Antibodies against the MUC1-C/extracellular domain (MUC1-C/ECD)
The present disclosure is directed to antibodies binding to MUC1-C/extracellular domain (MUC1-C/ECD) and methods of using such antibodies to treat cancers that express the MUC1 antigen.
1. An antibody or an antigen-binding fragment thereof that binds selectively to a conformational epitope from MUC1-C extracellular domain (MUC1-C/ECD) defined by SEQ ID NO: 1, wherein said antibody or antigen binding fragment comprises a variable light domain sequence of SEQ ID NO: 2, and a variable heavy domain sequence of SEQ ID NO: 6.
2. The antibody or antigen-binding fragment of claim 1 , wherein said antibody is a single chain antibody.
3. The antibody or antigen-binding fragment of claim 1 , wherein said antibody is a chimeric antibody.
4. The antibody or antigen-binding fragment of claim 1 , wherein said antibody fragment is a Fab fragment.
5. The antibody or antigen-binding fragment of claim 1 , wherein said antibody is a recombinant antibody or antigen binding fragment having specificity for the conformational epitope in MUC1-C/ECD and a distinct cancer cell surface antigen.
6. The antibody or antigen-binding fragment of claim 1 , wherein said antibody is an IgG.
7. The antibody or antigen-binding fragment of claim 1 , wherein said antibody further comprises a label.
8. The antibody or antigen-binding fragment of claim 7 , wherein said label is a peptide tag, an enzyme, a magnetic particle, a chromophore, a fluorescent molecule, a chemilluminescent molecule, or a dye.
9. The antibody or antigen-binding fragment of claim 1 , wherein said antibody or fragment further comprises an antitumor drug linked thereto.
10. The antibody or antigen-binding fragment of claim 9 , wherein said antitumor drug is linked to said antibody or fragment through a photolabile linker.
11. The antibody or antigen-binding fragment of claim 10 , wherein said antitumor drug is linked to said antibody or fragment through an enzymatically-cleaved linker.
12. The antibody or antigen-binding fragment of claim 10 , wherein said antitumor drug is a toxin, a radioisotope, a cytokine or an enzyme.
13. The antibody or antigen-binding fragment of claim 1 , wherein said antibody or fragment is conjugated to a nanoparticle or a liposome.
14. The antibody or antigen-binding fragment of claim 1 , wherein said antibody induces MUC1-positive tumor cell death, such as by antibody-dependent cytotoxicity, antibody-dependent cell cytotoxicity or complement-mediated cytoxocity.
15. A fusion protein comprising:
(i) an antibody that binds selectively to a conformational epitope in MUC1-C extracellular domain (MUC1-C/ECD) defined by SEQ ID NO: 1, wherein said antibody comprises a variable light domain sequence of SEQ ID NO: 2, and a variable heavy domain sequence of SEQ ID NO: 6; and
(ii) a second single chain antibody that binds to a T or B cell.
16. A chimeric antigen receptor comprising:
(i) an ectodomain comprising single chain antibody variable region that binds selectively to a conformational epitope in MUC1-C/extracellular domain (MUC1-C/ECD) defined by SEQ ID NO: 1, wherein said antibody comprises a variable light domain sequence of SEQ ID NO: 2, and a variable heavy domain sequence of SEQ ID NO: 6, with a flexible hinge attached at the C-terminus of said single chain antibody variable region;
(ii) a transmembrane domain; and
(iii) an endodomain,
wherein said endodomain comprises a signal transduction function when said single-chain antibody variable region is engaged with MUC 1.