Variant target binding agents and uses thereof
The present invention provides variant target binding agents and methods relating to the use of such binding agents for the prophylaxis or treatment of cancers and immunological disorders. The variant target binding agent is conjugated to a therapeutic agent that exerts a cytotoxic, cytostatic, or immunomodulatory effect on target cells.
1. A method of targeting a variant target binding agent conjugate to a target antigen on a target antigen-expressing cancer cell in a subject, comprising administering to the subject an effective amount of the variant target binding agent conjugate, the variant target binding agent comprising:
a binding region comprising an antibody Fv region or an antigen binding fragment thereof that specifically binds to the target antigen on the target antigen-expressing cancer cell;
at least a portion of a Fc region of a human immunoglobulin IgG1 constant region comprising an introduced cysteine residue at amino acid position 239, that is S239C, according to the EU index as set forth in Kabat;
a therapeutic agent conjugated directly or via a linker to the introduced cysteine residue, wherein the therapeutic agent exerts a cytotoxic effect on the target antigen-expressing cancer cell.
2. The method of claim 1 , wherein the binding region specifically binds to CD30, CD33, or CD70.
3. The method of claim 1 , wherein the therapeutic agent is conjugated to the introduced cysteine residue via a linker.
4. The method of claim 3 , wherein the therapeutic agent is conjugated to the introduced cysteine residue via a maleimide group of the linker.
5. The method of claim 1 wherein the variant target binding agent is an intact antibody conjugated to a therapeutic agent.
6. The method of claim 4 wherein the variant target binding agent is an intact antibody conjugated to a therapeutic agent.
7. The method of claim 1 , wherein the therapeutic agent is a DNA minor groove binding agent.
8. The method of claim 7 , wherein the DNA minor groove binding agent is a DNA minor groove alkylating agent.
9. The method of claim 1 , wherein the therapeutic agent is an anti-tubulin agent.
10. The method of claim 9 , wherein the anti-tubulin agent is an auristatin.
11. The method of claim 1 , wherein the therapeutic agent is a duocarmycin or a maytansinoid.
12. The method of claim 1 , wherein the cancer is a Hodgkin's Disease.
13. The method of claim 1 , wherein the cancer is non-Hodgkin's lymphoma.
14. The method of claim 1 , wherein the cancer is renal cell carcinoma.
15. The method of claim 1 wherein the cancer is acute myelocytic leukemia.
16. The method of claim 1 comprising administering the variant target binding agent conjugate as a composition comprising the variant target binding agent conjugate and at least one pharmaceutically compatible ingredient and wherein the therapeutic agent is conjugated to the introduced cysteine residue via a linker.
17. The method of claim 16 , wherein the therapeutic agent is conjugated to the introduced cysteine residue via a maleimide group of the linker.
18. The method of claim 17 wherein the variant target binding agent is an intact antibody conjugated to a therapeutic agent.
19. The method of claim 18 wherein the therapeutic agent is a DNA minor groove binding agent.
20. The method of claim 18 , wherein the composition comprises an average of two therapeutic agents per antibody in the composition.