Anti-transferrin receptor antibodies and uses thereof
Disclosed herein, in certain embodiments, are anti-transferrin receptor antibodies, anti-transferrin receptor antibody conjugates, and pharmaceutical compositions which comprise the anti-transferrin receptor antibodies or conjugates. In some embodiments, also disclosed herein are methods of delivering a payload utilizing an anti-transferrin receptor antibody described herein, and methods of treatment with use of an anti-transferrin receptor antibody described herein.
1. A method of treating a muscle atrophy or myotonic dystrophy in a subject in need thereof, comprising:
administering to the subject an anti-transferrin receptor antibody conjugate comprising i) anti-transferrin receptor antibody comprising a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises HCDR1 sequence comprising SEQ ID NO: 1; HCDR2 sequence EINPIX 1 GRSNYAX 2 KFQG (SEQ ID NO: 88), wherein X 1 is selected from N or Q and X 2 is selected from Q or E; and HCDR3 sequence comprising SEQ ID NO: 3, wherein the VL region comprises LCDR1 sequence RTSENIYX 3 NLA (SEQ ID NO: 89), LCDR2 sequence AX 4 TNLAX 5 (SEQ ID NO: 90), and LCDR3 sequence QHFWGTPLTX 6 (SEQ ID NO: 91), wherein X 3 is selected from N or S, X 4 is selected from A or G, X 5 is selected from D or E, and X 6 is present or absence, and if present, is F, and ii) a payload, wherein the payload mediates RNA interference against an atrogene, thereby treating muscle atrophy or myotonic dystrophy in the subject.
2. The method of claim 1 , wherein the payload comprises a small molecule, a peptide, a protein, or a polynucleic acid molecule.
3. The method of claim 1 , wherein the payload comprises a polynucleic acid molecule hybridizing to a target sequence of the atrogene.
4. The method of claim 1 , wherein the muscle atrophy is a diabetes-associated muscle atrophy or a cancer cachexia-associated muscle atrophy.
5. The method of claim 1 , wherein the muscle atrophy is associated with insulin deficiency, chronic renal failure, congestive heart failure, chronic respiratory disease, a chronic infection, fasting, denervation, sarcopenia, or myotonic dystrophy type 1 (DM1).
6. The method of claim 1 , wherein the myotonic dystrophy is DM1.
7. The method of claim 1 , wherein reticulocyte levels in the subject are not reduced following the administration of anti-transferrin receptor antibody.
8. The method of claim 1 , wherein the administration of anti-transferrin receptor antibody conjugate downregulates SSB siRNA or SSB mRNA levels in the subject.
9. The method of claim 8 , wherein downregulation of SSB siRNA or SSB mRNA is in muscle.
10. The method of claim 9 , wherein the muscle is skeletal muscle.
11. The method of claim 9 , wherein the muscle is cardiac muscle.
12. The method of claim 1 , wherein the atrogene comprises an upregulated gene within the IGF1-Akt-FoxO pathway, the glucocorticoids-GR pathway, the PGCla-FoxO pathway, the TNFa-NFO3 pathway, or the myostatin-ActRIlb-Smad2/3 pathway.
13. The method of claim 1 , wherein the atrogene encodes an E3 ligase.
14. The method of claim 1 , wherein the atrogene encodes a Forkhead box transcription factor.
15. The method of claim 1 , wherein the atrogene comprises atrogin-1 gene (FBXO32), MuRF1 gene (TRIM63), FOXO1, FOXO3, or MSTN.
16. The method of claim 1 , wherein the atrogene comprises DMPK.
17. The method of claim 1 , wherein the anti-transferrin receptor antibody comprises a humanized antibody or antigen binding fragment thereof, a chimeric antibody or antigen binding fragment thereof, or a multi-specific antibody or antigen binding fragment thereof.
18. The method of claim 1 , wherein the anti-transferrin receptor antibody comprises 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, or intrabody.
19. The method of claim 1 , wherein the anti-transferrin receptor antibody further comprises at least one mutation in the Fc region, and the at least one mutation is at residue position D265, N297, K322, L328, or P329, wherein the residue position is in reference to IgG1.
20. The method of claim 1 , wherein the anti-transferrin receptor antibody further comprises at least one mutation in the Fc region at L233 and L234, and wherein the residues correspond to position 233 and 234 of SEQ ID NO: 23.