, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 44.
  8. 8. The antigen binding protein construct of claim 5, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 16, the first light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 17, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 43, and the second light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 44.
  9. 9. The antigen binding protein construct of claim 5, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 23, the first light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 24, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 43, and the second light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 44.
  10. 10. The antigen binding protein construct of claim 5, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 30, the first light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 31, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 43, and the second light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 44.
  11. 11. The antigen binding protein construct of claim 5, wherein the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 35, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 36, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 43, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 44.
  12. 12. The antigen binding protein construct of claim 5, wherein the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 7, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 8, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 45, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 46.
  13. 13. The antigen binding protein construct of claim 5, wherein the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 9, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 10, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 45, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 45.
  14. 14. The antigen binding protein construct of claim 5, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 16, the first light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 17, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 45, and the second light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 46.
  15. 15. The antigen binding protein construct of claim 5, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 23, the first light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 24, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 45, and the second light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 46.
  16. 16. The antigen binding protein construct of claim 5, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 30, the first light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 31, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 45, and the second light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID No. 46.
  17. 17. The antigen binding protein construct of claim 5, wherein the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 35, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 36, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 45, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID No. 46.
  18. 18. The antigen binding protein construct of any one of claims 1-17, wherein the antigen binding protein construct is a bispecific antibody.
  19. 19. An antigen binding protein construct comprising: A first polypeptide chain optionally comprising, from N-terminus to C-terminus, a first heavy chain variable region (VH 1), a heavy chain constant region (CH), a first linker and an scFv, and A second polypeptide chain optionally comprising, from N-terminus to C-terminus, a first light chain variable region (VL 1) and a light chain constant region (CL).
  20. 20. The antigen-binding protein construct of claim 19, wherein the scFv optionally comprises, from N-terminus to C-terminus, a second light chain variable region (VL 2), a second linker, and a second heavy chain variable region (VH 2).

Description

Anti-IL-4 Rα/TSLP antibodies and uses thereof Priority claim The present application claims priority from chinese application No. 202311318859.2 filed 10/12 in 2023. The entire contents of the foregoing application are incorporated herein by reference. Technical Field The present disclosure relates to the field of immunopharmaceuticals, and in particular to anti-IL-4 ra antibodies or antigen-binding fragments thereof, anti-TSLP antibodies or antigen-binding fragments thereof, antigen-binding protein constructs (e.g., multispecific and bispecific antibodies) capable of specifically binding IL-4 ra and TSLP. The disclosure also relates to pharmaceutical compositions comprising them and their use. Background Autoimmune diseases are conditions caused by an abnormal immune response to a normal body part. There are at least 80 autoimmune diseases. The etiology of autoimmune diseases is often less clear. Some autoimmune diseases (e.g., lupus) are familial, while some other autoimmune diseases may be triggered by infection or other environmental factors. Some common autoimmune diseases include, for example, celiac disease, type 1 diabetes, graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. Recent clinical and commercial success of therapeutic antibodies has led to great interest in using antibodies to treat various immune-related disorders. There is a need to develop antibodies for use in various antibody-based therapies to treat immune disorders. Disclosure of Invention The present disclosure relates to antigen binding protein constructs (e.g., multispecific and bispecific antibodies) that target both IL-4 ra and TSLP, which can block Th2 pathways. The antigen binding protein construct may have greater Th2 inhibition than anti-IL-4 Rα antibodies or anti-TSLP antibodies administered alone, and may exhibit significant non-Th 2 inhibition than anti-IL-4 Rα antibodies, and thus may exert greater potency than monoclonal antibodies in the treatment of immune disorders such as type II and mixed allergic diseases. In one aspect, the disclosure relates to an antibody or antigen-binding fragment thereof that binds IL-4 ra (interleukin-4 receptor alpha subunit) comprising a heavy chain variable region (VH) comprising Complementarity Determining Regions (CDRs) 1,2, and 3, in some embodiments, the VH CDR1 region comprises an amino acid sequence that is at least 80%, 90%, or 100% identical to a selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR3 amino acid sequence, and the light chain variable region comprises CDR1, CDR2, and CDR3, in some embodiments, the VL CDR1 region comprises an amino acid sequence that is at least 80%, 90%, or 100% identical to a selected VL CDR1 amino acid sequence, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR2 amino acid sequence, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL 3 amino acid sequence. In some embodiments, the selected VH CDR1, VH CDR2, VH CDR3 amino acid sequences are shown as GFTFX1X2NAMN（SEQ ID NO:57）、RIRTKX3X4X5YATYHADSVKD（SEQ ID NO:59） and DVGRGFAY (SEQ ID NO: 3), respectively, in some embodiments, X 1 = N, E, K or D, X 2 =i or M, X 3 =s, G or T, X 4 = N, A or S, X 5 = N, K or D, in some embodiments, the selected VL CDR1, VL CDR2, VL CDR3 amino acid sequences are shown as RASKSVSX6X7X8X9SYX10H（SEQ ID NO:60）、LX11X12X13LQS（SEQ ID NO:61） and QHSX 14EX15PX16 T (SEQ ID NO: 62), respectively, in some embodiments, X 6 =T, F. h or Y, X 7 = S, G, R or H, X 8 = G or E, X 9 = Y or F, X 10 = M or L, X 11 = a or G, X 12 = S, T or R, X 13 = N, Y, F or H, X 14 =r or T, X 15 =l or I, X 16 =l or I. In some embodiments, the selected VH CDR1, VH CDR2, VH CDR3 amino acid sequences are shown at GFTFX 1MNAMN（SEQ ID NO:58）、RIRTKX3X4X5 YATYHADSVKD (SEQ ID NO: 59) and DVGRGFAY (SEQ ID NO: 3), respectively, in some embodiments, X 1 = N, E, K or D, X 3 = S, G or T, X 4 = N, A or S, X 5 = N, K or D, in some embodiments selected VL CDR1, VL CDR2, VL CDR3 amino acid sequences are shown as RASKSVSX6X7X8X9SYX10H（SEQ ID NO:60）、LX11X12X13LQS（SEQ ID NO:61） and QHSX 14EX15PX16 T (SEQ ID NO: 62), respectively, in some embodiments, X 6 = T, F. h or Y, X 7 = S, G, R or H, X 8 = G or E, X 9 = Y or F, X 10 = M or L, X 11 = a or G, X 12 = S, T or R, X 13 = N, Y, F or H, X 14 =r or T, X 15 =l or I, X 16 =l or I. In some embodiments, the selected VH CDR1, VH CDR2, VH CDR3 amino acid sequences are shown as X 2NAMN（SEQ ID NO:123）、RIRTKX3X4X5 YATYHADSVKD (SEQ ID NO: 59) and DVGRGFAY (SEQ ID NO: 3), respectively, in some embodiments, X 2 =i or M, X 3 =s, G or T, X 4 = N, A or S, X 5 = N, K or D, in so