Anti-transferrin receptor antibodies and uses thereof

1. An antibody or antigen-binding fragment thereof that binds to transferrin receptor, wherein the antibody or antigen-binding fragment comprises i) a variable heavy chain (VH) region comprising a sequence selected from SEQ ID NOs: 13-16, and ii) a variable light chain (VL) region comprising a sequence selected from SEQ ID NOs: 18-21.

2. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a humanized antibody or binding fragment thereof or a chimeric antibody or binding fragment thereof.

3. The antibody or antigen-binding fragment of claim 1 , wherein the antigen-binding fragment is selected from an IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, triple body, mini-antibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab′, F(ab′)2, F(ab′)3, F(ab′)2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, diabody-Fc, tandem scFv-Fc, and intrabody.

4. The antibody or antigen-binding fragment of claim 3 , wherein the antigen-binding fragment is selected from a nanobody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, triple body, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab′, F(ab′)2, F(ab′)3, F(ab′)2-scFv2, scFv, and scFv-KIH.

5. The antibody or antigen-binding fragment of claim 1 , wherein the antibody comprises a heavy chain (HC) sequence selected from SEQ ID NOs: 23-46 and a light chain (LC) sequence selected from SEQ ID NOs: 47-50.

6. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically acceptable excipient.

7. An anti-transferrin receptor antibody conjugate, comprising Formula (I):

A-(X 1 —B)n   Formula (I)

wherein A comprises an anti-transferrin receptor antibody or antigen-binding fragment thereof, wherein the anti-transferrin receptor antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising a sequence selected from SEQ ID NOs: 13-16, and a variable light chain (VL) region comprising a sequence selected from SEQ ID NOs: 18-21;

B comprises a polynucleic acid molecule;

X 1 consists of a bond or linker; and

n is an averaged value selected from 1-12.

8. The anti-transferrin receptor antibody conjugate of claim 7 , wherein the antigen-binding fragment is selected from an IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, triple body, mini-antibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab′, F(ab′)2, F(ab′)3, F(ab′)2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, diabody-Fc, tandem scFv-Fc, and intrabody.

9. The anti-transferrin receptor antibody conjugate of claim 7 , wherein the polynucleic acid molecule is selected from a short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA), antisense oligonucleotide (ASO), a phosphorodiamidate morpholino oligo (PMO), and mRNA.

10. The anti-transferrin receptor antibody conjugate of claim 7 , wherein the polynucleic acid molecule is a double-stranded RNA (dsRNA).

11. The anti-transferrin receptor antibody conjugate of claim 7 , wherein the polynucleic acid molecule is a single stranded antisense oligonucleotide (ASO).

12. The anti-transferrin receptor antibody conjugate of claim 7 , wherein the polynucleic acid molecule comprises a passenger strand and a guide strand.

13. The anti-transferrin receptor antibody conjugate of claim 12 , wherein the guide strand comprises at least one modified internucleotide linkage, at least one inverted abasic moiety, at least one 5′-vinylphosphonate modified non-natural nucleotide, or a combination thereof.

14. The anti-transferrin receptor antibody conjugate of claim 12 , wherein the polynucleic acid molecule further comprises a modification of a sugar moiety at the 2′ position, and wherein the modification at the 2′-position is selected from 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), and 2′-O—N-methylacetamido (2′-O-NMA) modified nucleotide.

15. The anti-transferrin receptor antibody conjugate of claim 12 , wherein the passenger strand comprises at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more phosphorodiamidate morpholino oligomer-modified non-natural nucleotides.

16. The anti-transferrin receptor antibody conjugate of claim 12 , wherein A-X 1 is conjugated to the 5′ end of the passenger strand or 3′ end of the passenger strand.

17. The anti-transferrin receptor antibody conjugate of claim 7 , wherein the polynucleic acid molecule hybridizes to a target sequence of a gene, and wherein the polynucleic acid molecule mediates RNA interference against the gene.

18. The anti-transferrin receptor antibody conjugate of claim 17 , the gene comprises an unregulated gene within the IGF1-Akt-FoxO pathway, the glucocorticoids-GR pathway, the PGC1α-FoxO pathway, the TNFα-NFκB pathway, or the myostatin-ActRIIb-Smad2/3 pathway, E3 ligase, Forkhead box transcription factor, atrogin-1 gene (FBXO32), MuRF1 gene (TRIM63), FOXO1, FOXO3, MSTN, DMD, or DMPK.

19. The anti-transferrin receptor antibody conjugate of claim 17 , wherein the RNA interference is preferentially mediated in a muscle when the anti-transferrin receptor antibody conjugate is administered to a subject.

20. A pharmaceutical composition comprising the anti-transferrin receptor antibody conjugate of claim 7 and a pharmaceutically acceptable excipient.