COMPOSITIONS AND METHODS FOR FIBROBLAST GROWTH FACTOR RECEPTOR 3-MEDIATED DELIVERY TO ASTROCYTES

20240173426

18/509030

November 14, 2023

The present invention provides, in part, protein-drug conjugates comprising an anti-fibroblast growth factor receptor 3 (FGFR3) (e.g., human FGFR3) antigen-binding protein (e.g., scFv, Fab) conjugated to a molecular cargo (e.g., polynucleotides, polypeptides, liposomes or lipid nanoparticles) for delivery of the molecular cargo to a targeted tissue (e.g., brain). Methods for treating various diseases or disorders, such as neurological diseases, with the conjugates are provided.

Regeneron Pharmaceuticals, Inc. (Tarrytown, NY, US)

1. A protein-drug conjugate comprising an antigen-binding protein that binds specifically to fibroblast growth factor receptor 3 (FGFR3) and is conjugated to a molecular cargo.

2. The protein-drug conjugate of claim 1 wherein the antigen binding protein comprises an antibody or antigen-binding fragment thereof.

3. The protein-drug conjugate of claim 1 or claim 2, wherein the protein drug conjugate comprises a heavy chain variable region (HCVR or VH) and/or a light chain variable region (LCVR or VL).

4. The protein-drug conjugate of claim 3, wherein the antigen-binding protein is selected from a humanized antibody or antigen binding fragment thereof, human antibody or antigen binding fragment thereof, murine antibody or antigen binding fragment thereof, chimeric antibody or antigen binding fragment thereof, monovalent Fab′, divalent Fab2, F(ab)′3 fragments, single-chain fragment variable (scFv), bis-scFv, (scFv)2, diabody, minibody, nanobody, triabody, tetrabody, disulfide stabilized Fv protein (dsFv), single-domain antibody (sdAb), Ig NAR, single heavy chain antibody, bispecific antibody or biding fragment thereof, bi-specific T-cell engager (BITE), trispecific antibody, or chemically modified derivatives thereof.

5. The protein-drug conjugate of claim 3, wherein the antigen-binding protein comprises a fragment antigen-binding region (Fab).

6. The protein-drug conjugate of claim 3, wherein the antigen-binding protein comprises a single chain fragment variable (scFv).

7. The protein-drug conjugate of claim 6, wherein the scFv comprises domains arranged in the following orientation from N-terminus to C-terminus: HCVR-LCVR.

8. The protein-drug conjugate of claim 6, wherein the scFv comprises domains arranged in the following orientation from N-terminus to C-terminus: LCVR-HCVR.

9. The protein-drug conjugate of any one of claims 6-8, wherein the scFv variable regions are connected by a linker.

10. The protein-drug conjugate of claim 9, wherein the linker is a peptide linker.

11. The protein-drug conjugate of claim 10, wherein the peptide linker is -(GGGGS)n—(SEQ ID NO: 321); wherein n is 1-10.

12. The protein-drug conjugate of any one of claims 1-11 which comprises: (i) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, 22, 42, 62, 82, 102, 122, 140, 159, 169, 179, 199 or 219 (or a variant thereof); and/or (ii) a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10, 30, 50, 70, 90, 110, 130, 148, 187, 207, or 227 (or a variant thereof).

13. The protein-drug conjugate of any one of claims 1-12 which comprises: (1) a HCVR comprising the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2 (or a variant thereof); and a LCVR comprising the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10 (or a variant thereof); (2) a HCVR comprising the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 22; and a LCVR comprising the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 30 (or a variant thereof); (3) a HCVR comprising the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42; and a LCVR comprising the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50 (or a variant thereof); (4) a HCVR comprising the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 62 (or a variant thereof); and a LCVR comprising the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 70 (or a variant thereof); (5) a HCVR comprising the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof); and a LCVR comprising the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90 (or a variant thereof); (6) a HCVR comprising the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof); and a LCVR comprising the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof); (7) a HCVR comprising the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof); and LCVR comprising the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (8) a HCVR comprising the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof); and a LCVR comprising the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof); (9) a HCVR comprising the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 159 (or a variant thereof); and LCVR comprising the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof); (10) a HCVR comprising the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 169 (or a variant thereof); and LCVR comprising the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof); (11) a HCVR comprising the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 179 (or a variant thereof); and LCVR comprising the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 187 (or a variant thereof); (12) a HCVR comprising the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 199 (or a variant thereof); and LCVR comprising the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 207 (or a variant thereof); or (13) a HCVR comprising the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 219 (or a variant thereof); and LCVR comprising the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof).

14. The protein-drug conjugate of any one of claims 1-13 which comprises: (a) a HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8 (or a variant thereof); and a LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16 (or a variant thereof); (b) a HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 24 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28 (or a variant thereof); and a LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36 (or a variant thereof); (c) a HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 46 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48 (or a variant thereof); and a LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 54 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56 (or a variant thereof); (d) a HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 64 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68 (or a variant thereof); and a LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 72 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76 (or a variant thereof); (e) a HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 86 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88 (or a variant thereof); and a LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96 (or a variant thereof); (f) a HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 104 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 108 (or a variant thereof); and a LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116 (or a variant thereof); (g) a HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128 (or a variant thereof), and a LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 134; (or a variant thereof) (h) a HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 142 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 144 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof), and a LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153 (or a variant thereof); (i) a HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 161 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 163 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165 (or a variant thereof), and a LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153 (or a variant thereof); (j) a HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 171 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 173 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175 (or a variant thereof), and a LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153 (or a variant thereof); (k) a HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 181 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 185 (or a variant thereof), and a LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 189 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 191 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193 (or a variant thereof); (l) a HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 205 (or a variant thereof), and a LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 209 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 211 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 213 (or a variant thereof); and/or (m) a HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 221 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 223 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225 (or a variant thereof), and a LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76 (or a variant thereof).

15. The protein-drug conjugate of any one of claims 1-14 which comprises: (i) a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2 (or a variant thereof); and a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10 (or a variant thereof); (ii) a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 22 (or a variant thereof); and a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 30 (or a variant thereof); (iii) a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof); and a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50 (or a variant thereof); (iv) a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 62 (or a variant thereof); and a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 70 (or a variant thereof); (v) a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof); and a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90 (or a variant thereof); (vi) a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof); and a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof); (vii) a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof); and a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (viii) a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof); and a LCVR that the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof); (ix) a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 159 (or a variant thereof); and a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof); (x) a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 169 (or a variant thereof); and LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof); (xi) a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 179 (or a variant thereof); and a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 187 (or a variant thereof); (xii) a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 199 (or a variant thereof); and LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 207 (or a variant thereof); or (xiii) a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 219 (or a variant thereof); and LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof).

16. The protein-drug conjugate of any one of claims 1-3, and 12-15, which comprises: (a) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 18, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 20; (b) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 38, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 40; (c) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 58, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 60; (d) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 78, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 80; (e) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 100; (f) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 118, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 120; (g) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 136, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 138; (h) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 155, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157; (i) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 167, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157; (j) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 177, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157; (k) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 195, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 197; (I) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 215, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 217; and/or (m) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 229, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 231.

17. The protein-drug conjugate of any one of claims 1-16, wherein the antigen-binding protein binds specifically to FGFR3b and/or FGFR3c.

18. The protein-drug conjugate of any one of claims 1-17, wherein the antigen-binding protein that binds specifically to human FGFR3b and/or FGFR3c.

19. The protein-drug conjugate of any one of claims 1-18, wherein the antigen-binding protein binds specifically to FGFR3b.

20. The protein-drug conjugate of any one of claims 17-19, wherein the FGFR3b is monomeric and/or dimeric FGFR3b.

21. The protein-drug conjugate of any one of claims 17-20, wherein the FGFR3b is monomeric FGFR3b.

22. The protein-drug conjugate of any one of claims 17-20, wherein the FGFR3b is dimeric FGFR3b.

23. The protein-drug conjugate of claim 22, which comprises: (a) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 18, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 20; (b) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 38, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 40; (c) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 58, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 60; (d) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 78, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 80; (e) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 100; (f) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 118, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 120; (g) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 136, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 138; (h) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 167, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157; (i) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 177, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157; (j) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 195, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 197; (k) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 215, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 217; and/or (l) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 229, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 231.

24. The protein-drug conjugate of any one of claims 17-18, wherein the FGFR3c is monomeric and/or dimeric FGFR3c.

25. The protein-drug conjugate of any one of claim 24, wherein the FGFR3c is monomeric FGFR3c.

26. The protein-drug conjugate of claim 25, which comprises: (a) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 100; (b) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 155, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157; (c) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 177, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157; (d) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 195, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 197; (e) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 215, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 217; and/or (f) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 229, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 231.

27. The protein-drug conjugate of any one of claims 1-26, wherein the antigen-binding protein binds specifically to both FGFR3b and FGFR3c.

28. The protein-drug conjugate of any one of claims 18-23 and 27, wherein the antigen-binding protein binds to human FGFR3b with a KD of about 1λ10−7 M or a stronger affinity.

29. The protein-drug conjugate of claim 28, wherein the antigen-binding protein binds to human FGFR3b with a KD of about 1×10−8 M or a stronger affinity.

30. The protein-drug conjugate of any one of claims 18 and 24-27, wherein the antigen-binding protein binds to human FGFR3c with a KD of about 1×10−7 M or a stronger affinity.

31. The protein-drug conjugate of claim 30, wherein the antigen-binding protein binds to human FGFR3c with a KD of about 1×10−8 M or a stronger affinity.

32. The protein-drug conjugate of any one of claims 1-20, which comprises a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 18, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 20.

33. The protein-drug conjugate of any one of claims 1-11, wherein the antigen-binding protein binds to the same epitope on FGFR3 as an antibody comprising an HCVR/LCVR amino acid sequence pair as set forth in Table 1-1.

34. The protein-drug conjugate of any one of claims 1-11, wherein the antigen-binding protein competes for binding to FGFR3 with an antibody comprising an HCVR/LCVR amino acid sequence pair as set forth in Table 1-1.

35. A protein-drug conjugate comprising an antigen-binding protein that binds specifically to fibroblast growth factor receptor 3 (FGFR3), wherein the antigen-binding protein is conjugated to a molecular cargo and comprises an antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof binds to one or more epitopes of FGFR3 selected from: a. an epitope comprising the sequence GPTVVVVK (SEQ ID NO: 378) and/or an epitope comprising the sequence TQR; b. an epitope comprising the sequence ADVR (SEQ ID NO: 376) and/or an epitope comprising the sequence IGVAEK (SEQ ID NO: 377); c. an epitope comprising the sequence HCKVY (SEQ ID NO: 379), and/or an epitope comprising the sequence KSWISE (SEQ ID NO: 380), and/or an epitope comprising the sequence ADVR (SEQ ID NO: 376); d. an epitope comprised within or overlapping with the sequence GPTVVVVK (SEQ ID NO: 378) and/or an epitope comprised within or overlapping with the sequence TQR; e. an epitope comprised within or overlapping with the sequence ADVR (SEQ ID NO: 376) and/or an epitope comprised within or overlapping with the sequence IGVAEK (SEQ ID NO: 377); and f. an epitope comprised within or overlapping with the sequence HCKVY (SEQ ID NO: 379), and/or an epitope comprised within or overlapping with the sequence KSWISE (SEQ ID NO: 380), and/or an epitope comprised within or overlapping with the sequence ADVR (SEQ ID NO: 376).

36. The protein-drug conjugate of claim 35, wherein the antibody or antigen-binding fragment thereof binds to one or more epitopes of FGFR3 selected from: a. an epitope consisting of the sequence GPTVWVK (SEQ ID NO: 378) and/or an epitope consisting of the sequence TQR; b. an epitope consisting of the sequence ADVR (SEQ ID NO: 376) and/or an epitope consisting of the sequence IGVAEK (SEQ ID NO: 377); and c. an epitope consisting of the sequence HCKVY (SEQ ID NO: 379), and/or an epitope consisting of the sequence KSWISE (SEQ ID NO: 380), and/or an epitope consisting of the sequence ADVR (SEQ ID NO: 376).

37. A protein-drug conjugate comprising an antigen-binding protein that binds specifically to fibroblast growth factor receptor 3 (FGFR3), wherein the antigen-binding protein is conjugated to a molecular cargo and comprises an antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof binds to one or more epitopes of FGFR3 selected from: a. an epitope comprising the sequence SCPPPGGGPMGPTVVVVKDGTGLVPSER (SEQ ID NO: 363) and/or an epitope comprising the sequence YSCRQRLTQRVL (SEQ ID NO: 364; b. an epitope comprising the sequence LLAVPAAN (SEQ ID NO: 365), and/or an epitope comprising the sequence VLERSPHRPILQAG (SEQ ID NO: 366) and/or an epitope comprising the sequence YVTVLKSWISE (SEQ ID NO: 367) and/or or an epitope comprising the sequence ADVRLR (SEQ ID NO: 368) and/or an epitope comprising the sequence LCRATNFIGVAEKAFW (SEQ ID NO: 369); c. an epitope comprising the sequence GQQEQLVFGSGDAVE (SEQ ID NO: 370) and/or an epitope comprising the sequence VLVGPQRL (SEQ ID NO: 371); d. an epitope comprising the sequence VLERSPHRPILQAG (SEQ ID NO: 372) and/or an epitope comprising the sequence HCKVYSDAQP (SEQ ID NO: 373) and/or an epitope comprising the sequence YVTVLKSWISESVEADVRLR (SEQ ID NO: 374) and/or an epitope comprising the sequence LCRATNFIGVAEKAF (SEQ ID NO: 375); e. an epitope comprised within or overlapping with the sequence SCPPPGGGPMGPTVWVKDGTGLVPSER (SEQ ID NO: 363) and/or an epitope comprised within or overlapping with the sequence YSCRQRLTQRVL (SEQ ID NO: 364); f. an epitope comprised within or overlapping with the sequence LLAVPAAN (SEQ ID NO: 365, and/or an epitope comprised within or overlapping with the sequence VLERSPHRPILQAG (SEQ ID NO: 366) and/or an epitope comprised within or overlapping with the sequence YVTVLKSWISE (SEQ ID NO: 367) and/or or an epitope comprised within or overlapping with the sequence ADVRLR (SEQ ID NO: 368) and/or an epitope comprised within or overlapping with the sequence LCRATNFIGVAEKAFW (SEQ ID NO: 369; g. an epitope comprised within or overlapping with the sequence GQQEQLVFGSGDAVE (SEQ ID NO: 370) and/or an epitope comprised within or overlapping with the sequence VLVGPQRL (SEQ ID NO: 371); and h. an epitope comprised within or overlapping with the sequence VLERSPHRPILQAG (SEQ ID NO: 372) and/or an epitope comprised within or overlapping with the sequence HCKVYSDAQP (SEQ ID NO: 373) and/or an epitope comprised within or overlapping with the sequence YVTVLKSWISESVEADVRLR (SEQ ID NO: 374) and/or an epitope comprised within or overlapping with the sequence LCRATNFIGVAEKAF (SEQ ID NO: 375.

38. The protein-drug conjugate of claim 37, wherein the antibody or antigen-binding fragment thereof binds to one or more epitopes of FGFR3 selected from: a. an epitope consisting of the sequence SCPPPGGGPMGPTVVVVKDGTGLVPSER (SEQ ID NO: 363) and/or an epitope consisting of the sequence YSCRQRLTQRVL (SEQ ID NO: 364); b. an epitope consisting of the sequence LLAVPAAN (SEQ ID NO: 365), and/or an epitope consisting of the sequence VLERSPHRPILQAG (SEQ ID NO: 366) and/or an epitope consisting of the sequence YVTVLKSWISE (SEQ ID NO: 367) and/or or an epitope consisting of the sequence ADVRLR (SEQ ID NO: 368) and/or an epitope consisting of the sequence LCRATNFIGVAEKAFW (SEQ ID NO: 369); c. an epitope consisting of the sequence GQQEQLVFGSGDAVE (SEQ ID NO: 370) and/or an epitope consisting of the sequence VLVGPQRL (SEQ ID NO: 371); and d. an epitope consisting of the sequence VLERSPHRPILQAG (SEQ ID NO: 372) and/or an epitope consisting of the sequence HCKVYSDAQP (SEQ ID NO: 373) and/or an epitope consisting of the sequence YVTVLKSWISESVEADVRLR (SEQ ID NO: 374) and/or an epitope consisting of the sequence LCRATNFIGVAEKAF (SEQ ID NO: 375).

39. The protein-drug conjugate of any one of claims 35-38, wherein the antigen-binding protein is selected from a humanized antibody or antigen binding fragment thereof, human antibody or antigen binding fragment thereof, murine antibody or antigen binding fragment thereof, chimeric antibody or antigen binding fragment thereof, monovalent Fab′, divalent Fab2, F(ab)′3 fragments, single-chain fragment variable (scFv), bis-scFv, (scFv)2, diabody, bivalent antibody, one-armed antibody, minibody, nanobody, triabody, tetrabody, disulfide stabilized Fv protein (dsFv), single-domain antibody (sdAb), Ig NAR, single heavy chain antibody, bispecific antibody or biding fragment thereof, bi-specific T-cell engager (BITE), trispecific antibody, or chemically modified derivatives thereof.

40. The protein-drug conjugate of any one of claims 1-39, wherein said molecular cargo is conjugated to: (i) a HCVR of the antigen-binding protein, (ii) a LCVR of the antigen-binding protein, (iii) a heavy chain of the antigen-binding protein, and/or (iv) a light chain of the antigen-binding protein.

41. The protein-drug conjugate of any one of claims 1-40, wherein said molecular cargo is conjugated to the antigen-binding protein via a glutamine residue and/or a lysine residue.

42. The protein-drug conjugate of claim 41, wherein the glutamine residue is: (i) introduced to the N-terminus and/or C-terminus of a heavy chain of the antigen-binding protein, (ii) introduced to the N-terminus and/or C-terminus of a light chain of the antigen-binding protein, (iii) naturally present in a CH2 or CH3 domain of the antigen-binding protein, (iv) introduced to the antigen-binding protein by modifying one or more amino acids, and/or (v) Q295 or mutated from N297 to Q297 (N297Q).

43. The protein-drug conjugate of claim 41 or 42, wherein the antigen-binding protein comprises a glutamine-containing tag, and the molecular cargo is conjugated to the antigen-binding protein via a glutamine residue of the glutamine-containing tag.

44. The protein-drug conjugate of claim 43, wherein the glutamine-containing tag comprises an amino acid sequence selected from the group consisting of LLQGG (SEQ ID NO: 290), LLQG (SEQ ID NO: 291), LSLSQG (SEQ ID NO: 292), GGGLLQGG (SEQ ID NO: 293), GLLQG (SEQ ID NO: 294), LLQ, GSPLAQSHGG (SEQ ID NO: 295), GLLQGGG (SEQ ID NO: 296), GLLQGG (SEQ ID NO: 297), GLLQ (SEQ ID NO: 298), LLQLLQGA (SEQ ID NO: 299), LLQGA (SEQ ID NO: 300), LLQYQGA (SEQ ID NO: 301), LLQGSG (SEQ ID NO: 302), LLQYQG (SEQ ID NO: 303), LLQLLQG (SEQ ID NO: 304), SLLQG (SEQ ID NO: 305), LLQLQ (SEQ ID NO: 306), LLQLLQ (SEQ ID NO: 307), and LLQGR (SEQ ID NO: 308).

45. The protein-drug conjugate of any one of claims 1-44, wherein the antigen-binding protein and the molecular cargo are conjugated via a linker.

46. The protein-drug conjugate of any one of claims 1-45, wherein the molecular cargo comprises a polynucleotide molecule, a polypeptide molecule, a carrier, a viral particle, a viral capsid protein, or a small molecule.

47. The protein-drug conjugate of claim 46, wherein the molecular cargo comprises a polynucleotide molecule.

48. The protein-drug conjugate of claim 47, wherein the polynucleotide molecule is an interfering nucleic acid molecule, a guide RNA, a ribozyme, an aptamer, a mixmer, a multimer, or an mRNA.

49. The protein-drug conjugate of claim 48, wherein the interfering nucleic acid molecule is an siRNA, an shRNA, a miRNA, an antisense oligonucleotide, or a gapmer.

50. The protein-drug conjugate of claim 48 or 49, wherein the interfering nucleic acid molecule is an siRNA.

51. The protein-drug conjugate of claim 50, wherein the siRNA comprises a sense strand of 21 nucleotides in length.

52. The protein-drug conjugate of claim 50 or 51, wherein the siRNA comprises an antisense strand of 23 nucleotides in length.

53. The protein-drug conjugate of any one of claims 50-52, wherein the siRNA comprises two phosphorothioate linkages at the first and second internucleoside linkages at the 5′ end of the sense strand.

54. The protein-drug conjugate of any one of claims 50-53, wherein the siRNA comprises two phosphorothioate linkages at the first and second internucleoside linkages at the 3′ and/or 5′ ends of the antisense strand.

55. The protein-drug conjugate of claim 48 or 49, wherein the interfering nucleic acid molecule is an antisense oligonucleotide.

56. The protein-drug conjugate of claim 48, wherein the polynucleotide molecule is a guide RNA.

57. The protein-drug conjugate of any one of claims 48-56, wherein the polynucleotide molecule targets a gene or gene product associated with a neurological disease and/or disorder.

58. The protein-drug conjugate of claim 57, wherein the gene is APOE4, GFAP, MECP2, AQP4, or STAT3.

59. The protein-drug conjugate of any one of claims 48-58, wherein the polynucleotide molecule comprises one or more modified nucleotides.

60. The protein-drug conjugate of claim 46, wherein the molecular cargo comprises a polypeptide molecule.

61. The protein-drug conjugate of claim 60, wherein the polypeptide molecule is an enzyme, a neuroprotective molecule, or an antigen-binding protein that binds to a target other than FGFR3.

62. The protein-drug conjugate of claim 60 or 61, wherein the polypeptide molecule is associated with a neurological disease and/or disorder.

63. The protein-drug conjugate of claim 62, wherein the polypeptide molecule is a protective ApoE isoform or variant, ATPase 13A2 (encoded by ATP13A2), sulfatase modifying factor 1 (encoded by SUMF1), fragile X messenger ribonucleoprotein (FMRP) (encoded by FMR1), or glutamate transporter-1 (encoded by GLT1).

64. The protein-drug conjugate of claim 63, wherein the protective ApoE isoform or variant is ApoE2, ApoE Christchurch, or ApoE Jacksonville.

65. The protein-drug conjugate of claim 62, wherein the polypeptide molecule is a neurotrophic factor, an antibody or antibody fragment, an antibody receptor fusion protein, or a suppressor of cytokine signaling.

66. The protein-drug conjugate of claim 65, wherein the neurotrophic factor is ciliary neurotrophic factor (CNTF), brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), or insulin-like growth factor 1 (IGF).

67. The protein-drug conjugate of claim 65, wherein the antibody receptor fusion protein is anti-amyloid beta Gas6 fusion protein.

68. The protein-drug conjugate of claim 65, wherein the suppressor of cytokine signaling is suppressor of cytokine signaling 3 (Socs3).

69. The protein-drug conjugate of any one of claims 1-68, wherein the molecular cargo is conjugated to the antigen-binding protein at a drug-to-antibody ratio (DAR) of a least 1 to at least 10.

70. The protein-drug conjugate of claim 69, wherein the molecular cargo is conjugated to the antigen-binding protein at a DAR of 1, 2, 3, or 4.

71. The protein-drug conjugate of claim 69 or 70, wherein the molecular cargo is conjugated to the antigen-binding protein at a DAR of 2.

72. The protein-drug conjugate of claim 69 or 70, wherein the molecular cargo is conjugated to the antigen-binding protein at a DAR of 4.

73. The protein-drug conjugate of any one of claims 1-72 for use in treating or preventing a neurological disease or disorder.

74. The protein-drug conjugate of any one of claims 57, 62, and 73, wherein the neurological disease or disorder is a neurodegenerative disease, a neurodevelopmental disease, a physical injury, a neuropsychiatric disease, or a brain cancer.

75. The protein-drug conjugate of claim 74, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), or prion disease (transmissible spongiform encephalopathy).

76. The protein-drug conjugate of claim 74, wherein the neurodevelopmental disease is Alexander disease, multiple sulfatase deficiency, autism, epilepsy, Rett syndrome, or Fragile X.

77. The protein-drug conjugate of claim 74, wherein the physical injury is traumatic brain injury, spinal cord injury, stroke, or brain edema.

78. The protein-drug conjugate of claim 74, wherein the neuropsychiatric disease or disorder is major depressive disorder, anxiety disorder, or bipolar disorder.

79. The protein-drug conjugate of claim 74, wherein the brain cancer is glioma.

80. The protein-drug conjugate of claim 79, wherein the glioma is an astrocytoma.

81. The protein-drug conjugate of claim 46, wherein the molecular cargo comprises a carrier.

82. The protein-drug conjugate of claim 81, wherein the carrier is a lipid-based carrier.

83. The protein-drug conjugate of claim 82, wherein the lipid-based carrier is a lipid nanoparticle (LNP), a liposome, a lipidoid, or a lipoplex.

84. The protein-drug conjugate of claim 83, wherein the lipid-based carrier is a lipid nanoparticle (LNP).

85. The protein-drug conjugate of claim 84, wherein the LNP further comprises a polynucleotide molecule and/or a polypeptide molecule.

86. The protein-drug conjugate of claim 84 or 85, wherein the LNP comprises one or more components of a gene editing system.

87. The protein-drug conjugate of claim 86, wherein the LNP comprises (a) a Cas nuclease, or a nucleic acid encoding the Cas nuclease, and/or (b) a guide RNA, or one or more DNAs encoding the guide RNA.

88. The protein-drug conjugate of claim 87, wherein the Cas nuclease is a Cas9 protein.

89. The protein-drug conjugate of claim 88, wherein the Cas9 protein is derived from a Streptococcus pyogenes Cas9 protein, a Staphylococcus aureus Cas9 protein, a Campylobacter jejuni Cas9 protein, a Streptococcus thermophilus Cas9 protein, or a Neisseria meningitidis Cas9 protein.

90. The protein-drug conjugate of any one of claims 87-89, wherein the nucleic acid encoding the Cas nuclease is codon-optimized for expression in a mammalian cell.

91. The protein-drug conjugate of claim 90, wherein the nucleic acid encoding the Cas nuclease is codon-optimized for expression in a human cell.

92. The protein-drug conjugate of any one of claims 87-91, wherein the nucleic acid encoding the Cas nuclease is an mRNA.

93. The protein-drug conjugate of any one of claims 48, 56, and 87-92, wherein the guide RNA is a single guide RNA (sgRNA).

94. The protein-drug conjugate of claim 86, wherein the LNP comprises a zinc finger nuclease (ZFN), or a transcription activator-like effector nuclease (TALEN).

95. The protein-drug conjugate of any one of claims 84-94, wherein the LNP comprises a cationic lipid, a neutral lipid, a helper lipid, a stealth lipid, or any combinations thereof.

96. The protein-drug conjugate of claim 95, wherein the neutral lipid is distearoylphosphatidylcholine (DSPC).

97. The protein-drug conjugate of claim 95, wherein the helper lipid is cholesterol.

98. The protein-drug conjugate of claim 95, wherein the stealth lipid is PEG2k-DMG.

99. A pharmaceutical composition comprising the protein-drug conjugate of any one of claims 1-98 and a pharmaceutically acceptable carrier.

100. A composition or kit comprising the protein-drug conjugate of any one of claims 1-98 or pharmaceutical composition of claim 99 and a further therapeutic agent.

101. A complex comprising the protein-drug conjugate of any one of claims 1-98 bound to fibroblast growth factor receptor 3 (FGFR3).

102. A method for making a protein-drug conjugate of any one of claims 1-98 comprising: (a) contacting the antigen-binding protein, with the molecular cargo under the conditions favorable for conjugation of the antigen-binding protein to the molecular cargo; and (b) optionally, isolating the protein-drug conjugate produced in step (a).

103. A method for making a protein-drug conjugate of any one of claims 60-68, wherein the molecular cargo comprises a polypeptide molecule, comprising: (a) culturing a host cell comprising a polynucleotide encoding the protein-drug conjugate under conditions that allow expression of the protein-drug conjugate; and (b) optionally, isolating the protein-drug conjugate produced in step (a).

104. A protein-drug conjugate which is produced by or obtainable by the method of claim 102 or 103.

105. A vessel or injection device comprising the protein-drug conjugate of any one of claims 1-98 and 104.

106. A method for administering the protein-drug conjugate of any one of claims 1-98 and 104 to a subject comprising introducing the protein-drug conjugate into the body of the subject.

107. A method for delivering a molecular cargo to a tissue or cell type expressing FGFR3 in the body of a subject comprising administering to the subject the protein-drug conjugate of any one of claims 1-98 and 104 or the pharmaceutical composition of claim 99.

108. The method of claim 107, wherein the tissue is brain, spinal cord, or eye.

109. The method of claim 107, wherein the cell type is astrocyte or astrocyte-derived tumor cell.

110. A method for treating or preventing a neurological disease or disorder in a subject in need thereof comprising administering to the subject an effective amount of the protein-drug conjugate of any one of claims 1-98 and 104.

111. The method of claim 110, wherein the neurological disease or disorder is associated with astrocytes.

112. The method of claim 110 or 111, wherein the neurological disease or disorder is a neurodegenerative disease, neurodevelopmental disease, physical injury, neuropsychiatric disease, or a brain cancer.

113. The method of claim 112, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or prion disease (transmissible spongiform encephalopathy).

114. The method of claim 112, wherein the neurodevelopmental disease is an Alexander disease, multiple sulfatase deficiency, autism, epilepsy, Rett syndrome, or Fragile X.

115. The method of claim 112, wherein the physical injury is traumatic brain injury, spinal cord injury, stroke, or brain edema.

116. The method of claim 112, wherein the neuropsychiatric disease or disorder is major depressive disorder, anxiety disorder, or bipolar disorder.

117. The method of claim 112, wherein the brain cancer is glioma.

118. The method of claim 117, wherein the glioma is an astrocytoma.

119. The method of any one of claims 110-118, further comprising administering an additional treatment to the subject.

120. The method of any one of claims 106-119, wherein the protein-drug conjugate is administered into the body of the subject via intrathecal, intracisternal, intracerebroventricular, or intraparenchymal administration into the central nervous system.

121. The method of any one of claims 106-119, wherein the protein-drug conjugate is administered into the body of the subject via intravitreal or intraocular administration into the eye.

122. The method of any one of claims 106-119, wherein the protein-drug conjugate is administered into the body of the subject via systemic administration.

123. The method of claim 122, wherein the protein-drug conjugate is administered into the body of the subject via intranasal administration.

61; 61; 12; 12; 12

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