Antibody-drug conjugate having cyclic benzylidene acetal linker

• US 10,377,837 B2
• Filed: 10/22/2015
• Issued: 08/13/2019
• Est. Priority Date: 10/24/2014
• Status: Active Grant

• Current Assignee: NOF Corporation
• Original Assignee: NOF Corporation
• Inventors: Tsubusaki, Takuma, Yamamoto, Yuji
• Primary Examiner(s): Mauro, John M
• Application Number:
  US15/512,727
• Publication Number:
  US 20170290919A1
• Time in Patent Office: 1,391 Days
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 45/00 Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/50 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
• CPC Class Codes: A61K 47/6809 Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6889 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 Class Codes: C07C 45/36 in compounds containing six-membered aromatic rings
• CPC Class Codes: C07D 317/28 Radicals substituted by nitrogen atoms nitro radicals C07D317/16
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 19/00 Hybrid peptides , i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/30 characterized by aspects of specificity or valency
• CPC Class Codes: C07K 2317/50 characterized by immunoglobulin fragments
• CPC Class Codes: C07K 2317/90 characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C08F 8/12 : Hydrolysis

Abstract

An antibody-drug conjugate having a cyclic benzylidene acetal linker represented by formula (1) or formula (2), wherein Y is an antibody; D is a drug; R¹ and R⁶ are each independently a hydrogen atom or a hydrocarbon group; R², R³, R⁴ and R⁵ are each independently an electron-withdrawing or electron-donating substituent or a hydrogen atom; s is 1 or 2, t is 0 or 1, and s+t is 1 or 2; w is an integer of 1 to 20; and Z¹ and Z² are each independently a selected divalent spacer:

Claims

1. An antibody-drug conjugate having a cyclic benzylidene acetal linker represented by formula (1) or formula (2):

2. The antibody-drug conjugate as claimed in claim 1, wherein Z¹ and Z² are each independently selected from the group consisting of structure (z1), structure (z2), structure (z3), structure (z4), structure (z5), structure (z6), structure (z7), structure (z8), structure (z9), and structure (z10):

3. The antibody-drug conjugate as claimed in claim 1, wherein s is 1 and t is 0, R² and R⁵ are each a hydrogen atom, and a sum (Σ

σ

) of substituent constants (σ

) in R³, R⁴ and Y—

Z¹ in the formula (1) or in R³, R⁴ and D-Z¹ in the formula (2) satisfies −

0.30≤

Σ

σ

≤

1.05.

4. The antibody-drug conjugate as claimed in claim 1, wherein s is 1 and t is 0, at least one of R² and R⁵ is the substituent, and a sum (Σ

σ

) of substituent constants (σ

) in R³, R⁴ and Y—

Z¹ in the formula (1) or in R³, R⁴ and D-Z¹ in the formula (2) satisfies −

1.71≤

Σ

σ

≤

0.88.

5. The antibody-drug conjugate as claimed in claim 1, wherein s is 1 and t is 1, or s is 2 and t is 0, R² and R⁵ are each a hydrogen atom, and a sum (Σ

σ

) of substituent constants (σ

) in R³, R⁴ and Y—

Z¹ in the formula (1) or in R³, R⁴ and D-Z¹ in the formula (2) satisfies −

0.19≤

Σ

σ

≤

0.57.

6. The antibody-drug conjugate as claimed in claim 1, wherein s is 1 and t is 1, or s is 2 and t is 0, at least one of R² and R⁵ is the substituent, and a sum (Σ

σ

) of substituent constants (σ

) in R³, R⁴ and Y—

Z¹ in the formula (1) or in R³, R⁴ and D-Z¹ in the formula (2) satisfies −

0.98≤

Σ

σ

≤

0.48.

7. The antibody-drug conjugate as claimed in claim 1, wherein the antibody is a monoclonal antibody, a single chain monoclonal antibody, a bispecific antibody or a monoclonal antibody fragment that binds to a target cell.

8. The antibody-drug conjugate as claimed in claim 1, wherein the antibody is a resurfaced monoclonal antibody, a resurfaced single chain monoclonal antibody or a resurfaced monoclonal antibody fragment that binds to a target cell.

9. The antibody-drug conjugate as claimed in claim 1, wherein the antibody is a human monoclonal antibody, a humanized monoclonal antibody, a humanized single chain monoclonal antibody or a humanized monoclonal antibody fragment that binds to a target cell.

10. The antibody-drug conjugate as claimed in claim 7, wherein the antibody is a chimeric antibody, a chimeric antibody fragment, a domain antibody or a domain antibody fragment.

11. The antibody-drug conjugate as claimed in claim 1, wherein the drug is a chemotherapeutic drug.