High affinity anticalins directed against human CD98hc

1. A cluster of differentiation 98 heavy chain (CD98hc)-specific binding protein, wherein the CD98hc-specific binding protein is a lipocalin 2 (Lcn2)-derived binding protein, and wherein the CD98hc-specific binding protein

(a) comprises or consists of an amino acid sequence as represented in formula I:

QDSTSD(X 1 )(X 2 )PAPPLSKVPLQQNFQDNQF(Q/H)GKWY(X 3 )VG

(X 4 )AG(X 5 )(X 6 )(X 7 )(X 8 )(X 9 )E(X 10 )(X 11 )(X 12 )(X 13 )

(X 14 )(X 15 )M(X 16 )ATIYELKEDKS(Y/F)NVT(X 17 )V(X 18 )

(X 19 )(X 20 )(X 21 )(K/T)KC(X 22 )(Y/N)(X 23 )(X 24 )(X 25 )

(T/S)(X 26 )VPG(C/S)QPGE(F/Y)(T/N)(X 27 )G(N/K)I(X 28 )

S(Y/R/G/A)P(X 29 )(X 30 )(X 31 )S(X 32 )L(X 33 )RVVSTNYNQ

(H/Y)A(M/L)VF(X 34 )K(X 35 )(V/E)(X 36 )(X 37 )N(X 38 )E

(X 39 )(X 40 )(X 41 )I(X 42 )L(X 43 )GRTKELTSELKE(N/I/Y)FIR

FSKSLGLPE(X 44 )(X 45 )IVFPVPIDQCIDG,

wherein

(X 1 ) is L;

(X 2 ) is I;

(X 3 ) is V;

(X 4 ) is R;

(X 5 ) is N;

(X 6 ) is L or T;

(X 7 ) is G;

(X 8 ) is L;

(X 9 ) is R;

(X 10 ) is D;

(X 11 ) is K;

(X 12 ) is D;

(X 13 ) is P;

(X 14 ) is A or G;

(X 15 ) is K;

(X 16 ) is F;

(X 17 ) is Y;

(X 18 ) is W;

(X 19 ) is F or S;

(X 20 ) is D or G;

(X 21 ) is L or Q;

(X 22 ) is K or M;

(X 23 ) is S;

(X 24 ) is I;

(X 25 ) is H, G or V;

(X 26 ) is F;

(X 27 ) is L;

(X 28 ) is K;

(X 29 ) is G;

(X 30 ) is H, R or Q;

(X 31 ) is T;

(X 32 ) is W;

(X 33 ) is V;

(X 34 ) is F;

(X 35 ) is W or S;

(X 36 ) is G or T;

(X 37 ) is Q;

(X 38 ) is R;

(X 39 ) is N, G or E;

(X 40 ) is F;

(X 41 ) is A;

(X 42 ) is T;

(X 43 ) is Y;

(X 44 ) is N; and

(X 45 ) is H; or

(b) comprises or consists of an amino acid sequence which is at least 80% identical to the amino acid sequence of (a), provided that amino acid positions (X 1 ) to (X 45 ) are maintained as defined in item (a).

2. The CD98hc-specific binding protein of claim 1 , wherein the CD98hc-specific binding protein

(a) comprises or consists of the amino acid sequence of

(SEQ ID NO: 14)

QDSTSDLIPAPPLSKVPLQQNFQDNQF HGKWYVVGIAGNSMLREDKDPF

KMTATIYEL KEDK SYNVTRVRFDDKKCLYRILTFV PGSQPG EFTLGNIK

SRPGVVTSWLVRVVST NYNQ HAMVFFKRVHQNRETFWITLYG RTKELTS

ELKENFIRFSKSLGLPENHIVFPVPIDQCIDG;

or

(b) comprises or consists of an amino acid sequence which is at least 80% identical to the amino acid sequence of (a), provided that the underlined amino acids are maintained as defined in item (a).

3. The CD98hc-specific binding protein of claim 1 , wherein the CD98hc-specific binding protein comprises or consists of

the amino acid sequence of any one of SEQ ID NOs 2 to 13.

4. A protein conjugate or fusion protein comprising the CD98hc-specific binding protein of claim 1 .

5. The protein conjugate or fusion protein of claim 4 , wherein the CD98hc-specific binding protein is conjugated to or is part of a fusion protein wherein the fusion partner is

(a) a fluorescent dye or a fluorescent protein,

(b) a radionuclide,

(c) a toxic compound,

(d) a photosensitizer,

(e) an enzyme or truncated version thereof,

(f) a membrane protein or functional fragment thereof retaining the enzyme function,

(g) a contrast agent,

(h) a cytokine,

(i) a chemokine,

(j) a pro-coagulant factor,

(k) an acetylcholineesterase inhibitor,

(l) an inhibitor of Aβ aggregation,

(m) a nucleic acid molecule, or

(n) a nanoparticle.

6. The protein conjugate or fusion protein of claim 4 , wherein the CD98hc-specific binding protein is conjugated to a binding protein.

7. A pharmaceutical composition or a diagnostic composition comprising

(i) the CD98hc-specific binding protein of claim 1 ; or

(ii) a protein conjugate or fusion protein comprising the CD98hc-specific binding protein of (i).

8. The CD98hc-specific binding protein of claim 1 for use in therapy and/or diagnosis of a tumor, wherein the tumor is located in the brain and/or the spinal cord.

9. The protein conjugate or fusion protein of claim 4 for use in therapy and/or diagnosis of a tumor, wherein the tumor is located in the brain and/or the spinal cord.

10. The protein conjugate or fusion protein of claim 6 , wherein the binding protein is selected from an antibody or immunoglobulin, an antibody fragment, and an antibody mimetic.

11. The protein conjugate or fusion protein of claim 10 , wherein the antibody mimetic is selected from the group consisting of an Anticalin, Affibody, Adnectin, DARPin, Avimer, Nanofitin, Affilin, β-Wrapin, ADAPT, Monobody, RasIn, FingR, Pronectin, Centyrin, Affimer, Adhiron, Affitin, αRep, Repebody, i-body, Fynomer, and a Kunitz domain protein.