ANTIBODY DRUG CONJUGATE PLATFORM USING BISPECIFIC ANTIBODY

• US 20190328894A1
• Filed: 06/21/2017
• Published: 10/31/2019
• Est. Priority Date: 06/21/2016
• Status: Active Grant

• Current Assignee: Seoul National University R&DB Foundation (Seoul National University)
• Original Assignee: Seoul National University R&DB Foundation (Seoul National University)
• Inventors: CHUNG, Junho, JIN, Junyeong, KIM, Hyori, PARK, Gunwoo, KIM, Soohyun
• Granted Patent: US 11,167,037 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4188 condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• CPC Class Codes: A61K 47/555 pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6879 the immunoglobulin having two or more different antigen-binding sites, e.g. bispecific or multispecific immunoglobulin
• 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: A61K 47/6897 Pre-targeting systems with two or three steps using antibody conjugates; Ligand-antiligand therapies
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/468 Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/526 CH3 domain
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention relates to an antibody drug conjugate using a bispecific antibody and its use. The antibody drug conjugate of the present invention can easily form a conjugate of an antibody and a drug without a multistep synthetic process though binding of a conjugate of a bivalent cotinine-peptide and a drug, and an anti-cotinine single chain variable fragment. In addition, the antibody drug conjugate can effectively deliver a drug to a target to which the antibody binds specifically, and can enhance a half-life of a drug in the body, thereby improving a therapeutic effect.

Claims

1. An antibody drug conjugate comprising:

a bispecific antibody comprising an anti-cotinine single chain variable fragment (scFv); and

a conjugate of bivalent cotinine which is cross-linked with a peptide, and a drug.

2. The antibody drug conjugate according to the claim 1, wherein the anti-cotinine single chain variable fragment is combined with the bivalent cotinine.

3. The antibody drug conjugate according to the claim 1, wherein the bivalent cotinine is that two cotinines are cross-linked to the N terminal and C-terminal of a 6-18 mer peptide, respectively.

4. The antibody drug conjugate according to the claim 1, wherein the drug is conjugated with a lysine residue in the 6-18 mer peptide cross-linked with the bivalent cotinine.

5. The antibody drug conjugate according to the claim 1, wherein the bispecific antibody is that a peptide linker (Gly-Gly-Gly-Gly-Ser)₃ is inserted between C_H3 domain and the anti-cotinine single chain variable fragment (scFv).

6. The antibody drug conjugate according to the claim 1, wherein the drug is any one selected from the group consisting of duocarmycin, auristatin, colchicine, anthracycline, calicheamicin, maytansinoid, pyrrolobenzodiazepine, dolastatin, tubulysin, maytansinoid, doxorubicin, cryptophycin, epothilone, safranin, deacetyl colchicine, maytansinol, vedotin, mafodotin, emtansine, mertansine, ravtansine, soravtansine, talirine, tesirine, indolinobenzodiazepines, irinotecan prodrug, exatecan derivative and tubulin inhibitor;

or siRNA inhibiting expression of a gene occurring cancer.

7. The antibody drug conjugate according to the claim 1, wherein the bispecific antibody comprises any one selected from the group consisting of cetuximab, trastuzumab, oregovomab, edrecolomab, alemtuzumab, labetuzumab, bevacizumab, ibritumomab, ofatumumab, panitumumab, rituximab, tositumomab, ipilimumab, gemtuzumab, brentuximab, vadastuximab, glembatumumab, depatuxizumab, polatuzumab, denintuzumab, enfortumab, telisotuzumab, tisotumab, pinatuzumab, lifastuzumab, indusatumab, vandortuzumab, sofituzumab, vorsetuzumab, trastuzumab, mirvetuximab, coltuximab, naratuximab, indatuximab, anetumab, lorvotuzumab, cantuzumab, laprituximab, bivatuzumab, vadastuximab, rovalpituzumab, inotuzumab, sacituzumab, labetuzumab, milatuzumab, lupartumab and aprutumab.

8. A pharmaceutical composition for treating cancer comprising the antibody drug conjugate of claim 1.

9. The pharmaceutical composition for treating cancer according to claim 8, wherein the cancer is lung adenocarcinoma having KRAS mutation.

14. A method for treating cancer comprising a step of treating an effective dose of the antibody drug conjugate of claim 1 into an animal.

15. A method for enhancing a half-life of a drug using the antibody drug conjugate of claim 1 into an animal.

10. A method for preparing an antibody drug conjugate comprising:

(s1) a step of preparing a bispecific antibody comprising an anti-cotinine single chain variable fragment (scFv);

(s2) a step of preparing a conjugate of a bivalent cotinine which is cross-linked with a peptide and a drug; and

(s3) a step of mixing the bispecific antibody produced in the (s1) step and the conjugate produced in the (s2) step.

11. The method for preparing an antibody drug conjugate according to claim 10, wherein the (s3) step is that the anti-cotinine single chain variable fragment and the bivalent cotinine bind specifically.

12. The method for preparing an antibody drug conjugate according to claim 10, wherein the bivalent cotinine is that two cotinines are cross-linked to the N terminal and C-terminal of a 6-18 mer peptide, respectively.

13. The method for preparing an antibody drug conjugate according to claim 10, wherein the drug is conjugated with a lysine residue in the 6-18 mer peptide cross-linked with the bivalent cotinine.