Dual transporters and methods of use

Abstract

Described are dual transporters and methods of making and using the dual transporters. The dual transporters bind to a blood brain barrier transport protein and a second protein that is expressed on the luminal surface of the blood brain barrier or is a brain retention protein. The dual transporters improve delivery to the central nervous system.

Description

This invention provides a dual transporter, its preparation method, and its applications. The dual transporter binds to a blood-brain barrier transporter and a second protein, wherein the second protein is expressed on the luminal surface of the blood-brain barrier or is a brain retention protein. The dual transporter provided by this invention can improve delivery to the central nervous system. Abstract

Claims

Claims:

1. A dual transporter comprising:(a) a first binding region that specifically binds to a blood brain barrier (BBB) transport protein, wherein the BBB transport protein is the transferrin receptor (TfR) or CD98hc: and(b) a second binding region that specifically binds to a second protein wherein the second protein is expressed on the luminal surface of the BBB or is a brain retention protein, and wherein the second protein is different from the BBB transport protein.

2. The dual transporter of claim 1, wherein the second protein is selected from the group consisting of: TfR, CD98hc, Large neutral amino acids transporter small subunit 1 (CD98 light chain), glucose transporter 1 (GLUT1). major facilitator superfamily domaincontaining protein 2A (MFSD2A), carbonic anhydrase IV (CA-IV), Low density lipoprotein receptor, Insulin-like grow th factor 1 receptor (IGF1R), Insulin-like grow th factor 2 receptor, IgG receptor FcRn large subunit p51, Low' density lipoprotein receptor-related protein 1, Low density lipoprotein receptor-related protein 2, Insulin receptor, Cell cycle control protein 50A. Transmembrane protein 50A, Basigin. Leptin Receptor. Claudin-5, P-selectin, Lactoferrin receptor, Folate receptor. Sodium-dependent lysophosphatidylcholine symporter 1, Solute carrier organic anion transporter family member 1C1, Sodium-coupled neutral amino acid transporter 5, LDL receptor-related protein 8, High affinity cationic amino acid transporter 1. Sodium- and chloride-dependent taurine transporter, Insulin-like growth factorbinding protein 7, Solute carrier family 40 member 1, Zinc transporter 6, heparin-binding epidermal growth factor-like growth factor, and Myelin-oligodendrocyte glycoprotein (MOG).

3. The dual transporter of claim 1, wherein the second protein is a brain retention protein.

4. The dual transporter of claim 3, wherein the brain retention protein is CD98hc, MOG, GLUT1, IGF1R, or CA-IV, or MFSD2A.

5. The dual transporter of any one of claims 1-4, wherein the transferrin receptor is human TfR I6. The dual transporter of any one of claims 1-4, wherein the CD98hc is human CD98hc.

7. The dual transporter of claim 2, wherein(a) the BBB transport protein is human TfRl and the second protein is human CD98hc;(b) the BBB transport protein is human TfRl and the second protein is human MOG;(c) the BBB transport protein is human TfRl and the second protein is human GLUT1;(d) the BBB transport protein is human TfRl and the second protein is human IGF1R;(d) the BBB transport protein is human TfRl and the second protein is human C A-IV ; or(d) the BBB transport protein is human TfRl and the second protein is human MFSD2A.

8. The dual transporter of any one of claims 1-7, wherein the second protein undergoes receptor-mediated transcytosis.

9. The dual transporter of any one of claims 1-8, wherein the first binding region comprises:(a) a first peptide that specifically binds the BBB transport protein;(b) a first antibody antigen binding domain that specifically binds the BBB transport protein;(c) a first Fc polypeptide modified to specifically bind the BBB transport protein;(d) a first CH3 peptide modified to specifically bind the BBB transport protein;(e) a first fibronectin type III domain peptide modified to specifically bind the BBB transport protein; or(f) a first bicyclic peptide that specifically binds the BBB transport protein.

10. The dual transporter of claim 9, wherein the first antibody antigen binding domain comprises: an antibody, a single chain antibody, a F(ab')2 fragment, a Fab fragment, a single chain Fab (scFab), a Fv fragment, a single chain variable fragment (scFv), or a heavy chain only antibody variable domain (nanobody).

11. The dual transporter of any one of claims 1-10, wherein the second binding region comprises:(a) a second peptide that specifically binds the second protein,(b) a second antibody antigen binding domain that specifically binds the second protein,(c) a second Fc polypeptide modified to specifically bind the second protein,(d) a second CH3 peptide modified to specifically bind the second protein,(e) a second fibronectin type III domain peptide modified to specifically bind the second protein, or(f) a second bicyclic peptide that specifically binds the second protein.

12. The dual transporter of claim 11, wherein the second antibody antigen binding domain comprises: an antibody, a single chain antibody, a F(ab')2 fragment, a Fab fragment, a single chain Fab (scFab). a Fv fragment, a single chain variable fragment (scFv), or a heavy chain only antibody variable domain (nanobody).

13. The dual transporter of any one of claims 1-12, wherein the first binding region comprises a first antibody antigen binding domain that specifically binds the BBB transport protein and the second binding region comprises a second antibody antigen binding domain that specifically binds the second protein.

14. The dual transporter of claim 13, comprising a bispecific antibody selected from the group consisting of a full-length IgG bispecific antibody, a bispecific heavy chain antibody, and a bispecific F(ab')2 comprising the first antibody antigen binding domain and the second antibody antigen binding.

15. The dual transporter of claim 13. wherein the first binding region comprises a Fab fragment, a scFab. a Fv fragment, a scFv. or a nanobody and the second binding region comprises a Fab fragment, scFab, a Fv fragment, a scFv, or a nanobody.

16. The dual transporter of claim 15, wherein(a) the first binding region comprises a Fab fragment and the second binding region comprises a Fab fragment;(b) the first binding region comprises a scFab and the second binding region comprises a scFab;(c) the first binding region comprises a Fv fragment and the second binding region comprises a Fv fragment;(d) the first binding region comprises a scFv and the second binding region comprises a scFv; or(e) the first binding region comprises a nanobody and the second binding region comprises a nanobody.

17. The dual transporter of claim 11 or 12, wherein(a) the first binding region comprises the first antibody antigen binding domain and the second binding region comprises the second peptide, the second Fc polypeptide, the second CH3 peptide, the second fibronectin type III domain peptide, or the second bicyclic peptide; or(b) the first binding region comprises the first peptide, the first Fc polypeptide, the first CH3 peptide, the first fibronectin type III domain peptide, or the first bicyclic peptide and the second binding region comprises the second antibody antigen binding domain.

18. The dual transporter of claim 11 or 12, wherein(a) the first binding region comprises the first Fc polypeptide and the second binding region comprises the second peptide, the second antibody antigen binding domain, the second Fc polypeptide, the second CH3 peptide, the second fibronectin type III domain peptide, or the second bicyclic peptide;(b) the first binding region comprises the first CH3 peptide and the second binding region comprises the second peptide, the second antibody antigen binding domain, the second Fc polypeptide, the second CH3 peptide, the second fibronectin type III domain peptide, or the second bicyclic peptide;(c) the first binding region comprises the first peptide, the first antibody antigen binding domain, the first Fc polypeptide, the first CH3 peptide, the first fibronectin type III domain peptide, or the first bicyclic peptide and the second binding region comprises the second Fc polypeptide; or(d) the first binding region comprises the first peptide, the first antibody antigen binding domain, the first Fc polypeptide, the first CH3 peptide, the first fibronectin type III domain peptide, or the first bicyclic peptide and the second binding region comprises the second CH3 peptide.

19. The dual transporter of claim 11 or 12, wherein(a) the first binding region comprises the first Fc polypeptide and the second binding region comprises the second Fc polypeptide, optionally wherein the first Fc polypeptide and the second Fc polypeptide form a Fc dimer;(b) the first binding region comprises the first CH3 peptide and the second binding region comprises the second CH3 polypeptide;(c) the first binding region comprises the first fibronectin type III domain peptide and the second binding region comprises the second fibronectin type III domain peptide; or(d) the first binding region comprises the first bicyclic peptide and the second binding region comprises the second bicyclic peptide.

20. The dual transporter of any one of claims 1-19, wherein the first binding region is linked to the second binding region.

21. The dual transporter of any one of claims 1-19, wherein(a) the first binding region forms a dimer with the second binding region;(b) the first binding region is linked to a polypeptide that forms a dimer with the second binding region;(c) the second binding region is linked to a polypeptide that forms a dimer with the first binding region; or(d) the first binding region is linked to a first polypeptide and the second binding region is linked to a second polypeptide, wherein the first polypeptide and the second polypeptide form a dimer.

22. The dual transporter of any one of claims 1-19, wherein the first binding region, the second binding region, or both the first binding region and the second binding region are linked to a scaffold.

23. The dual transporter of claim 22, w herein the scaffold comprises an antibody or a fragment thereof.

24. The dual transporter of claim 23, w herein the scaffold comprises an antibody and wherein(a) the first binding region is linked to a heavy chain of the antibody, the second binding region is linked to a heavy chain of the antibody, or the first and the secondbinding regions are both linked to a heavy chain of the antibody, optionally wherein the first binding region is linked to the C terminal end of a heavy chain of the antibody and / or the second binding region is linked to the C terminal end a heavy chain of the antibody:(b) the first binding region is linked to a Fc region of the antibody, the second binding region is linked to a Fc region of the antibody, or the first and the second binding regions are both linked to a Fc region of the antibody, optionally wherein the first binding region is linked to the C terminal end of a Fc region of the antibody and / or the second binding region is linked to the C terminal end a Fc region of the antibody:(c) the first binding region is linked to a light chain of the antibody, the second binding region is linked to a light chain of the antibody, or the first and the second binding regions are both linked to a light chain of the antibody, optionally wherein the first binding region is linked to the C terminal end of a light chain of the antibody and / or the second binding region is linked to the C terminal end of a light chain of the antibody; or(d) the first binding region is linked to a light chain of the antibody and the second binding region is linked to a heavy chain of the antibody or the first binding region is linked to a heavy chain of the antibody and the second binding region is linked to a light chain of the antibody.

25. The dual transporter of claim 24. wherein the first binding region comprises a Fab fragment, a scFab. a Fv fragment, a scFv. a nanobody, and the second binding region comprises a Fab fragment, a scFab, a Fv fragment, a scFv, or a nanobody.

26. The dual transporter of claim 24 or 25, wherein the scaffold is a full-length IgG antibody that binds to a therapeutic brain target, and the first and the second binding regions are each attached to a respective C-terminal end of a heavy chain of the full-length IgG antibody.

27. The dual transporter of claim 26. wherein the first and second binding regions are each an antibody antigen binding domain.

28. The dual transporter of claim 27, wherein each antibody antigen binding domain independently comprises a Fab fragment or an scFab.

29. The dual transporter of claim 27, wherein the first and second binding regions are each an scFv.

30. The dual transporter of any one of claims 1-29, wherein the dual transport binds to the BBB transport protein with greater affinity than the dual transporter binds to the second protein, optionally wherein the dual transporter binds to the BBB transport protein with an affinity of about 50 nM to about 1000 nM and binds to the second protein with an affinity of about 5- to about 10-fold less than the affinity to the BBB transport protein.

31. The dual transporter of any one of claims 1-29, wherein the dual transport binds to the BBB transport protein with lesser affinity' than the dual transporter binds to the second protein, optionally wherein the dual transporter binds to the BBB transport protein with an affinity of about 50 nM to about 6000 nM and binds to second protein with an affinity of about 5- to about 10-fold greater than the affinity to BBB transport protein.

32. The dual transporter of any one of claims 1-29, wherein the first binding region has moderate or w eak affinity to the BBB transport protein and the second binding region has strong affinity’ to the second protein.

33. The dual transporter of any one of claims 24-29, w herein the first and second binding regions bind hTfRl and human CD98hc, respectively.

34. The dual transporter of claim 33, w herein the first binding region comprises the CDRs or the variable chain regions of a Brain shuttle anti-TfR antibody, a TfR.12 anti- TfR antibody, a TfR.13 anti-TfR scFv, a 13E4v2ii anti-TfR antibody, a JC-141 anti-TfR antibody, a JC-171 anti-TfR antibody, a 17H10 anti-TfR Fab or scFv, or a 17H10. 1 anti-TfR Fab or scFv.

35. The dual transporter of any one of claims 33 or 34, wherein the second binding region comprises the CDRs or the variable chain regions of 1C03-4 anti-CD98hc VHH, a 1C03-5 anti-CD98hc VHH, a CD98hc2 anti-CD98hc nanobody, a CD98hc4 anti- CD98hc scFv, or a CD98hc5 anti-CD98hc scFv.

36. The dual transporter of any one of claims 23-25. wherein the scaffold comprises a full-length antibody directed to a therapeutic brain target and the first and second binding regions are each respectively linked to a C-terminal end of a light chain of the full- length antibody.

37. The dual transporter of any one of claims 23-25, wherein the antibody comprises a bispecific antibody.

38. The dual transporter of any one of claims 23-37, wherein the antibody specifically binds to a therapeutic target.

39. The dual transporter of any one of claims 23-25 and 37-38, wherein the dual transport molecule comprises a bispecific antibody, wherein(a) the bispecific antibody specifically binds to the BBB transport protein and specifically binds to a therapeutic target and wherein the second binding region is linked to the bispecific antibody; or(b) the bispecific antibody specifically binds to the second protein and specifically binds to a therapeutic target and wherein the first binding region is linked to the bispecific antibody.

40. The dual transporter of any one of claims 1-13, wherein the dual transport molecule comprises a tri-specific antibody, a tri-specific antibody -like molecule, a tetra- specific antibody, or tetra-specific antibody -like molecule.

41. The dual transporter of any one of claims 1-13, wherein the dual transport molecule comprises a DVD-Ig, wherein a first Fab arm of the DVD-Ig comprises a first Fv fragment that specifically binds to a first target protein and a second Fv fragment that specifically binds to the BBB transport protein, and a second Fab arm of the DVD-Ig comprises a third Fv fragment that specifically binds to a second target protein and a fourth Fv fragment that specifically binds to the second protein.

42. The dual transporter of claim 19. wherein the first binding region comprises the first Fc polypeptide and the second binding region comprises the second Fc polypeptide, wherein the first Fc polypeptide and the second Fc polypeptide from a Fc dimer, and wherein the Fc dimer is linked to one or more Fabs, one or more F(ab')2s, one or more scFabs, one or more scFvs, or one or more nanobodies, optionally wherein the Fab, F(ab')2, scFab, scFv, or nanobody comprises a therapeutic Fab, F(ab')2, scFab, scFv, or nanobody.

43. The dual transporter of any one of claims 1-42, wherein the dual transport molecule is linked to a therapeutic agent.

44. The dual transporter of claim 18 or 19, wherein the dual transport molecule comprises a therapeutic antibody comprising the first Fc polypeptide or CH3 peptide modified to specifically bind the BBB transport protein and the second Fc polypeptide or CH3 peptide modified to specifically bind a second protein.

45. The dual transporter of any one of claims 1-4, 6-19, and 44, wherein the BBB transport protein comprises TfR.

46. The dual transporter of claim 45, wherein the first binding region binds to the apical domain of TfR.

47. The dual transporter of claim 46, wherein first binding region binds TfR without inhibiting binding of transferrin to the TfR.

48. The dual transporter of any one of claims 45-47, wherein the first binding region comprises a first antibody antigen binding domain that specifically binds TfR.

49. The dual transporter of claim 48. wherein the first antibody antigen binding domain comprises the CDR sequences of a JC-141 anti-TfR antibody, a JC-171 anti-TfR antibody, a Brain shuttle anti-TfR antibody, a 13E4v2ii anti-TfR antibody, a TfR12 anti-TfR antibody, a TfR13 anti-TfR antibody, a 17H10 anti-TfR Fab or scFv, or a 17H10. 1 anti-TfR Fab or scFv.

50. The dual transporter of claim 49, wherein the first antibody antigen binding domain comprises an antibody antigen binding domain from the JC-141 anti-TfR antibody, the JC-171 anti-TfR antibody, the Brain shuttle anti-TfR antibody, the 13E4v2ii anti-TfR antibody, the TfR12 anti-TfR antibody, the TfR13 anti-TfR antibody, the 17H10 anti-TfR Fab or scFv, or the 17H10.1 anti-TfR Fab or scFv.

51. The dual transporter of any one of claims 45-47, wherein the first binding region comprises a first Fc polypeptide or a first CH3 peptide modified to specifically bind TfR.

52. The dual transporter of any one of claims 45-51, wherein the first binding region specifically binds TfR with an affinity of less than about 100 nM.

53. The dual transporter of any one of claims 45-51, wherein the first binding region specifically binds TfR with an affinity of about 100 nM to about 1000 nM or about 100 nM to about 600 nM.

54. The dual transporter of any claim 45-51, wherein the first binding region specifically binds TfR. with an affinity of about 600 nM to about 6000 nM or about 600 nM to about 1000 nM.

55. The dual transporter of claim 51, wherein the first CH3 peptide modified to specifically bind TfR comprises five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen substitutions in a set of ammo acid positions consisting of: 380, 384, 386, 387, 388, 389, 390, 391, 392, 413, 414, 415, 416, 421, 424, and 426 wherein the positions are determined with reference to EU numbering.

56. The dual transporter of claim 55. wherein the substitutions are selected from: a L, Q, S, V, W, or Y at position 380; a F, L, M, P, V, W, Y, or I at position 384; a F, H, I, L, N, P, T, or V at position 386; a D, E, I, or V at position 387; a W, F, or Y at position 388; an A, G. I, S, T, or V at position 389; an A. D, E. F, G, H, K, L, Q, R, S. T, V. or Y at position 390; a F, Q, S, T, or V at position 391; a Q, F. or H at position 392; an A, E, H, I, L, P. S, or T at position 413; a R, G, or P at position 414; a D, E, G, T, P, Q, or R at position 415; a D, E, N, or T at position 416; a F, H, K, W, or Y at position 421; a T, W, E, or K at position 424; and a C, P, M, W, or G at position 426.

57. The dual transporter of claim 46, wherein the first CH3 peptide modified to specifically bind TfR comprises a F, L, M, P, V, W, Y, or I at position 384; a F, H, I, L, N, P, T, or V at position 386; a W, F, or Y at position 388; an A, G, I, S, T, or V at position 389; and; a F, H, K, W, or Y at position 421.

58. The dual transporter of claim 57, wherein the first CH3 peptide modified to specifically bind TfR further comprises one, two, three, four, five, six, seven, eight, nine, ten, or eleven substitutions selected from: a L, Q, S, V, W, or Y at position 380; a D, E, I, or V at position 387; an A. D, E. F, G. H, K, L, Q, R, S. T, V. or Y at position 390: a F, Q. S, T, or V at position 391; a Q, F, or H at position 392; an A, E, H, I, L, P, S, or T at position 413; a R, G, or P at position 414; a D, E, G, T, P, Q, or R at position 415; a D, E, N, or T at position 416; a T, W, E, or K at position 424; and a C, P. M, W, or G at position 426.

59. The dual transporter of claim 51, wherein the first CH3 peptide modified to specifically bind TfR comprises: four, five, six, seven, eight, or nine substitutions in a set of amino acid positions consisting of: 384, 386, 387, 388, 389, 413, 415, 416, and 421; wherein the positions are determined with reference to EU numbering.

60. The dual transporter of claim 59. wherein the substitutions are selected from: a Y at position 384; a T at position 386; an E at position 387; a W at position 388; a V, S, or A at position 389; a T or S at position 413; an E at position 415; an E at position 416; and a F at position 421.

61. The dual transporter of claim 60, wherein the first CH3 peptide modified to specifically bind TfR comprises: a Y at position 384; a T at position 386; an E at position 387; a W at position 388; a V, S, or A at position 389; a T or S at position 413; an E at position 415; an E at position 416; and a F at position 421.

62. The dual transporter of any one of claims 55-61, wherein the first CH3 peptide modified to specifically bind TfR comprises Y at position 391, a K at position 392, a S at position 424; and S at position 426.

63. The dual transporter of any one of claims 55-61, wherein the first CH3 peptide modified to specifically bind TfR comprises (a) a polypeptide having at least 85%, at least 90%, at least 95%, or 100% identify to the amino acid sequence of any of SEQ ID NOs:6-14 and 124-125; or (b) a polypeptide having at least 85%, at least 90%, at least 95%, or 100% identify to the amino acids 111-217 of any of SEQ ID NOs:6-14 and 124-125.

64. The dual transporter of claim 51, wherein the first CH3 peptide modified to specifically bind TfR comprises six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty -four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thi rty, or thirty-one amino acid substitutions in a set of amino acid positions consisting of: 378, 380, 382, 383. 384, 385, 386, 387, 388. 389, 390, 391, 414, 417, 419, 420. 421, 422, 424, 426, 427, 428. 429, 433, 434. 437, 438. 439, 440, 442, and 443, and 426; wherein the positions are determined with reference to EU numbering.

65. The dual transporter of claim 64, wherein the substitutions are selected from: an E. L, or I at position 378; aN, R. Y, I, S. or F at position 380; a F at position 382; a Y, A.G, T, or a deletion at position 383; an A, D, E, F, G. or T at position 384; an A. D, or N at position 385; an A. G, K, N, S, or Y at position 386; a G, I, K, N. R, S, or T at position 387; a L, Q, or D at position 388; an I, P, Q, R, S, or T at position 389; a G, T, Y, or L at position 390; a S, T, I, L, or P at position 391; a P at position 414; a K at position 417; a P at position 419; a R or Q at position 420; an A, F, G, S, or Y at position 421; a L at position 422; an A at position 424; an E at position 426; an E at position 427; an E at position 428; a G at position 429; an E at position 433; a G at position 434; a D at position 437; a Y at position 438; a D, E, or S at position 439; a L at position 440; a G or W at position 442; and an E or Y at position 443.

66. The dual transporter of claim 65. wherein the first CH3 peptide modified to specifically bind TfR comprises a F at position 382, a L at position 422, an A at position 424, an E at position 426, a Y at position 438, and a L at position 440.

67. The dual transporter of claim 66. wherein the first CH3 peptide modified to specifically bind TfR further comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty -one, twenty-two, twenty -three, twenty-four, or twenty -five substitutions selected from: an E. L, or I at position 378; a N, R. Y, I, S. or F at position 380; a Y, A, G, T, or a deletion at position 383; an A, D, E, F, G, or T at position 384; an A, D, or N at position 385; an A, G, K, N, S, or Y at position 386; a G, I, K, N, R, S, or T at position 387; a L, Q, or D at position 388; an I, P, Q, R, S, or T at position 389; a G, T, Y, or L at position 390; a S, T, I, L, or P at position 391; a P at position 414; a K at position 417; a P at position 419; a R or Q at position 420; an A, F, G, S, or Y at position 421; an E at position 427; an E at position 428; a G at position 429; an E at position 433; a G at position 434; a D at position 437; a D, E, or S at position 439; a G or W at position 442; and an E or Y at position 443.

68. The dual transporter of any one of claims 64-67. wherein the first CH3 peptide modified to specifically bind TfR comprises (a) a polypeptide having at least 85%, at least 90%, at least 95%, or 100% identify to the amino acid sequence of any of SEQ ID NOs:57-64 and 126; or (b) a polypeptide having at least 85%, at least 90%, at least 95%, or 100% identify to the amino acids 111-217 of any of SEQ ID NOs:57-64 and 126.

69. The dual transporter of claim 51, wherein the first CH3 peptide modified to specifically bind TfR comprises four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, fifteen, or sixteen substitutions in a set of amino acid positions consisting of: 378, 380, 382, 383. 384, 385, 386, 421, 422, 424, 426. 428, 434, 438, 440, and 442; wherein the positions are determined with reference to EU numbering.

70. The dual transporter of claim 69, wherein the substitutions are selected from: a D, E, F, H, N, Q. S, V. or Y at position 378; an A. D, F. H, I, K, L, M, Q. S, T, or Y at position 380; a G at position 382; a T at position 383; an A, E, F, H, I, K, L, Q, S, V, or Y at position 384; an I, T, or V at position 385; an A, H, N, S, T, or V at position 386; an A, F, H, K, L, M, Q, S, T, V, or Y at position 421; an A, F, H, I, K, L, R, T, or Y at position 422; an A, G. or P at position 424; an A, I. L, T, or V at position 426; an A or L at position 428; a S at position 434; an I, F. L, V. or Y at position 438; an A. G, I, M, N, P, T. or V at position 440; and an A, K, M, R, T, or V at position 442.

71. The dual transporter of claim 70, wherein the first CH3 peptide modified to specifically bind TfR comprises: a G at position 382; an A, E, F, H. I, K, L, Q, S, V, or Y at position 384; an I, T, or V at position 385; and an I, F, L, V, or Y at position 438.

72. The dual transporter of claim 71, wherein the first CH3 peptide modified to specifically bind TfR further comprises one. two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen substitutions selected from: a D, E, F, H, N, Q, S, V, or Y at position 378; an A, D, F, H, I, K, L, M, Q, S, T, or Y at position 380; a T at position 383; an A, H, N, S, T, or V at position 386; an A, F, H, K, L, M, Q, S. T, V, or Y at position 421; an A, F, H, I, K. L, R, T, or Y at position 422; an A, G. or P at position 424; an A, I, L, T, or V at position 426; an A or L at position 428; a S at position 434; an A, G, I, M, N, P, T, or V at position 440; and an A, K, M, R, T, or V at position 442.

73. The dual transporter of any one of claims 1-72, wherein the second protein comprises CD98hc.

74. The dual transporter of claim 73, wherein the second binding region comprises a second antibody antigen binding domain that specifically binds CD98hc.

75. The dual transporter of claim 74, wherein the second antibody antigen binding domain comprises the CDR sequences of: a 1C03-4 anti-CD98hc VHH, a 1C03-5 anti- CD98hc VHH, a CD98hc2 anti-CD98hc nanobody, a CD98hc4 anti-CD98hc scFv, or a CD98hc5 anti-CD98hc scFv.

76. The dual transporter of claim 75, wherein the second antibody antigen binding domain comprises: the 1C03-4 anti-CD98hc VHH, the 1C03-5 anti-CD98hc VHH. the CD98hc2 anti-CD98hc nanobody, the CD98hc4 anti-CD98hc scFv, or the CD98hc5 anti- CD98hc scFv.

77. The dual transporter of claim 73. wherein the second binding region comprises a second Fc polypeptide or a second CH3 peptide modified to specifically bind CD98hc.

78. The dual transporter of any one of claims 73-77, wherein the second binding region specifically binds CD98hc with an affinity of less than about 15 nM to about 5000 nM, or about 100 nM to about 500 nM.

79. The dual transporter of claim 77 or 78, wherein the second CH3 peptide modified to specifically bind CD98hc comprises five, six. seven, eight, or nine substitutions in a set of amino acid positions consisting of 382. 384, 385. 387, 422, 424, 426, 438. and 440; wherein the positions are determined according to EU numbering.

80. The dual transporter of claim 79, wherein the substitutions are selected from: a R, Y. F, S, W, Y, K, or N at position 382; a L. Y, A, S, or F at position 384; a F, K, D. M, I, N, Y, L, or H at position 385; aN, L, Y, R, F, G, S, D, or T at position 387; an I, K, L, R, T, F, or H at position 422; a V, W, G, L, I, P, or Y at position 424; a D, A, Q, W, L, or P at position 426; an I, V, F, N, P, or S at position 438; and a K, T, P, I, or F at position 440.81 . The dual transporter of claim 77 or 78, wherein the second CH3 peptide modified to specifically bind CD98hc comprises at least five, six, seven, eight, or nine substitutions in a set of amino acid positions consisting of 382, 383, 384, 385, 386, 387, 389, 421, 422. 424, 426, 428, 434, 436. 438, 440, and 442; wherein the positions are determined according to EU numbering.

82. The dual transporter of claim 81, w herein the substitutions are selected from: a S or V at position 378; a D, M, N, P, F, or H at position 380; a R, Y, F, S, W. Y, K, or N at position 382; a T at position 383; a L, Y, A, S, or F at position 384; a F, K, D, M, I, N, Y, L, or H at position 385; a T, P, E, K, A, V, D, T, or F at position 386; a N, L, Y, R, F, G, S, D, or T at position 387; a T , Y, or F at position 389; a D, E, or Q at position 421; an I, K, L, R, T, F, or H at position 422; a V, W. G, L. I, P, or Y at position 424; a D, A, Q, W, L, or P atposition 426; a L or Y at position 428; a S at position 434; a F at position 436; an I, V, F. N, P, or S at position 438; a K, T. P, I, or F at position 440; and Q or M at position 442.

83. The dual transporter of claim 77 or 78, wherein the second CH3 peptide modified to specifically bind CD98hc comprises at least eleven, twelve, thirteen, fourteen, or fifteen substitutions in a set of amino acid positions consisting of 378, 380. 382, 383. 384, 385, 386, 387, 389, 391, 421, 422, 424, 426, 428, 434, 436, 438, 440, 441, and 442; wherein the positions are determined according to EU numbering.

84. The dual transporter of claim 83, wherein the substitutions are selected from: a S, V, D, E, or Y at position 378; a L, I, M, A, Q, V, or K at position 380; aN, S, L, M, P, Y, K, A, or T at position 382; a T, F, N, P, D, L, H, or Q at position 383; a K, R, H, I, L, F, Y, V, or Q at position 384; a F or Y at position 385; a V, L, A, I, F, Y, S, T, H, R, or E at position 386; a L or I at position 387; a D, Q. A, T. H, or V at position 389; a T, V, or A at position 391; an E, Q. or A at position 421; a L, M, I, T, or P at position 422; an A at position 424; a N at position 426; a L, T, P, Y F, I, A, K, H, or W at position 428; a S at position 434; a L, V, H, F, P, R or W at position 436; a F or W at position 438; a L, P, E, N, V, A, I, or D at position 440; a P at position 441 ; and an A, V, M, Q, F, P, L, Y, K, R, H, or M at position 442.

85. The dual transporter of claim 77 or 78, wherein the second CH3 peptide modified to specifically bind CD98hc comprises eleven, twelve, thirteen, fourteen, or fifteen substitutions in a set of amino acid positions consisting of:

380. 382, 384, 385, 386, 387, 421, 422, 424, 426, 428, 436, 438, 440, and 442; wherein the positions are determined according to EU numbering.

86. The dual transporter of claim 85, wherein the substitutions are selected from: a L at position 380; a N at position 382; a R, H. or Q at position 384; a F or Y at position 385; a V, L, I, F, Y, or E at position 386; a L at position 387; an E, Q or A at position 421; an I, T, or P at position 422; an A at position 424; a N at position 426; a Y or W at position 428; a R or W at position 436; a F or W at position 438; aN at position 440; and an A, Q, K, R, H, or M at position 442.

87. The dual transporter of any one of claims 69-72, wherein the second CH3 peptide modified to specifically bind CD98hc comprises (a) a polypeptide having at least 85%. at least 90%. at least 95%, or 100% identify to the amino acid sequence of any of SEQID NOs: 15-30; or (b) a polypeptide having at least 85%, at least 90%, at least 95%, or 100% identify to the amino acids 111-217 of any of SEQ ID NOs: 15-30.

88. The dual transporter of claim 77 or 78, wherein the second CH3 peptide modified to specifically bind CD98hc comprises eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, or nineteen substitutions in a set of amino acid positions consisting of: 378, 380, 382, 383, 384, 385, 386, 387, 389, 421, 422, 424, 426, 428, 434, 436, 438, 440, and 442; wherein the positions are determined according to EU numbering.

89. The dual transporter of claim 88, wherein the substitutions are selected from: a S or V at position 378; a D, M, N, P, F, or H at position 380; a R, Y, F, S, W, Y, K, or N at position 382; a T at position 383; a L, Y, A, S, or F at position 384; a F, K, D, M, I, N, Y, L, or H at position 385; a T, P, E. K, A, V, D, T, or F at position 386; a N. L, Y. R, F, G, S, D, or T at position 387; a T , Y. or F at position 389; a D, E, or Q at position 421; a I, K, L, R, T, F, or H at position 422; a V, W, G, L, I, P, or Y at position 424; a D, A, Q, W, L, or P at position 426; a L or Y at position 428; a S at position 434; a F at position 436; a I, V, F, N, P, or S at position 438; a K, T, P, I, or F at position 440; and a Q or M at position 442.

90. The dual transporter of claim 77 or 78, wherein the second CH3 peptide modified to specifically bind CD98hc comprises eight, nine, ten, eleven, twelve, or thirteen substitutions in a set of amino acid positions consisting of 380, 382, 384, 385, 386, 387, 422, 424, 426. 428, 434, 438, and 440; wherein the positions are determined according to EU numbering.

91. The dual transporter of claim 90, wherein the substitutions are selected from: a D, M, N, P, F, or H at position 380; a R. Y, F, S, W, Y, K, or N at position 382; a L, Y, A, S, or F at position 384; a F. K, D. M. I. N, Y. L, or H at position 385; a T. P, E, K, A. V, D. T, or F at position 386; aN, L, Y, R, G, S, D, or T at position 387; an I, K, R, T, F, or H at position 422; a V, W, G, L, I, P, or Y at position 424; a D, A, Q, W, L, or P at position 426; a L at position 428; a S at position 434; an I, F, N, P, or S at position 438; and a K, T, I, or F at position 440.

92. The dual transporter of claim 77 or 78, wherein the second CH3 peptide modified to specifically bind CD98hc comprises eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, or nineteen substitutions in a set of amino acidpositions consisting of 378, 380, 382, 383, 384, 385, 386, 387, 389, 421, 422, 424, 426, 428, 434, 436. 438, 440, and 442; wherein the positions are determined according to EU numbering.

93. The dual transporter of claim 92, wherein the substitutions are selected from: a S or V at position 378; a D at position 380; a R at position 382; a T at position 383; a Y at position 384; a K at position 385; a P at position 386; a Y at position 387; a T, Y, or F at position 389; a D, E, or Q at position 421 ; an I at position 422; a V at position 424; a D at position 426; a L or Y at position 428; a S at position 434; a F at position 436; an I or V at position 438; a K at position 440; and a Q or M at position 442.

94. The dual transporter of any one of claims 88-93, wherein the first CH3 peptide modified to specifically bind TfR comprises (a) a polypeptide having at least 85%, at least 90%, at least 95%, or 100% identify to the amino acid sequence of SEQ ID NOs:34 or 35; or (b) a polypeptide having at least 85%, at least 90%, at least 95%, or 100% identify to the ammo acids 111-217 of SEQ ID NOs: 34 or 35.

95. The dual transporter of any one of claims 1-94, wherein the dual transporter comprises an Fc polypeptide having one or more mutations that (a) promote heterodimer formation; (b) modulate effector function; or (c) extend serum half-life.

96. The dual transporter of any one of claims 1-32 and 36-72, wherein the first binding region specifically binds TfR and the second binding region specifically binds CD98hc.

97. The dual transporter of any one of claims 1-9, 11, 18-24, 30-32, 36-38, 42-47, 51, and 55-73, wherein the first binding region comprises a first Fc polypeptide or CH3 peptide modified to specifically bind TfR and the second binding region comprises a second Fc polypeptide or CH3 peptide modified to specifically bind CD98hc.

98. The dual transporter of any one of claims 77-97. wherein the first Fc polypeptide and the second Fc polypeptide form a Fc dimer.

99. The dual transporter of claim 98, wherein the dual transporter comprises an antibody comprising the first Fc polypeptide and the second Fc polypeptide.

100. The dual transporter of any one of claims 1-13, 16, 22-25, 30-38, 43, 45-50, and 73-76, wherein the first binding region comprises an anti-TfR antibody antigen binding domain linked to the C terminal end of a first light chain of an antibody and the second binding region comprises an anti-CD98hc antibody antigen binding domain linked to the C terminal end of a second light chain of the antibody.

101. The dual transporter of any one of claims 1-13, 16, 22-36, 37-38, 43, 45-50, and 73-76, wherein the first binding region comprises an anti-TfR antibody antigen binding domain linked to the C terminal end of a first heavy chain of an antibody and the second binding region comprises an anti-CD98hc antibody antigen binding domain linked to the C terminal end of a second heavy chain of the antibody.

102. The dual transporter of claim 100 or 101, wherein the antibody comprises a monospecific antibody, a bispecific antibody, a monospecific therapeutic antibody, or a bispecific therapeutic antibody.

103. The dual transporter of any one of claims 100-102, wherein the first binding region comprises a Fab fragment, a scFab. a Fv fragment, a scFv, a nanobody, and the second binding region comprises a Fab fragment, a scFab, a Fv fragment, a scFv, or a nanobody.

104. The dual transporter of any one of claims 1-16, 22-36, 43, 45-50, and 73-76, wherein the dual transporter comprises a bispecific antibody wherein one Fab arm of the antibody specifically binds TfR and the other Fab arm of the antibody specifically binds CD98hc.

105. The dual transporter of any one of claims 1-16, 22-25, 30-35, 37-40, 46-50, and 73-76, wherein the dual transporter comprises a bispecific antibody wherein one Fab arm of the antibody specifically binds TfR or CD98hc and the other Fab arm of the antibody specifically binds a target protein.

106. The dual transporter of any one of claims 1-12, 19, and 30-33. wherein(a) the first binding region comprises a first fibronectin type III domain peptide modified to specifically bind TfR and the second binding region comprises a second fibronectin ty pe III domain peptide modified to specifically bind, wherein the first and second binding regions are linked to an antibody; or(b) the first binding region comprises a first bicyclic peptide that specifically binds TfR and the second binding region comprises a second bicyclic peptide that specifically binds CD98hc, wherein the first and second binding regions are linked to an antibody.

107. The dual transporter of any one of claims 1-18, 20-25. 30-35, 46-50, and 73- 76, wherein the dual transporter comprises(a) an anti-TfR monospecific or bispecific antibody linked to the second binding region; or(b) an anti-CD98hc monospecific or bispecific antibody linked to the first binding region.

108. The dual transporter of any one of claims 1-29, 33-51, 55-77, and 79-107, wherein the first binding region has moderate or weak affinity to TfR and the second binding region has strong affinity’ to CD98hc.

109. The dual transporter of any one of claims 1-29, 33-51, 55-77, and 79-107, wherein(a) the first binding region binds to TfR with an affinity of about 1000 nM to about 6000 nM and the second binding region binds to CD98hc with an affinity of about 1000 nM to about 6000 nM;(b) the first binding region binds to TfR with an affinity of about 900 nM to about 6000 nM and the second binding region binds to CD98hc with an affinity of about 900 nM to about 6000 nM;(c) the first binding region binds to TfR with an affinity of about 1000 nM to about 6000 nM and the second binding region binds to CD98hc with an affinity’ of about 300 nM to about 900 nM;(d) the first binding region binds to TfR with an affinity of about 900 nM to about 6000 nM and the second binding region binds to CD98hc with an affinity of about 300 nM to about 900 nM;(e) the first binding region binds to TfR with an affinity of about 1000 nM to about 6000 nM and the second binding region binds to CD98hc with an affinity of less than about 250 nM; or(f) the first binding region binds to TfR with an affinity of about 900 nM to about 6000 nM and the second binding region binds to CD98hc with an affinity of about 50 nM to about 250 nM.

110. The dual transporter of any one of claims 1-29, 33-51, 55-77, and 79-107. wherein(a) the first binding region binds to TfR with an affinity of about 300 nM to about 900 nM and the second binding region binds to CD98hc with an affinity of about 1000 nM to about 6000 nM;(b) the first binding region binds to TfR with an affinity of about 300 nM to about 900 nM and the second binding region binds to CD98hc with an affinity of about 300 nM to about 900 nM;(c) the first binding region binds to TfR with an affinity7of about 300 nM to about 900 nM and the second binding region binds to CD98hc with an affinity of less than about 250 nM; or(d) the first binding region binds to TfR with an affinity of about 300 nM to about 900 nM and the second binding region binds to CD98hc with an affinity of about 50 nM to about 250 nM.

111. The dual transporter of any one of claims 1-29, 33-51, 55-77, and 79-107, wherein(a) the first binding region binds to TfR with an affinity of less than about 250 nM and the second binding region binds to CD98hc with an affinity of about 1000 nM to about 6000 nM;(b) the first binding region binds to TfR with an affinity of less than about 250 nM and the second binding region binds to CD98hc with an affinity of about 300 nM to about 900 nM;(c) the first binding region binds to TfR with an affinity of about 50 nM to about 250 nM and the second binding region binds to CD98hc with an affinity of about 300 nM to about 900 nM;(d) the first binding region binds to TfR with an affinity of less than about 250 nM and the second binding region binds to CD98hc with an affinity of less than about 250 nM; or(e) the first binding region binds to TfR with an affinity of about 50 nM to about 250 nM and the second binding region binds to CD98hc with an affinity of about 50 nM to about 250 nM.

112. The dual transporter of any one of claims 1-29, 33-51, 55-77, and 79-107. wherein(a) the first binding region binds to TfR with an affinity of about 300 nM to about 6000 nM and the second binding region binds to CD98hc with an affinity of about 1000 nM to about 6000 nM;(b) the first binding region binds to TfR with an affinity of about 300 nM to about 6000 nM and the second binding region binds to CD98hc with an affinity of about 900 nM to about 6000 nM;(c) the first binding region binds to TfR w ith an affinity of about 300 nM to about 6000 nM and the second binding region binds to CD98hc with an affinity of about 300 nM to about 900 nM;(d) the first binding region binds to TfR with an affinity of about 300 nM to about 6000 nM and the second binding region binds to CD98hc with an affinity of less than about 250 nM;(e) the first binding region binds to TfR with an affinity of about 300 nM to about 6000 nM and the second binding region binds to CD98hc with an affinity of about 50 nM to 250 nM; or(f) the first binding region binds to TfR with an affinity of about 300 nM to about 6000 nM and the second binding region binds to CD98hc with an affinity of about 50 nM to 900 nM.

113. The dual transporter of any one of claims 1-29, 33-51, 55-77, and 79-107, wherein(a) the first binding region binds to TfR with an affinity of about 50 nM to about 1000 nM and the second binding region binds to CD98hc with an affinity of about 1 nM to about 500 nM;(b) the first binding region binds to TfR with an affinity of about 100 nM to about 600 nM and the second binding region binds to CD98hc with an affinity of about 50 nM to about 300 nM; or(c) the first binding region binds to TfR with an affinity of about 100 nM to about 400 nM and the second binding region binds to CD98hc with an affinity of about 50 nM to about 200 nM.

114. The dual transporter of any one of claims 1-29, 33-51, 55-77, and 79-107. wherein(a) the first binding region binds to TfR with an affinity of about 250 nM to about 6000 nM and the second binding region binds to CD98hc with an affinity of about 1 nM to about 250 nM;(b) the first binding region binds to TfR with an affinity of about 250 nM to about 1000 nM and the second binding region binds to CD98hc with an affinity of about 1 nM to about 100 nM; or(c) the first binding region binds to TfR with an affinity of about 50 nM to about 250 nM and the second binding region binds to CD98hc with an affinity of about 1 nM to about 100 nM.

115. The dual transporter of any one of claims 1-29, 33-51, 55-77, and 79-107, wherein(a) the first binding region binds to TfR with an affinity of about 1000 nM to about 6000 nM and the second binding region binds to CD98hc with an affinity of about 1 nM to about 500 nM;(b) the first binding region binds to TfR with an affinity of about 250 nM to about 1000 nM and the second binding region binds to CD98hc with an affinity of about 250 nM to about 1000 nM;(c) the first binding region binds to TfR with an affinity of about 50 nM to about 250 nM and the second binding region binds to CD98hc with an affinity of about 500 nM to about 6000 nM.1 16. The dual transporter of any one of claims 1-29, 33-51, 55-77, and 79-107, wherein the dual transporter binds to TfR with an affinity of about 50 nM to about 1000 nM and binds to CD98hc with an affinity' of about 5- to about 10-fold less than the affinity to TfR.

117. The dual transporter of any one of claims 1-29, 33-51, 55-77, and 79-107, wherein the dual transporter binds to TfR with an affinity of about 50 nM to about 6000 nMand binds to CD98hc with an affinity' of about 5- to about 10-fold greater than the affinity' to TfR.

118. The dual transporter of any one of claims 1-117, wherein the dual transporter is capable of being actively transported across the blood brain barrier.

119. The dual transporter of any one of claims 1-117, wherein the dual transporter is capable facilitating transport of a therapeutic agent across the blood brain barrier.

120. The dual transporter of claim 119, wherein the therapeutic agent targets: ABCA1, ABCA7, ADAM 17, ALK, alpha-synuclein or a derivative or fragment thereof, an amyloid-beta peptide or a derivative or fragment thereof, AXL, B7H3, BCMA, CD125, CD166, CD19, CD20, CD205, CD22, CD25, CD25, CD30, CD33, CD37, CD39, CD44v6, CD46, CD56 (NCAM), CD73, CD79b, CDH6 (cadherin 6), CEACAM 5 (CD66E), CR1, EGFR viii. EGFR. ETBR. FGFR (1-4), Folate Receptor alpha, GAL-3BP (galectin binding protein), GD2, GD3, GloboH (globohexasylceramide), gplOO, gpNMB, HER2, HER3, HER4, HLA-DR1, HLA-DR5, huntingtin, IGFR1, IL1RAP, IL-34, KIT, LIV1A, LRRC15 (leucine rich repeat containing 15), MET, MS4A4A, MS4A4E, MS4A6A, NaPi2B, TAR DNA-binding protein 43 (TDP-43) or a derivative or fragment thereof, PDL1, PILRA. PMEL17, PRAME, PSMA, pTau, PTK7 (CCK4; colon carcinoma kinase), RON, ROR1, Siglecl 1, SORL1, Tau or a derivative or fragment thereof, TF (tissue factor), transthyretin, TREM2, TREML2, TROP2, or a tumor cell.

121. A nucleic acid encoding the dual transporter of any one of claims 1-120.

122. A vector comprising the nucleic acid of claim 121.

123. A host cell expressing the dual transporter of any one of claims 1-120.

124. The host cell of claim 110, wherein the cell comprises the nucleic acid of claim 121 or the vector of claim 121.

125. A method for producing a dual transporter comprising:(a) culturing a host cell comprising one or more nucleic acids encoding the dual transporter of any one of claims 1-120 under conditions in which the dual transporter encoded by the nucleic acid or vector is expressed; and(b) isolating the dual transporter from the culture.

126. A composition comprising the dual transporter of any one of claims 1-120.

127. A pharmaceutical composition comprising the dual transporter of any one of claims 1-120 or the composition of claim 126, and a pharmaceutically acceptable excipient.

128. A method of delivering a molecule to the brain of a subject comprising administering the dual transporter of any one of claims 1-120 to the subject, the composition of claim 126, or the pharmaceutical composition of claim 127, wherein the dual transporter is linked to the molecule.

129. The method of claim 128, wherein the molecule comprises a therapeutic agent.

130. A method of delivering a molecule across the BBB into the brain of a subject comprising administering the dual transporter of any one of claims 1-120, the composition of claim 126, or the pharmaceutical composition of claim 127 to the subject, wherein the molecule is linked to the dual transporter.

131. The method of claim 130, wherein the molecule comprises a therapeutic agent132. The method of claim 130 or 131, wherein the therapeutic agent targets: ABCA1, ABCA7, ADAMI 7, ALK, alpha-synuclein or a derivative or fragment thereof, an amyloid-beta peptide or a derivative or fragment thereof, AXL, B7H3, BCMA. CD 125, CD166, CD19. CD20. CD205, CD22. CD25, CD25, CD30. CD33. CD37, CD39, CD44v6, CD46, CD56 (NCAM), CD73, CD79b, CDH6 (cadherin 6), CEACAM 5 (CD66E), CR1, EGFR viii, EGFR, ETBR, FGFR (1-4), Folate Receptor alpha, GAL-3BP (galectin binding protein), GD2, GD3, GloboH (globohexasylceramide), gplOO, gpNMB, HER2, HER3. HER4, HLA-DR1. HLA-DR5. huntingtin. IGFR1, IL1RAP, IL-34. KIT, LIV1A. LRRC15 (leucine rich repeat containing 15), MET, MS4A4A, MS4A4E, MS4A6A, NaPi2B, TAR DNA-binding protein 43 (TDP-43) or a derivative or fragment thereof, PDL1, PILRA, PMEL17, PRAME, PSMA, pTau, PTK7 (CCK4; colon carcinoma kinase), RON, ROR1, Siglecl 1. SORL1, Tau or a derivative or fragment thereof, TF (tissue factor), transthyretin, TREM2, TREML2, TROP2, or a tumor cell.

133. A method of treating a disease or condition of the central nervous system (CNS) in a subject comprising administering the dual transporter of any one of claims 1-120, the composition of claim 126, or the pharmaceutical composition of claim 127 to the subject.

134. The method of claim 133, wherein the disease or condition of the CNS comprises: a neurological disease or condition, a neurodegenerative disease or condition, cancer, or an infection.

135. The method of claim 133, wherein the subject has or has been diagnosed with a neurological disease or condition, a neurodegenerative disease or condition, a cancer of the CNS or brain, or an infection of the CNS or brain.

136. A method of manufacturing a dual transporter comprising:(a) providing (i) a first polypeptide comprising a first binding region known to specifically binds to a BBB transport protein and (ii) a second polypeptide comprising a second binding region known to specifically binds a second protein, wherein the second protein is expressed on the luminal surface of the BBB or is a brain retention protein, and wherein the second protein is different from the BBB transport protein; and(b) forming a single molecule that incorporates the first polypeptide and the second polypeptide, thereby forming the dual transporter; wherein the dual transporter has increased and / or prolonged brain exposure in an animal as compared to a corresponding control molecule that binds to only the BBB transport protein or only the second protein.

137. The method of claim 136, wherein the BBB transport protein is TfR or CD98hc.

138. The method of claim 136, wherein the BBB transport protein is TfR.

139. The method of any one of claims 136-138, w herein the second protein is selected from the group consisting of: TfR, CD98hc, Large neutral amino acids transporter small subunit 1 (CD98 light chain), GLUT1, MFSD2A, CA-IV, Low density lipoprotein receptor, IGF1R, Insulin-like growth factor 2 receptor, IgG receptor FcRn large subunit p51, Low7density7lipoprotein receptor-related protein 1, Low density lipoprotein receptor-related protein 2, Insulin receptor, Cell cycle control protein 50A, Transmembrane protein 50A, Basigin, Leptin Receptor, Claudin-5, P-selectin. Lactoferrin receptor. Folate receptor, Sodium-dependent lysophosphatidylcholine symporter 1, Solute carrier organic anion transporter family member 1C1, Sodium-coupled neutral amino acid transporter 5, LDL receptor-related protein 8, High affinity cationic amino acid transporter 1, Sodium- and chloride-dependent taurine transporter, Insulin-like growth factor-binding protein 7, Solutecarrier family 40 member 1, Zinc transporter 6, heparin-binding epidermal growth factor-like growth factor, and MOG.

140. The method of claim 138 or 139, wherein the second protein is CD98hc.

141. The method of claim 140, wherein the first binding domain comprises the first binding domain of any one of claims 9-10, 13-29, 34, and 45-72; and the second binding domain comprises the second binding domain of any one of claims 11-29, 35, and 73-94.

142. The method of claim 136 or 137. wherein the second binding region specifically binds CD98hc.

143. A method of identifying a dual transporter comprising:(a) providing (i) a first polypeptide comprising a first binding region known to specifically binds to a BBB transport protein and (ii) a second polypeptide comprising a second binding region known to specifically binds a second protein, wherein the second protein is expressed on the luminal surface of the BBB or is a brain retention protein, and wherein the second protein is different from the BBB transport protein;(b) forming a single molecule that incorporates the first polypeptide and the second polypeptide; and(c) measuring the brain concentration of the single molecule at a predetermined time and identifying the single molecule as a dual transporter if the single molecule is present in the brain at a higher concentration than a corresponding control molecule that binds only to the BBB transport protein or the second protein.

144. The method of claim 143, further comprising administering the single molecule peripherally to the animal prior to step (c).

145. The method of claim 144, wherein the animal is a non-human animal, optionally wherein the animal is a mouse, rat, or non-human primate.

146. The method of any one of claims 143-145, wherein presence in the brain at a higher concentration comprises increased rate of transport to the brain or prolonged brain exposure.

147. The method of any one of claims 143-146, wherein the method further comprises determining the affinity or avidity of the first binding region for the BBB transportprotein and determining the affinity or avidity of the second binding region for the second protein.

148. The method of any one of claims 146-147, wherein the BBB transport protein is TfR or CD98hc.

149. The method of claim 148, wherein the BBB transport protein is TfR.

150. The method of any one of claims 143-149, wherein the second protein is selected from the group consisting of: TfR, CD98hc, CD981c. GLUT1, MFSD2A, CA-IV, Low density lipoprotein receptor, IGF1R, Insulin-like growth factor 2 receptor, IgG receptor FcRn large subunit p51, Low density lipoprotein receptor-related protein 1, Low density lipoprotein receptor-related protein 2, Insulin receptor, Cell cycle control protein 50A, Transmembrane protein 50A, Basigin. Leptin Receptor. Claudin-5, P-selectin, Lactoferrin receptor. Folate receptor, Sodium-dependent lysophosphatidylcholine symporter 1. Solute carrier organic anion transporter family member 1 C 1 , Sodium-coupled neutral amino acid transporter 5, LDL receptor-related protein 8, High affinity cationic amino acid transporter 1, Sodium- and chloride-dependent taurine transporter, Insulin-like growth factor-binding protein 7, Solute carrier family 40 member 1, Zinc transporter 6, heparin-binding epidermal growth factor-like growth factor, and MOG.

151. The method of claim 149 or 150, wherein the second protein is CD98hc.

152. The method of claim 151 , wherein the first binding domain comprises the first binding domain of any one of claims 9-10, 13-29, 34, and 45-72; and the second binding domain comprises the second binding domain of any one of claims 11-29, 35, and 73-94.

153. The method of any one of claims 143-152, further comprising measuring the binding of the single molecule to the BBB transport protein and / or the second protein.

154. The method of claim 153, wherein the binding is measured using surface plasmon resonance, ELISA, or flow cytometry.

155. The method of claim 153 or 154, wherein the binding is measured on the surface of a cell that expresses on its surface the BBB transport protein, the second protein, or both.

156. A method for improving delivery' to the central nervous system of a therapeutic agent linked to a delivery vehicle having a first binding region that specially binds to a BBB transport protein, the method comprising linking the delivery vehicle to a second binding region that specifically binds to a second protein wherein the second protein is expressed on the luminal surface of the BBB or is a brain retention protein, and wherein the second protein is different from the BBB transport protein.

157. A method for improving delivery to the central nervous system of a delivery vehicle having a first binding region the specially binds to a BBB transport protein, the method comprising linking the delivery vehicle to a second binding region that specifically binds to a second protein wherein the second protein is expressed on the luminal surface of the BBB or is a brain retention protein, and wherein the second protein is different from the BBB transport protein.

158. The method of claim 156 or 157. wherein the BBB transport protein is TfR or CD98hc.

159. The method of claim 156 or 157, wherein the BBB transport protein is TfR and the second protein is CD98hc.

160. A method for improving delivery of a therapeutic agent to the central nervous system wherein the therapeutic agent is linked to a polypeptide that specifically binds TfR. the method comprising linking the polypeptide that specifically binds TfR to a second binding region that specifically binds to a second protein wherein the second protein is expressed on the luminal surface of the BBB or is a brain retention protein, and wherein the second protein is not TfR.

161. A method for improving delivery of a therapeutic agent to the central nervous system wherein the therapeutic agent is linked to a polypeptide that specifically binds CD98hc, the method comprising linking the polypeptide that specifically binds CD98hc to a second binding region that specifically binds to a second protein wherein the second protein is expressed on the luminal surface of the BBB or is a brain retention protein, and wherein the second protein is not CD98hc.

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