Protein-polymer-drug conjugates and methods of using same

Patent metadata

Field	Value
Publication number	US-9808528-B2
Application number	US-201514742936-A
Country	US
Kind code	B2
Filing date	Jun 18, 2015
Priority date	Jun 18, 2014
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

A polymeric scaffold useful for conjugating with a protein based recognition-molecule (PBRM) to form a PBRM-polymer-drug conjugate is described herein. The scaffold includes one or more terminal maleimido groups. Also disclosed is a PBRM-polymer-drug conjugate prepared from the scaffold. Compositions comprising the conjugates, methods of their preparation, and methods of treating various disorders, such as cancer in a subject having low HER2 expression with the conjugates or their compositions are also described.

First claim

What is claimed is:

1. A method of alleviating a symptom of a cancer in a subject in need thereof, wherein the subject is identified as having low HER2 expression, comprising administering a conjugate to the subject in an amount sufficient to alleviate the symptom of the cancer, wherein the conjugate is of Formula (Ie), comprising a polymeric scaffold comprising a poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF):

wherein:
the PHF has a molecular weight ranging from about 2 kDa to about 40 kDa;
PBRM is trastuzumab or a biosimilar thereof;
each occurrence of D independently is a therapeutic agent having a molecular weight of ≦5kDa, and the

the between D and the carbonyl group denotes direct or indirect attachment of D to the carbonyl group,
X is CH 2 , O, or NH;
one of X a and X b is H and the other is a water-soluble maleimido blocking moiety, or X a and X b , together with the carbon atoms to which they are attached for a carbon-carbon double bond,
m 1 is an integer from 1 to about 140,
m 7 is an integer from 1 to about 40, wherein the sum of m 1 and m 7 is about 2 to about 180,
m is an integer from 1 to about 300,
m 3a is an integer from 0 to about 17,
m 3b is an integer from 1 to about 8, wherein the sum of m 3a and m 3b is an integer between 1 and about 18,
the sum of m, m 1 , m 7 , m 3a , and m 3b ranges from about 15 to about 300, and
m 5 is an integer from 1 to about 10.

2. The method of claim 1 , wherein the PHF has a molecular weight ranging from about 2 kDa to about 20 kDa, the sum of m, m 1 , m 7 , m 3a and m 3b ranges from about 15 to about 150, m 1 is an integer from 1 to about 70, m 7 is an integer from 1 to about 20, m 3a is an integer from 0 to about 9, m 3b is an integer from 1 to about 8 and m 5 is an integer from 2 to about 8.

3. The method of claim 1 , wherein the PHF has a molecular weight ranging from about 3 kDa to about 15 kDa, the sum of m, m 1 , m 7 , m 3a and m 3b ranges from about 20 to about 110, m 1 is an integer from 2 to about 50, m 7 is an integer from 2 to about 15, m 3a is an integer from 0 to about 7, m 3b is an integer from 1 to about 8 and m 5 is an integer from 2 to about 8.

4. The method of claim 1 , wherein the PHF has a molecular weight ranging from about 5 kDa to about 10 kDa, the sum of m, m 1 , m 7 , m 3a and m 3b ranges from about 40 to about 75, m 1 is an integer from about 2 to about 35, M 7 is an integer from about 2 to about 10, m 3a is an integer from 0 to about 4, m 3b is an integer from 1 to about 5 and m 5 is an integer from 2 to about 8.

5. The method of claim 1 , wherein the conjugate is of Formula (B):

wherein:
the PHF has a molecular weight ranging from about 5 kDa to about 10 kDa;
m is an integer from 1 to about 75,
m 1 is an integer from about 2 to about 35,
m 2 is an integer from about 2 to about 10,
m 3a is an integer from 0 to about 4,
m 3b is an integer from 1 to about 5,
the sum of m, m 1 , m 2 , m 3a , and m 3b ranges from about 40 to about 75, and
m 5 is an integer from 2 to about 4.

6. The method of claim 1 , wherein the total number of sulfide bonds formed between the PBRM and the PHF is 10 or less.

7. The method of claim 6 , wherein the total number of sulfide bonds formed between the PBRM and the PHF is 4 or less.

8. The method of claim 1 , wherein the subject is human.

9. The method of claim 1 , wherein the cancer is selected from the group consisting of anal cancer, astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye cancer, laryngeal cancer, mouth cancer, mesothelioma, skin cancer, myeloma, oral cancer, rectal cancer, throat cancer, bladder cancer, breast cancer, uterine cancer, ovarian, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, pancreatic cancer, renal cancer, and gastric cancer.

10. The method of claim 9 , wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, non-small cell lung cancer (NSCLC), and ovarian cancer.

11. The method of claim 1 , further comprising administering a second agent to the subject.

12. The method of claim 11 , wherein the second agent is at least a second antibody or antigen binding fragment thereof that specifically binds HER2.

13. The method of claim 12 , wherein the second antibody or antigen binding fragment thereof is a HER2 antibody, a HER2 dimerization inhibitor antibody, or a combination of a HER2 antibody and a HER2 dimerization inhibitor antibody.

14. The method of claim 13 , wherein the HER2 antibody, the HER2dimerization inhibitor antibody or the combination of a HER2 antibody and a HER2dimerization inhibitor antibody comprises trastuzumab or pertuzumab or a combination thereof.

15. The method of claim 12 , wherein the second antibody or antigen binding fragment thereof is pertuzumab.

16. The method of claim 1 , wherein the subject is identified as having a scoring of 1+or 2+for HER2 expression as detected by immunohistochemistry (IHC) analysis performed on a test cell population, and wherein the HER2 gene is not amplified in the test cell population.

17. The method of claim 1 , wherein the subject is refractory to chemotherapy.

18. The method of claim 1 , wherein the subject is resistant to treatment with ado-trastuzumab emtansine.

19. The method of claim 1 , wherein the subject is not resistant to treatment with ado-trastuzumab emtansine.

20. The method of claim 1 , wherein the subject is identified as having a scoring of 2+or 3+for HER2 expression as detected by immunohistochemistry (IHC) analysis performed on a test cell population, and wherein the HER2 gene is amplified or mutated in the test cell population.

Assignees

• Mersana Therapeutics Inc

Inventors

• Bodyak Natalya D
• Lowinger Timothy B
• Park Peter U
• Yurkovetskiy Aleksandr V

Classifications

• C07K2317/76

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

• C07K16/32

  against translation products of oncogenes · CPC title

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K2039/505

  comprising antibodies · CPC title