Monoclonal antibodies against prostate specific membrane antigen (PSMA) lacking in fucosyl residues
View Patent ↗The invention pertains to anti-PSMA antibodies that lack fucosyl residues. The antibodies of the invention exhibit increased antibody-dependent cellular cytotoxicity (ADCC) activity as compared to the fucosylated form of the antibodies. The invention also provides host cells that express the anti-PSMA antibodies that lack fucosyl residues, wherein the host cells are deficient for a fucosyl transferase. Methods of using the antibodies to inhibit the growth of PSMA + cells, such as tumor cells, are also provided.
1. An isolated antibody that binds human prostate specific membrane antigen (PSMA) comprising a heavy chain variable region CDR1 comprising SEQ ID NO: 24, a heavy chain variable region CDR2 comprising SEQ ID NO: 33, and a heavy chain variable region CDR3 comprising SEQ ID NO: 42, a light chain variable region CDR1 comprising SEQ ID NO: 51, a light chain variable region CDR2 comprising SEQ ID NO: 60, and a light chain variable region CDR3 comprising SEQ ID NO: 69, wherein the antibody is linked to a therapeutic agent.
2. An isolated antibody that binds human prostate specific membrane antigen (PSMA) comprising heavy and light chain variable regions, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 15 set forth in SEQ ID NOs: 6 and 15, respectively, wherein the antibody is linked to a therapeutic agent.
3. The isolated antibody of claim 1 or 2 , wherein the therapeutic agent is a cytotoxin, drug, or radioactive isotope.
4. The antibody of claim 1 or 2 , which lacks fucose residues.
5. The antibody of claim 1 or 2 , which is a monoclonal antibody.
6. The antibody of claim 1 or 2 , which is a human, humanized or chimeric antibody.
7. An isolated full length antibody that binds to prostate specific membrane antigen (PSMA) comprising heavy and light chain variable regions set forth in SEQ ID NOs: 6 and 15, respectively.
8. The antibody of claim 3 , wherein the cytotoxin is selected from the group consisting of antimetabolites, alkylating agents, anthracyclines, antibiotics, and anti-mitotic agents.
9. The antibody of claim 3 , wherein the cytotoxin is selected from the group consisting of duocarmycins, calicheamicins, maytansines, and auristatins.
10. The antibody of claim 3 , wherein the cytotoxin is selected from the group consisting of paclitaxel, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin.
11. The antibody of claim 8 , wherein the antimetabolite is selected from the group consisting of methotrexate, 6 -mercaptopurine, 6-thioguanine, cytarabine, and 5-fluorouracil decarbazine.
12. The antibody of claim 8 , wherein the alkalating agent is selected from the group consisting of mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis- dichlorodiamine platinum (II) (DDP) cisplatin.
13. The antibody of claim 8 , wherein the anthracycline is daunorubicin or doxorubicin.
14. The antibody of claim 8 , wherein the antibiotic is selected from the group consisting of dactinomycin, bleomycin, mithramycin, and anthramycin.
15. The antibody of claim 8 , wherein the anti-mitotic agent is vincristine or vinblastine.
16. The antibody of claim 3 , wherein the drug is selected from the group consisting of an enzymatically active toxin or cytotoxic fragment thereof and a proinflammatory cytokine.
17. The antibody of claim 16 , wherein the enzymatically active toxin is selected from the group consisting of abrin, ricin A, pseudomonas exotoxin, and diphtheria toxin.
18. The antibody of claim 16 , wherein the proinflammatory cytokine is tumor necrosis factor or interferon gamma.
19. The antibody of claim 3 , wherein the drug is selected from the group consisting of lymphokines, interleukin-1, interleukin-2, interleukin-6, granulocyte macrophage colony stimulating factor, and granulocyte colony stimulating factor.
20. A composition comprising the antibody of claim 1 and a carrier.
21. A composition comprising the antibody of claim 2 and a carrier.
22. A composition comprising the antibody of claim 7 and a carrier.