Anti-transferrin receptor antibodies with tailored affinity

1. A humanized antibody that specifically binds to human transferrin receptor, wherein the antibody comprises

in the heavy chain variable domain the HVRs of SEQ ID NO: 66, 68 and 72,

and

in the light chain variable domain the HVRs of SEQ ID NO: 75, 76 and 78.

2. The humanized antibody according to claim 1 comprising a heavy chain variable domain of SEQ ID NO: 24 and a light chain variable domain of SEQ ID NO: 37.

3. The humanized antibody according to claim 1 , wherein the humanized antibody specifically binds to human transferrin receptor and to cynomolgus transferrin receptor.

4. The humanized antibody according to claim 1 , wherein the humanized antibody is a multispecific antibody having at least one binding specificity for the human transferrin receptor and at least one binding specificity for a therapeutic target.

5. The humanized antibody according to claim 4 , wherein the humanized antibody comprises a first antigen binding site which binds the human transferrin receptor and a second antigen binding site which binds a brain antigen.

6. The humanized antibody according to claim 5 , wherein the humanized antibody is a bispecific antibody comprising

i) a first binding site binding to human transferrin receptor and comprising a heavy chain variable domain of SEQ ID NO: 24 and a light chain variable domain of SEQ ID NO: 37,

and

ii) a second binding site

a) binding to Abeta and comprising a heavy chain variable domain of SEQ ID NO: 81 and a light chain variable domain of SEQ ID NO: 82, or

b) binding to alpha-synuclein and comprising a heavy chain variable domain of SEQ ID NO: 83 and a light chain variable domain of SEQ ID NO: 84, or

c) binding to alpha-synuclein and comprising a heavy chain variable domain of SEQ ID NO: 85 and a light chain variable domain of SEQ ID NO: 86, or

d) binding to alpha-synuclein and comprising a heavy chain variable domain of SEQ ID NO: 87 and a light chain variable domain of SEQ ID NO: 88, or

e) binding to alpha-synuclein and comprising a heavy chain variable domain of SEQ ID NO: 91 and a light chain variable domain of SEQ ID NO: 92, or

f) binding to alpha-synuclein and comprising a heavy chain variable domain of SEQ ID NO: 89 and a light chain variable domain of SEQ ID NO: 90, or

g) binding to alpha-synuclein and comprising a heavy chain variable domain of SEQ ID NO: 93 and a light chain variable domain of SEQ ID NO: 94, or

h) binding to CD20 and comprising a heavy chain variable domain of SEQ ID NO: 79 and a light chain variable domain of SEQ ID NO: 80.

7. The humanized antibody according to claim 1 , wherein the humanized antibody is

a) a full length antibody of the human subclass IgG1, or

b) a full length antibody of the human subclass IgG4, or

c) a full length antibody of the human subclass IgG1 with the mutations L234A, L235A and P329G,

d) a full length antibody of the human subclass IgG4 with the mutations S228P, L235E and optionally P329G,

e) a full length antibody of the human subclass IgG1 with the mutations L234A, L235A and P329G in both heavy chains and the mutations T366W and S354C in one heavy chain and the mutations T366S, L368A, Y407V and Y349C in the respective other heavy chain, or

f) a full length antibody of the human subclass IgG4 with the mutations S228P, L235E and optionally P329G in both heavy chains and the mutations T366W and S354C in one heavy chain and the mutations T366S, L368A, Y407V and Y349C in the respective other heavy chain.

8. The humanized antibody according to claim 1 , wherein the humanized antibody comprises

i) a homodimeric Fc-region of the human IgG1 subclass optionally with the mutations P329G, L234A and L235A, or

ii) a homodimeric Fc-region of the human IgG4 subclass optionally with the mutations P329G, S228P and L235E, or

iii) a heterodimeric Fc-region whereof

a) one Fc-region polypeptide comprises the mutation T366W, and the other Fc-region polypeptide comprises the mutations T366S, L368A and Y407V, or

b) one Fc-region polypeptide comprises the mutations T366W and Y349C, and the other Fc-region polypeptide comprises the mutations T366S, L368A, Y407V, and S354C, or

c) one Fc-region polypeptide comprises the mutations T366W and S354C, and the other Fc-region polypeptide comprises the mutations T366S, L368A, Y407V and Y349C,

or

iv) a heterodimeric Fc-region of the human IgG4 subclass whereof both Fc-region polypeptides comprise the mutations P329G, L234A and L235A and

a) one Fc-region polypeptide comprises the mutation T366W, and the other Fc-region polypeptide comprises the mutations T366S, L368A and Y407V, or

b) one Fc-region polypeptide comprises the mutations T366W and Y349C, and the other Fc-region polypeptide comprises the mutations T366S, L368A, Y407V, and S354C, or

c) one Fc-region polypeptide comprises the mutations T366W and S354C, and the other Fc-region polypeptide comprises the mutations T366S, L368A, Y407V and Y349C,

or

v) a heterodimeric Fc-region of the human IgG4 subclass whereof both Fc-region polypeptides comprise the mutations P329G, S228P and L235E and

a) one Fc-region polypeptide comprises the mutation T366W, and the other Fc-region polypeptide comprises the mutations T366S, L368A and Y407V, or

b) one Fc-region polypeptide comprises the mutations T366W and Y349C, and the other Fc-region polypeptide comprises the mutations T366S, L368A, Y407V, and S354C, or

c) one Fc-region polypeptide comprises the mutations T366W and S354C, and the other Fc-region polypeptide comprises the mutations T366S, L368A, Y407V and Y349C.

9. A pharmaceutical formulation comprising a humanized antibody according to claim 1 and a pharmaceutically acceptable carrier.