Anti-ROR1 antibody conjugates, compositions comprising anti ROR1 antibody conjugates, and methods of making and using anti-ROR1 antibody conjugates preliminary class

Patent metadata

Field	Value
Publication number	US-12226490-B2
Application number	US-202318349337-A
Country	US
Kind code	B2
Filing date	Jul 10, 2023
Priority date	Jun 30, 2022
Publication date	Feb 18, 2025
Grant date	Feb 18, 2025

Abstract

The present disclosure relates to antibodies and antibody conjugates, for instance antibody drug conjugates, with binding specificity for receptor tyrosine kinase orphan receptor 1 (ROR1) and its isoforms and homologs, and compositions comprising the antibodies or antibody conjugates, including pharmaceutical compositions. Also provided are methods of producing the antibodies and antibody conjugates and compositions thereof as well as methods of using the antibodies and antibody conjugates and compositions thereof, such as in therapeutic and diagnostic methods.

First claim

What is claimed is:

1. An antibody conjugate comprising an antibody that specifically binds to receptor tyrosine kinase orphan receptor 1 (ROR1) linked site-specifically to at least one payload moiety, wherein the antibody comprises one or more non-natural amino acids and wherein the antibody conjugate is according to the structure of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
COMP is a residue of the anti-ROR1 antibody comprising one or more non-natural amino acids;
L 1 is —C 1-6 alkylene-;
Y is —X 1 —C 1-6 alkylene-[X 1 —C 1-6 alkylene] n -[X 1 ] p —, —X 1 —C 2-6 alkenylene-[X 1 —C 2-6 alkenylene] n -[X 1 ] p —, —X 1 —C 2-6 alkynylene-[X 1 —C 2-6 alkynylene] n -[X 1 ] p —, wherein at least one alkylene, alkenylene or alkynylene in Y is substituted with one or more substituents selected from R 50 ; and
wherein the alkylene, alkenylene, or alkynylene in Y is optionally substituted with one or more substituents selected from R 51 ;
R 50 is —C 1-6 alkylene-X 2 —[C 1-6 alkylene] m -POLY, —C 2-6 alkenylene-X 2 —[C 2-6 alkenylene] m -POLY, or —C 2-6 alkynylene-X 2 —[C 2-6 alkynylene] m -POLY, wherein each alkylene, alkenylene or alkynylene of R 50 is optionally substituted with one or more substituents selected from halogen, —CN, —NO 2 , —OH, —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —C(O)—, —C(S)—, —C(O)OCH 2 C 6 H 5 , —NHC(O)OCH 2 C 6 H 5 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, 3- to 12-membered heterocycle, and C 1-10 haloalkyl;
R 51 is independently selected from halogen, —CN, —NO 2 , —OH, —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —C(O)—, —C(S)—, —C(O)OCH 2 C 6 H 5 , —NHC(O)OCH 2 C 6 H 5 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, 3- to 12-membered heterocycle, and C 1-10 haloalkyl;
X 1 and X 2 are independently selected from —C(O)— and —N(R 10 )C(O)—;
R 10 is independently selected at each occurrence from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, 3- to 12-membered heterocycle, and C 1-10 haloalkyl;
POLY is a water-soluble polymer;
n is an integer selected from zero, one, two, and three;
m is an integer selected from zero and one;
p is an integer selected from zero and one;
Su is a hexose form of a monosaccharide;
D is a drug moiety; and
RL is a reactive group residue.

2. The antibody conjugate of claim 1 , wherein the antibody conjugate has a structure selected from the group consisting of:

wherein n2 is an integer from 1 to 10.

3. The antibody conjugate of claim 1 , wherein the antibody conjugate has a structure selected from the group consisting of:

wherein n2 is an integer from 1 to 10.

4. The antibody conjugate of claim 1 , wherein the antibody comprises three heavy chain CDRs from a V H sequence selected from SEQ ID NOs:854-1020, and three light chain CDRs from a V L sequence selected from SEQ ID NOs:1021-1026.

5. A kit comprising the antibody conjugate of claim 1 , and instructions for use.

6. A pharmaceutical composition comprising the antibody conjugate of claim 1 and a pharmaceutically acceptable carrier.

7. The antibody conjugate of claim 1 , wherein the antibody conjugate is according to the structure of Formula II:

or a pharmaceutically acceptable salt thereof, wherein
COMP is a residue of the ROR1 antibody comprising one or more non-natural amino acids;
Y is —X 1 —C 1-6 alkylene-[X 1 —C 1-6 alkylene] n -X 1 —, —X 1 —C 2-6 alkenylene-[X 1 —C 2-6 alkenylene] n -X 1 —, —X 1 —C 2-6 alkynylene-[X 1 —C 2-6 alkynylene] n -X 1 —, wherein at least one alkylene, alkenylene or alkynylene in Y is substituted with one or more substituents selected from R 50 ; and
R 50 is —C 1-6 alkylene-X 2 —[C 1-6 alkylene] m -POLY, —C 2-6 alkenylene-X 2 —[C 2-6 alkenylene] m -POLY, or —C 2-6 alkynylene-X 2 —[C 2-6 alkynylene] m -POLY, wherein each alkylene, alkenylene or alkynylene of R 50 is optionally substituted with one or more substituents selected from halogen, —CN, —NO 2 , —OH, —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —C(O)—, —C(S)—, —C(O)OCH 2 C 6 H 5 , —NHC(O)OCH 2 C 6 H 5 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, 3- to 12-membered heterocycle, and C 1-10 haloalkyl.

8. The conjugate of claim 7 , wherein the compound of Formula (II) is according to Formula (IIA):

9. The antibody conjugate of claim 1 , wherein Su is

wherein

represents attachment to the remainder of the compound.

10. The antibody conjugate of claim 1 , wherein Su is

wherein

represents attachment to the remainder of the compound.

11. The antibody conjugate of claim 1 , wherein D is a cytotoxic payload.

12. The antibody conjugate of claim 11 , wherein the cytotoxic payload is a tubulin inhibitor, a DNA topoisomerase I inhibitor, or a DNA topoisomerase II inhibitor.

13. The antibody conjugate of claim 1 , wherein D is selected from the group consisting of hemiasterlins, camptothecins, anthracyclines, PNU-159682, and EDA PNU-159682 derivatives.

14. The antibody conjugate of claim 1 , wherein D is hemiasterlin, exatecan, PNU-159682, or a EDA PNU-159682 derivative.

15. The antibody conjugate of claim 1 , wherein L 1 is —C 1-3 alkylene-.

16. The antibody conjugate of claim 1 , wherein L 1 is —CH 2 —.

17. The antibody conjugate of claim 1 , wherein Y is —X 1 —C 1-6 alkylene-[X 1 —C 1-6 alkylene] n -X 1 —, wherein at least one alkylene in Y is substituted with one or more substituents selected from R 50 .

18. The antibody conjugate of claim 1 , wherein Y is —X 1 —C 1-4 alkylene-X 1 —C 1-4 alkylene-X 1 —C 1-4 alkylene-X 1 —, wherein at least one alkylene in Y is substituted with one or more substituents selected from R 50 .

19. The antibody conjugate of claim 1 , wherein R 50 is —C 1-6 alkylene-X 2 —[C 1-6 alkylene] m -POLY, wherein each alkylene of R 50 is optionally substituted with one or more substituents selected from halogen, —CN, —NO 2 , —OH, —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —C(

Assignees

• Sutro Biopharma Inc

Inventors

• Gakhal Amandeep
• Yu Abigail
• Stafford Ryan
• Hanson Jeffrey
• Yam Alice
• Bajjuri Krishna
• Maderna Andreas
• Abrahams Cristina
• Li Xiaofan
• Yin Gang
• Wen Miao
• Bedard Kristin
• Calarese Daniel
• Kiefel Helena

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K16/28

  against receptors, cell surface antigens or cell surface determinants · CPC title

• A61K31/502

  ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine · CPC title

• A61K47/6809

  Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin · CPC title

• A61K47/68037

  the drug being a camptothecin [CPT] or derivatives · CPC title