Agents, uses and methods
The present invention relates to agents comprising a binding moiety with binding specificity for SRCR domain 1 of the CD163 receptor, for use in medicine. The invention also relates to methods, uses, kits and compositions comprising such agents.
1. An agent comprising a binding moiety with binding specificity for SRCR domain 1 of the CD163 receptor, wherein the agent comprises a cytotoxic moiety and/or a drug to be delivered to a cell having a CD163 receptor localized on its surface, wherein the agent is internalized into the cell when bound to the CD163 receptor,
wherein said cytotoxic moiety and/or a drug is selected from the group consisting of an alkylating agent, an antimetabolite, an antimitotic, a topoisomerase inhibitor, a toxin, an immunosuppressive drug, an immunostimulatory drug, and a protein having biological activity having efficacy in the treatment of a condition or disorder affecting macrophage.
2. An agent according to claim 1 wherein the binding moiety with specificity for SRCR domain 1 of the CD163 receptor is selected from the group consisting of:
(a) an antibody or an antigen-binding fragment thereof, or a variant, fusion or derivative of said antibody or an antigen-binding fragment, or a fusion of a said variant or derivative thereof, which retains the binding specificity for SRCR domain 1 of the CD163 receptor;
(b) antibody mimics (for example, based on non-antibody scaffolds);
(c) RNA aptamers;
(d) small molecules; and
(e) CovX-bodies.
3. An agent according to claim 1 wherein the CD163 receptor is a human CD163 receptor.
4. An agent according to claim 1 wherein the binding moiety is capable of binding to the consensus sequence:
SEQ ID NO: 26
K-X 1 -VKVQEE-X 2 -R
wherein:
X 1 represents Xaa 5-8 (wherein Xaa represents any amino acid(s)); and;
X 2 is absent or represents Xaa 38-42 (wherein Xaa represents any amino acid(s)).
5. An agent according to claim 1 wherein the binding moiety is capable of binding to the sequence:
SEQ ID NO: 27
KCSGRVEVKVQEEWGTVCNNGWSMEAVSVICNQLGCPTAIKAPGWANSSAGSGR.
6. An agent according to claim 1 wherein the CD163 receptor is localised on the surface of a cell.
7. An agent according to claim 6 wherein the cell is a malignant cell, immune modulatory cell, inflamed cell or infected cell expressing the CD163 receptor.
8. An agent according to claim 6 wherein the cell is a monocyte and/or monocyte-derived cell.
9. An agent according to claim 1 wherein the binding moiety exhibits greater binding affinity for SRCR domain 1 of the CD163 receptor in the presence of calcium than in the absence of calcium.
10. An agent according to claim 2 wherein the binding moiety comprises an antibody or an antigen-binding fragment thereof, or a variant, fusion or derivative of said antibody or an antigen-binding fragment, or a fusion of a said variant or derivative thereof, which retains the binding specificity for SRCR domain 1 of the CD163 receptor.
11. An agent comprising a binding moiety with binding specificity for SRCR domain 1 of the CD163 receptor, wherein the agent is internalized into the cell when bound to the CD163 receptor, wherein the agent comprises a cytotoxic moiety and/or a drug to be delivered to a cell having a CD163 receptor localized on its surface, wherein the binding moiety comprises an antibody or an antigen-binding fragment thereof, or a variant, fusion or derivative of said antibody or an antigen-binding fragment, or a fusion of a said variant or derivative thereof, which retains the binding specificity for SRCR domain 1 of the CD163 receptor, wherein the antibody, antigen-binding fragment, variant, fusion or derivative thereof comprises:
a heavy-chain variable (V H ) region comprising SEQ ID NO: 20 and a light-chain variable (V L ) region comprising SEQ ID NO: 21; or
a heavy-chain variable (V H ) region comprising SEQ ID NO: 22 and a light-chain variable (V L ) region comprising SEQ ID NO: 23.
12. An agent according to claim 1 wherein said cytotoxic moiety and/or a drug is a immunosuppressive drug, an immunostimulatory drug, or a protein having biological activity having efficacy in the treatment of a condition or disorder affecting macrophage.
13. A pharmaceutical composition comprising an effective amount of an agent as defined in claim 1 and a pharmaceutically-acceptable diluent, carrier or excipient.
14. A kit comprising an agent as defined in claim 1 .
15. An agent according to claim 1 , wherein said cytotoxic moiety and/or a drug is selected from the group consisting of an alkylating agent, an antimetabolite, an antimitotic, a topoisomerase inhibitor, and a toxin.
16. An agent according to claim 15 , wherein said cytotoxic moiety and/or a drug is an alkylating agent.
17. An agent according to claim 16 , wherein said alkylating agent is cisplatin or carboplatin.
18. An agent according to claim 15 , wherein said cytotoxic moiety and/or a drug is an antimetabolite.
19. An agent according to claim 18 , wherein said antimetabolite is azathioprine or methotrexate.
20. An agent according to claim 15 , wherein said cytotoxic moiety and/or a drug is an antimitotic.
21. An agent according to claim 20 , wherein said antimitotic is vincristine.
22. An agent according to claim 15 , wherein said cytotoxic moiety and/or a drug is a topoisomerase inhibitor.
23. An agent according to claim 22 , wherein said topoisomerase inhibitor is doxorubicin or etoposide.
24. An agent according to claim 15 , wherein said cytotoxic moiety and/or a drug is a toxin.
25. An agent according to claim 24 , wherein said toxin is calicheamicin.
26. An agent according to claim 12 , wherein said cytotoxic moiety and/or a drug is an immunosuppressive drug.
27. An agent according to claim 26 , wherein said immunosuppressive drug is an anti-inflammatory drug, a glucocorticoid, methotrexate, cyclophosphamide, 6-mercaptopurin, cyclosporine, tacrolimus, mycophenolate mofetil, sirulimus, everolimus, an siRNA molecule inhibiting synthesis of proinflammatory cytokines, a non-steroidal anti-inflammatory drug (NSAIDs), a steroid, and a disease-modifying anti-rheumatic drug.
28. An agent according to claim 26 , wherein said immunosuppressive drug is a glucocorticoid.
29. An agent according to claim 12 , wherein said cytotoxic moiety and/or a drug is an immunostimulatory drug.
30. An agent according to claim 29 , wherein said immunostimulatory drug is an siRNA molecule.
31. An agent according to claim 12 , wherein said cytotoxic moiety and/or a drug is a protein having biological activity having efficacy in the treatment of a condition or disorder affecting macrophage.
32. An agent according to claim 31 , wherein said protein having biological activity having efficacy in the treatment of a condition or disorder affecting macrophage is glucocerebrosidase.