ANTIBODY-DRUG CONJUGATES AND THERAPEUTIC METHODS USING THE SAME

• US 20190328900A1
• Filed: 06/30/2017
• Published: 10/31/2019
• Est. Priority Date: 07/01/2016
• Status: Abandoned Application

• Current Assignee: Glaxosmithkline Intellectual Property Limited (GSK plc)
• Original Assignee: GlaxoSmithKline Intellectual Property Development Limited (GSK plc)
• Inventors: JEFFREY, Jerry, TANG, Jun, TAI, Vincent Wing-Fai, TEMELKOFF, David, VELTHUISEN, Emile Johann, WEATHERHEAD, Jason Gordon
• Application Number:
  US16/308,862
• Publication Number:
  US 20190328900A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61K 47/6841 the antibody targeting a RNA virus
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07K 16/1063 env, e.g. gp41, gp110/120, gp160, V3, PND, CD4 binding site

Abstract

The invention discloses an antibody-drug conjugate of Formula (I):

Ab-[L-D_n]_x  (I)

• • wherein:
  • Ab comprises a broadly neutralizing anti-HIV antibody;
  • L comprises a linker molecule covalently bonded to said broadly neutralizing anti-HIV antibody;
  • D comprises one or more drugs comprising an HIV therapeutic compound covalently bonded to said linker molecule L, wherein said one or more broadly neutralizing anti-HIV antibodies Ab specifically bind to an HIV envelope glycoprotein and said one or more drugs D specifically bind to an HIV envelope glycoprotein;
  • n is selected from 1-4; and
  • x is selected from 1-12.

Claims

1. An antibody-drug conjugate of the Formula (I):

Ab-L-D 

 

(I)

wherein;

Ab comprises a broadly neutralizing antibody having a binding affinity for an HIV envelope glycoprotein;

L comprises a linker molecule covalently bonded to said broadly neutralizing antibody; and

D comprises one or more drugs covalently bonded to said linker molecule, said one or more drugs capable of binding to said HIV envelope glycoprotein.

2. The antibody-drug conjugate according to claim 1, wherein the broadly neutralizing antibody binds to the CD4 binding site, the gp120-gp41 interface, or the gp41 membrane-proximal external region (MPER).

12. The antibody-drug conjugate according to claim 1, wherein the linker molecule is a non-cleavable linker.

14. The antibody-drug conjugate according to claim 1, wherein the one or more drugs is an attachment inhibitor.

15. The antibody-drug conjugate according to claim 1, wherein the one or more drugs is a compound of the formula:

16. The antibody-drug conjugate according to claim 1, wherein the one or more drugs is a compound of the formula:

18. A pharmaceutical composition comprising an antibody-drug conjugate according to claim 1, and a pharmaceutically acceptable excipient.

20. A method of treating an HIV infection in a subject comprising administering to the subject an antibody-drug conjugate according to claim 1.

21. A method of treating an HIV-infection in a subject comprising administering to the subject a pharmaceutical formulation according to claim 18.

3-11. -11. (canceled)

13. (canceled)

17. (canceled)

19. (canceled)

22. An antibody-drug conjugate of Formula (I):

Ab-[L-D_n]_x 

 

(I)

wherein;

Ab comprises a broadly neutralizing anti-HIV antibody;

L comprises a linker molecule covalently bonded to said broadly neutralizing anti-HIV antibody;

D comprises one or more drugs comprising an HIV therapeutic compound covalently bonded to said linker molecule L, wherein said one or more broadly neutralizing anti-HIV antibodies Ab specifically bind to an HIV envelope glycoprotein and said one or more drugs D specifically bind to an HIV envelope glycoprotein;

n is selected from 1-4; and

x is selected from 1-12.

23. The antibody-drug conjugate according to claim 22, wherein the broadly neutralizing antibody Ab binds to the HIV envelope glycoprotein selected from the group consisting of gp160, gp120 and gp41.

26. The antibody-drug conjugate according to claim 22, wherein the broadly neutralizing antibody Ab binds to the HIV envelope glycoprotein at the gp120/gp41-interface, at the CD4-binding site, or to the gp41 membrane-proximal external region (MPER).

47. The antibody-drug conjugate according to claim 22, wherein the linker molecule is a non-cleavable linker.

50. The antibody-drug conjugate according to claim 22, wherein the drug D specifically binds to a HIV envelope glycoprotein selected from the group consisting of gp160, gp120 and gp41.

51. The antibody-drug conjugate according to claim 22, wherein the drug D is an attachment inhibitor.

54. The antibody-drug conjugate according to claim 22, wherein the drug D is a compound of the formula:

55. The antibody-drug conjugate according to claim 22, wherein the drug D is a compound of the formula:

56. The antibody-drug conjugate according to claim 22, wherein the drug D is a peptide which binds to CD4.

59. The antibody-drug conjugate according to claim 22, wherein the drug D is of the formula A:

60. The antibody-drug conjugate according to claim 59, wherein:

X is selected from Cl and F;

Y is H;

m is 2;

n is 1;

R₁, R₂, R₃, R₄ and R₅ are each independently H;

r ranges from 1 to 4;

p ranges from 1 to 4; and

q ranges from 1 to 4.

67. A pharmaceutical composition comprising an antibody-drug conjugate according to claim 22, and a pharmaceutically acceptable excipient.

68. The pharmaceutical composition according to claim 67, comprising one or more additional HIV therapeutic agents.

69. A method of treating, curing or preventing an HIV infection in a subject comprising administering to the subject an antibody-drug conjugate according to claim 22.

70. A method of treating, curing or preventing an HIV-infection in a subject comprising administering to the subject a pharmaceutical composition according to claim 67.

24-25. -25. (canceled)

27-46. -46. (canceled)

48-49. -49. (canceled)

52-53. -53. (canceled)

57-58. -58. (canceled)

61. (canceled)

62. An antibody-drug conjugate of Formula (I):

Ab-[L-D_n]_x 

 

(I)

wherein;

Ab comprises a broadly neutralizing anti-HIV antibody;

L comprises a linker molecule covalently bonded to said broadly neutralizing anti-HIV antibody;

D comprises one or more drugs comprising an HIV therapeutic compound covalently bonded to said linker molecule L, wherein said one or more broadly neutralizing anti-HIV antibodies Ab specifically bind to an HIV envelope glycoprotein and said one or more drugs D specifically bind to an HIV envelope glycoprotein;

n is selected from 1-4;

x is selected from 1-12, wherein the antibody-drug-conjugate comprises (1) a first drug D covalently bonded to a first linker molecule L, which is covalently bonded to said broadly neutralizing antibody and (2) a second drug D covalently bonded to a second linker molecule L, which is covalently bonded to said broadly neutralizing antibody.

63. The antibody-drug conjugate according to claim 62, wherein the first drug D is the same as the second drug D.

64. The antibody-drug conjugate according to claim 62, wherein the first drug D is different than the second drug D.

65. The antibody-drug-conjugate according to claim 62, wherein the two drugs are selected from the group consisting of gp120 attachment inhibitors, gp160 attachment inhibitors and combinations thereof.

66. (canceled)

71-77. -77. (canceled)