PHARMACEUTICAL COMPOSITION CONTAINING ANTI-CD79B ANTIBODY-DRUG CONJUGATE AND ITS USE

Claims

1. A pharmaceutical composition comprising a ligand-drug conjugate and a buffer, wherein said ligand is an antibody to cluster of differentiation 79b (CD79b) or an antigen-binding fragment thereof, and the drug is selected from the group consisting of MMAE or a derivative thereof, exatecan or a derivative thereof, and eribulin or a derivative thereof, wherein: the buffer is selected from the group consisting of an acetate buffer, a histidine salt buffer, a tris-hydrochloride buffer, a tris-citrate buffer, a phosphate buffer, and a succinate buffer; the CD79b antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1 with the amino acid sequence set forth in SEQ ID NO: 11 or 5, and HCDR2 and HCDR3 with the amino acid sequences set forth in SEQ ID NO: 6 and SEQ ID NO: 7, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 with the amino acid sequences set forth in SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10; Preferably, the buffer is a histidine salt buffer or a succinate buffer; preferably, the buffer is a histidine hydrochloride buffer or a succinic acid and sodium succinate buffer.

2. The pharmaceutical composition according to claim 1, characterized in that the buffer or pharmaceutical composition has a pH of 4.0-8.5, preferably 5.0-6.5 and more preferably 5.5-6.

0.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that the concentration of the buffer is from 1 mM to 30 mM, preferably from 5 mM to 15 mM and more preferably about 10 mM.

4. A pharmaceutical composition according to any one of claims 1 to 3, characterized in that the concentration of the ligand-drug conjugate is from 0.1 mg / ml to 50 mg / ml, preferably from 10 mg / ml to 30 mg / ml and more preferably from 15 mg / ml to 25 mg / ml.

5. A pharmaceutical composition according to any one of paragraphs. 1-4, additionally containing a surfactant, wherein: preferably, said surfactant is selected from the group consisting of poloxamer 188, polysorbate 80 and polysorbate 20; more preferably, said surfactant is polysorbate 80.

6. The pharmaceutical composition according to claim 5, characterized in that the concentration of the surfactant is from 0.01 mg / ml to 1 mg / ml, preferably from 0.05 mg / ml to 0.6 mg / ml and more preferably from 0.1 mg / ml to 0.3 mg / ml.

7. A pharmaceutical composition according to any one of paragraphs 1-6, additionally containing an osmotic pressure regulator, wherein: preferably, said osmotic pressure regulator is selected from the group consisting of one or a combination of more than one substance selected from sucrose, trehalose, sorbitol, arginine, proline, glycine and sodium chloride; more preferably, said osmotic pressure regulator is sucrose.

8. The pharmaceutical composition according to claim 7, characterized in that the concentration of the osmotic pressure regulator is from 1 mg / ml to 300 mg / ml, preferably from 30 mg / ml to 130 mg / ml and more preferably about 80 mg / ml.

9. A pharmaceutical composition containing: (a) a ligand-drug conjugate at a concentration of from 0.1 mg / ml to 50 mg / ml, (b) a histidine salt buffer or a succinate buffer at a concentration of 0.5 mM to 50 mM, (c) sucrose or trehalose at a concentration of 1 mg / ml to 300 mg / ml and (d) polysorbate at a concentration of 0.01 mg / ml to 1 mg / ml, the pH of the pharmaceutical composition is from 4.0 to 8.5; or (a) a ligand-drug conjugate at a concentration of 10 mg / ml to 30 mg / ml, (b) a histidine salt buffer or a succinate buffer at a concentration of 1 mM to 30 mM, (c) sucrose or trehalose at a concentration of 30 mg / ml to 130 mg / ml and (d) polysorbate 80 at a concentration of 0.05 mg / ml to 0.6 mg / ml, the pH of the pharmaceutical composition is from 5.0 to 6.5; or (a) a ligand-drug conjugate at a concentration of 10 mg / ml to 50 mg / ml, (b) a histidine salt buffer or a succinate buffer at a concentration of 1 mM to 30 mM, (c) sucrose or trehalose at a concentration of 30 mg / ml to 130 mg / ml and (d) polysorbate 80 at a concentration of 0.05 mg / ml to 0.6 mg / ml, the pH of the pharmaceutical composition is from 5.0 to 6.5; or (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) a histidine salt buffer or a succinate buffer at a concentration of 5 mM to 15 mM, (c) sucrose at a concentration of 70 mg / ml to 90 mg / ml and (d) polysorbate 80 at a concentration of 0.1 mg / ml to 0.3 mg / ml, the pH of the pharmaceutical composition is from 5.0 to 6.5; or (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) approximately 10 mM histidine salt buffer, (c) sucrose at a concentration of approximately 80 mg / ml and (d) polysorbate 80 at a concentration of 0.1 mg / ml to 0.3 mg / ml, the pH of the pharmaceutical composition is from 5.5 to 6.0; or (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) approximately 10 mM succinate buffer, (c) sucrose at a concentration of approximately 80 mg / ml and (d) polysorbate 80 at a concentration of 0.1 mg / ml to 0.3 mg / ml, wherein the pH of the pharmaceutical composition is from 5.0 to 6.0; or (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) approximately 10 mM histidine hydrochloride buffer, (c) sucrose at a concentration of approximately 80 mg / ml and (d) polysorbate 80 at a concentration of 0.1 mg / ml to 0.3 mg / ml, the pH of the pharmaceutical composition is from 5.5 to 6.0; or (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) approximately 10 mM succinic acid-sodium succinate buffer, (c) sucrose at a concentration of approximately 80 mg / ml and (d) polysorbate 80 at a concentration of 0.1 mg / ml to 0.3 mg / ml, wherein the pH of the pharmaceutical composition is from 5.0 to 6.0; preferably the pharmaceutical composition contains: (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) approximately 10 mM histidine-histidine hydrochloride buffer, (c) sucrose at a concentration of approximately 80 mg / ml and (d) polysorbate 80 at a concentration of approximately 0.2 mg / ml, the pH of the pharmaceutical composition is 5.6; or (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) approximately 10 mM histidine-histidine hydrochloride buffer, (c) sucrose at a concentration of approximately 80 mg / ml and (d) polysorbate 80 at a concentration of approximately 0.2 mg / ml, the pH of the pharmaceutical composition is approximately 5.5; or (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) approximately 10 mM histidine-histidine hydrochloride buffer, (c) sucrose at a concentration of approximately 80 mg / ml and (d) polysorbate 80 at a concentration of approximately 0.2 mg / ml, wherein the pH of the pharmaceutical composition is approximately 5.75; or (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) approximately 10 mM histidine-histidine hydrochloride buffer, (c) sucrose at a concentration of approximately 80 mg / ml and (d) polysorbate 80 at a concentration of approximately 0.2 mg / ml, wherein the pH of the pharmaceutical composition is approximately 6.0; or (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) approximately 10 mM histidine-histidine hydrochloride buffer, (c) sucrose at a concentration of approximately 80 mg / ml and (d) polysorbate 80 at a concentration of approximately 0.3 mg / ml, the pH of the pharmaceutical composition is approximately 5.5; or (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) approximately 10 mM histidine-histidine hydrochloride buffer, (c) sucrose at a concentration of approximately 80 mg / ml and (d) polysorbate 80 at a concentration of approximately 0.3 mg / ml, wherein the pH of the pharmaceutical composition is approximately 5.75; or (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) approximately 10 mM histidine-histidine hydrochloride buffer, (c) sucrose at a concentration of approximately 80 mg / ml and (d) polysorbate 80 at a concentration of approximately 0.3 mg / ml, wherein the pH of the pharmaceutical composition is approximately 6.0; or (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) approximately 10 mM histidine-histidine hydrochloride buffer, (c) sucrose at a concentration of approximately 80 mg / ml and (d) polysorbate 80 at a concentration of approximately 0.1 mg / ml, the pH of the pharmaceutical composition is approximately 5.5; or (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) approximately 10 mM histidine-histidine hydrochloride buffer, (c) sucrose at a concentration of approximately 80 mg / ml and (d) polysorbate 80 at a concentration of approximately 0.1 mg / ml, wherein the pH of the pharmaceutical composition is approximately 5.75; or (a) a ligand-drug conjugate at a concentration of 15 mg / ml to 25 mg / ml, (b) approximately 10 mM histidine-histidine hydrochloride buffer, (c) sucrose at a concentration of approximately 80 mg / ml and (d) polysorbate 80 at a concentration of approximately 0.1 mg / ml, wherein the pH of the pharmaceutical composition is approximately 6.0; the ligand is an anti-CD79b antibody or antigen-binding fragment thereof, wherein the anti-CD79b antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1 with the amino acid sequence set forth in SEQ ID NO: 11 or 5, and HCDR2 and HCDR3 with the amino acid sequences set forth in SEQ ID NO: 6 and SEQ ID NO: 7, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 with the amino acid sequences set forth in SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10; the medicinal product is selected from the group consisting of MMAE or a derivative thereof, exatecan or a derivative thereof, and eribulin or a derivative thereof, and is preferably exatecan or a derivative thereof.

10. The pharmaceutical composition according to any one of claims 1-9, characterized in that the antibody to CD79b or an antigen-binding fragment thereof comprises a variable region of the heavy chain of the antibody and a variable region of the light chain of the antibody, wherein: the sequence of the variable region of the heavy chain comprises SEQ ID NO: 3 or an amino acid sequence having at least 90% identity therewith, and the sequence of the variable region of the light chain comprises SEQ ID NO: 4 or an amino acid sequence having at least 90% identity therewith.

11. The pharmaceutical composition according to any one of claims 1-10, characterized in that the antibody to CD79b or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein: the heavy chain sequence comprises SEQ ID NO: 12 or an amino acid sequence having at least 80% identity thereto, and the light chain sequence comprises SEQ ID NO: 13 or an amino acid sequence having at least 80% identity thereto.

12. A pharmaceutical composition according to any one of paragraphs 1-11, characterized in that the ligand-drug conjugate is represented by the general formula (Pc-LYD) of formula (I): , where Y is selected from the group consisting of -O-(CR a R b ) m -CR 1 R 2 -C(O)-, -O-CR 1 R 2 -(CR a R b ) m -, -O-CR 1 R 2 -, -NH-(CR a R b ) m -CR 1 R 2-C(O)- and -S-(CR a R b ) m -CR 1 R 2 -C(O)-; R a and R b are the same or different and each is independently selected from the group consisting of hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, deuterated alkyl, alkoxy, hydroxy, amino, cyano, nitro, hydroxyalkyl, cycloalkyl and heterocyclyl; or R a and R b together with the carbon atom to which they are attached, they form cycloalkyl and heterocyclyl; R 1 selected from the group consisting of hydrogen, halogen, haloalkyl, deuterated alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl and heteroaryl; R 2 selected from the group consisting of hydrogen, halogen, haloalkyl, deuterated alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl and heteroaryl; or R 1 and R 2together with the carbon atom to which they are attached, they form cycloalkyl or heterocyclyl; or R a and R 2 together with the carbon atom to which they are attached, they form cycloalkyl or heterocyclyl; m is an integer between 0 and 4; n is 1-10 and n is a decimal or integer number; preferably n is 2-8 or 5-9; L represents a linker unit; RS is an antibody to CD79b or its antigen-binding fragment; preferably, the ligand-drug conjugate has a structure represented by the following formula: , where n is 1-10 and n is a decimal or integer number; More preferably n is 1-6 and n is a decimal or integer number.

13. A lyophilized preparation, wherein said lyophilized preparation is obtained by lyophilizing a pharmaceutical composition according to any one of claims 1-12 or said lyophilized preparation can be diluted to form a pharmaceutical composition according to any one of claims 1-12.

14. A method for producing a lyophilized preparation, including a stage of lyophilization of a pharmaceutical composition according to any one of paragraphs 1-12.

15. A reconstituted solution obtained by diluting the lyophilized preparation according to paragraph 13.

16. A pharmaceutical composition according to any one of claims 1-12 or a reconstituted solution according to claim 15, which is an agent for intravenous, subcutaneous, intraperitoneal or intramuscular injection, preferably an agent for intravenous injection.

17. A product comprising a container, wherein said container comprises a pharmaceutical composition according to any one of claims 1-12, a lyophilized preparation according to claim 13, or a reconstituted solution according to claim 15.

18. Use of a pharmaceutical composition according to any one of claims 1-12, a lyophilized preparation according to claim 13, a reconstituted solution according to claim 15, or a product according to claim 17 for the production of a medicinal product for the treatment or prevention of a proliferative disease or the delay of the progression of a proliferative disease, wherein: preferably the proliferative disorder is a cancer or tumor; more preferably, the cancer or tumor is selected from the group consisting of lymphoma, diffuse large B-cell lymphoma, non-Hodgkin's lymphoma (NHL), aggressive NHL, relapsed and aggressive NHL, relapsed and indolent NHL, poorly responsive NHL, poorly responsive and indolent NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, leukemia, hairy cell leukemia (HCL), acute lymphocytic leukemia (ALL), and / or mantle cell lymphoma.

19. A method for treating or preventing a proliferative disease or delaying the progression of a proliferative disease, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a pharmaceutical composition according to any one of claims 1-12, a lyophilized preparation according to claim 13, a reconstituted solution according to claim 15, or a product according to claim 17, wherein: preferably the proliferative disorder is a cancer or tumor; more preferably, the cancer or tumor is selected from the group consisting of lymphoma, diffuse large B-cell lymphoma, non-Hodgkin's lymphoma (NHL), aggressive NHL, relapsed and aggressive NHL, relapsed and indolent NHL, poorly responsive NHL, poorly responsive and indolent NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, leukemia, hairy cell leukemia (HCL), acute lymphocytic leukemia (ALL), and / or mantle cell lymphoma.

20. A method for enhancing immune function in a subject having a B-cell proliferative disorder or an autoimmune disorder, comprising administering to the subject an amount effective to treat or delay the disease of a pharmaceutical composition of any one of claims 1-12, a lyophilized preparation of claim 13, a reconstituted solution of claim 15, or a product of claim 17, wherein: preferably the B cell proliferative disorder is a cancer or tumor; more preferably, the B-cell proliferative disorder is lymphoma, non-Hodgkin's lymphoma (NHL), aggressive NHL, relapsed and aggressive NHL, relapsed and indolent NHL, poorly responsive NHL, poorly responsive and indolent NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, leukemia, hairy cell leukemia (HCL), acute lymphocytic leukemia (ALL), and / or mantle cell lymphoma.