Anti-CD70 antibody drug conjugates

Patent metadata

Field	Value
Publication number	US-12037405-B2
Application number	US-202217898384-A
Country	US
Kind code	B2
Filing date	Aug 29, 2022
Priority date	Jun 19, 2012
Publication date	Jul 16, 2024
Grant date	Jul 16, 2024

Abstract

This invention relates to anti-CD70 antibodies and antibody drug conjugates comprising at least one non-naturally-encoded amino acid. Disclosed herein are αCD70 antibodies with one or more non-naturally encoded amino acids and further disclosed are antibody drug conjugates wherein the αCD70 antibodies of the invention are conjugated to one or more toxins. Further disclosed are methods for using such non-natural amino acid antibody drug conjugates, including therapeutic, diagnostic, and other biotechnology uses.

First claim

What is claimed is:

1. A compound comprising Formula (VIII) or (IX), wherein the compound is an anti-CD70 antibody conjugated to a dolastatin, wherein the conjugation occurs via a non-natural amino acid in the anti-CD70 antibody, and Formula (VIII) or (IX) has the following structure:

wherein:
A is optional, and when present is lower alkylene, substituted lower alkylene, lower cycloalkylene, substituted lower cycloalkylene, lower alkenylene, substituted lower alkenylene, alkynylene, lower heteroalkylene, substituted heteroalkylene, lower heterocycloalkylene, substituted lower heterocycloalkylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, alkarylene, substituted alkarylene, aralkylene, or substituted aralkylene;
B is optional, and when present is a linker selected from the group consisting of lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, lower heteroalkylene, substituted lower heteroalkylene, —O—, -O-(alkylene or substituted alkylene)-, -S-, -S-(alkylene or substituted alkylene)-, —S(O) k — wherein k is 1, 2, or 3, —S(O) k (alkylene or substituted alkylene)-, —C(O)—, —C(O)-(alkylene or substituted alkylene)-, —C(S)—, —C(S)-(alkylene or substituted alkylene)-, —N(R′)—, —NR′-(alkylene or substituted alkylene)-, —C(O)N(R′)-, —CON(R′)-(alkylene or substituted alkylene)-, —CSN(R′)—, —CSN(R′)-(alkylene or substituted alkylene)-, —N(R′)CO-(alkylene or substituted alkylene)-, —N(R′)C(O)O—, —S(O) k N(R′)-, —N(R′)C(O)N(R′)-, —N(R′)C(S)N(R′)-, —N(R′)S(O) k N(R′)-, —N(R′)—N═, —C(R′)═N-, —C(R′)═N—N(R′)-, —C(R′)=N-N═, —C(R′) 2 -N═N-, and —C(R′) 2 -N(R′)-N(R′)-, wherein each R′ is independently H, alkyl, or substituted alkyl;
R is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl;
R 1 is a polypeptide, wherein the polypeptide comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 1;
R 2 is a polypeptide;
R 3 and R 4 are each independently H, halogen, lower alkyl, or substituted lower alkyl, or R 3 and R 4 or two R 3 groups optionally form a cycloalkyl or a heterocycloalkyl;
Z has the structure of:

wherein:
R 5 is H, COR 8 , C 1 -C 6 alkyl or thiazole;
R 8 is OH;
R 6 is OH or H; and
Ar is phenyl or pyridine;

R 7 is H or C 1 -C 6 alkyl; and
L is a linker selected from the group consisting of -alkylene-, -alkylene-C(O)—, -(alkylene-O) n -alkylene-, -(alkylene-O) n -alkylene-C(O)—, -(alkylene-O) n —(CH 2 ) n′ —NHC(O)—(CH 2 ) n″ —C(Me) 2 -S—S—(CH 2 ) n′″ —NHC(O)-(alkylene-O) n″″ -alkylene-, -(alkylene-O) n -alkylene-W—, -alkylene-C(O)—W—, -(alkylene-O) n -alkylene-U-alkylene-C(O)—, and -(alkylene-O) n -alkylene-U-alkylene-;
wherein:
W has the structure of:

U has the structure of:

 and

each n, n′, n″, n′″ and n″″ is independently an integer greater than or equal to one;

or an active metabolite, or a pharmaceutically acceptable prodrug or solvate thereof.

2. The compound of claim 1 , wherein the R 2 polypeptide comprises a heavy chain constant region.

3. The compound of claim 2 , wherein the heavy chain constant region amino acid sequence shares at least 90% sequence identity with SEQ ID NO: 3.

4. The compound of claim 3 , wherein the heavy chain constant region amino acid sequence shares at least 95% identity with SEQ ID NO: 3.

5. The compound of claim 4 , wherein the heavy chain constant region has the amino acid sequence of SEQ ID NO: 3.

6. The compound of claim 2 , wherein the heavy chain constant region has the amino acid sequence of SEQ ID NO: 4.

7. The compound of claim 1 , wherein the anti-CD70 antibody comprises a light chain, wherein the light chain comprises a variable region and a constant region.

8. The compound of claim 7 , wherein the light chain variable region has the amino acid sequence of SEQ ID NO: 2.

9. The compound of claim 8 , wherein the light chain constant region has the amino acid sequence of SEQ ID NO: 5 or 12.

10. The compound of claim 1 , wherein A is arylene or substituted arylene and B is absent.

11. The compound of claim 1 , wherein L is -(alkylene-O) n -alkylene-, wherein n is an integer from 1 to 20.

12. The compound of claim 1 , wherein:
R 3 and R 4 are each H;
Z has the structure of:

wherein:
R 5 is COR 8 , wherein R 8 is OH;
R 6 is H; and
Ar is phenyl; and

R 7 is C 1 -C 6 alkyl.

13. The compound of claim 1 , wherein the dolastatin has the following structure:

14. The compound of claim 13 , wherein the anti-CD70 antibody comprises a heavy chain constant region.

15. The compound of claim 14 , wherein the R 2 polypeptide comprises the heavy chain constant region.

16. The compound of claim 15 , wherein the heavy chain constant region shares at least 95% identity with SEQ ID NO: 3.

17. The compound of claim 16 , wherein the anti-CD70 antibody comprises a light chain, wherein the light chain comprises a variable region having the amino acid sequence of SEQ ID NO: 2.

18. The compound of claim 17 , wherein the light chain further comprises a constant region having the amino acid sequence of SEQ ID NO: 5.

19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, excipient or binder.

Assignees

• Ambrx Inc

Inventors

• Barnett Richard S
• Knudsen Nickolas
• Sun Ying
• Biroc Sandra
• Buss Timothy
• Javahishvili Tsotne
• Bresson Damien
• Srinagesh Shailaja
• Hewet Amha
• Pinkstaff Jason

Classifications

• A61K47/6845

  the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon · CPC title

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• A61K47/6889

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• A61K47/42

  Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34) · CPC title