Trop2 conjugated biological molecules, pharmaceutical compositions and methods

Abstract

Disclosed herein are antibody drug complexes comprising a drug unit coupled to an antibody capable of binding to TROP2 or an antigen-binding fragment thereof, and methods of using the antibody drug complexes. The methods of use include, but are not limited to, cancer treatment and detection. The antibody drug complexes disclosed herein can bind to specific cancer cell surfaces. Exemplary targets of the antibody drug complexes disclosed herein include epithelial cancers, such as lung cancer, breast cancer, head and neck cancer, esophageal cancer, gastric cancer, bladder cancer, pancreatic cancer, colorectal cancer, cervical cancer, endometrial cancer, ovarian cancer, laryngeal cancer, prostate cancer, thyroid cancer, and oral cancer.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480021819.8 (22) Application Date 2024.03.27 (30) Priority Data 63 / 492,343 2023.03.27 US 63 / 549,781 2024.02.05 US (85) PCT International Application Entering National Phase Date 2025.09.25 (86) PCT International Application Application Data PCT / US2024 / 021729 2024.03.27 (87) PCT International Application Publication Data WO2024 / 206480 EN 2024.10.03 (71) Applicant: OBI Pharma Inc., Taiwan Address: Taipei, Taiwan (72) Inventors: Lai Ming-tien, Li Wan-fen, Yang Ming-zhen, Chen Jun-de, Huang Deng-yi (74) Patent Agency: Beijing Liu Shen Law Firm, 11105 Patent Attorney: Zhang Wen-hui (51) Int.Cl. A61K 47 / 68 (2006.01) A61P 35 / 00 (2006.01) (54) Invention Title: TROP2 Coupled Biomolecule, Pharmaceutical Composition and Method (57) Abstract: This document discloses an antibody-drug complex comprising a pharmaceutical unit coupled to an antibody or its antigen-binding fragment capable of binding TROP2, and discloses a method of using the antibody-drug complex. The method of use includes, but is not limited to, cancer treatment and detection. The antibody-drug complex disclosed herein can bind to the surface of specific cancer cells. The exemplary targets of the antibody-drug complexes disclosed herein include epithelial cancers, such as lung cancer, breast cancer, head and neck cancer, esophageal cancer, gastric cancer, bladder cancer, pancreatic cancer, colorectal cancer, cervical cancer, endometrial cancer, ovarian cancer, laryngeal cancer, prostate cancer, thyroid cancer, and oral cancer. Claims: 4 pages; Description: 66 pages; Sequence List (electronic publication); Figures: 13 pages; CN 120916790 A; 2025.11.07; CN 1 20 91 67 90 A

Claims

1. An antibody drug conjugate (ADC) comprising a drug unit and an antibody or antigen-binding fragment thereof that binds to TROP2 (tumor-associated calcium signal transducer 2), wherein the antibody drug conjugate has the structure of Formula (I): wherein the drug unit (D) is covalently linked to the antibody or antigen-binding fragment thereof (Ab) through a linker molecule (L); Ab-(L-D) n (I), wherein the antibody is an anti-TROP2 antibody, and wherein n is an integer between 1 and 8.

2. The antibody drug conjugate of claim 1, wherein the antibody is a monoclonal antibody, an antigen-binding fragment, a chimeric antibody, or a humanized antibody.

3. The antibody drug conjugate of claim 2, wherein the antigen-binding fragment is a Fab, a F(ab’)2, a Fv, or a single chain Fv (scFv).

4. The antibody drug conjugate of claim 1, wherein the anti-TROP2 antibody is a hRS7 antibody, a Hu2G10 antibody, a hu4D3 antibody, a MAAP-9001a antibody, a Pr1E11 antibody, a R4702 antibody, datopotamab, or sacituzumab.

5. The antibody drug conjugate of claim 1, wherein the drug unit is exatecan, deruxtecan, SN-38, or monomethyl auristatin E (MMAE).

6. The antibody drug conjugate of claim 1, wherein the linker molecule comprises a maleimide or a derivative thereof coupled to a sulfur-containing group of the antibody.

7. The antibody drug conjugate of claim 6, wherein the linker molecule is 4-(N- maleimidomethyl)-cyclohexane-1-carboxylate.

8. The antibody drug conjugate of claim 1, wherein the drug unit is a chemotherapeutic agent, a photodynamic therapy agent, or a biomolecule. ​ 9. The antibody drug conjugate of claim 8, wherein the photodynamic therapy agent is Photofrin, Laserphyrin, Aminolevulinic acid (ALA), Silicon Phthalocyanine 4 (Pc 4), m-tetrahydroxyphenylchlorin (mTHPC), chlorin e6 (Ce6), Allumera, Levulan, Foscan, Metvix, Hexvix, Photochlor, Photosens, Photrex, Lumacan, Visonac, Amphinex, Verteporfin, Purlytin, ATMPn, Zinc phthalocyanine (ZnPc), Protoporphyrin IX (PpIX), pyropheophorbide a (PPa), or pheophorbide a (PhA).

10. The antibody drug conjugate of claim 1, wherein the drug unit is an anti-proliferative agent.

11. The antibody drug conjugate of claim 10, wherein the anti-proliferative agent is exatecan, irinotecan, topotecan, camptothecin, rubitecan, MLN576, belotecan, seconeolitsine, SN-38, Genz-644282, betulinic acid, β-lapachone, karenitecin, gimatecan, namitecan, edotecarin, SW044248, LMP744, T-2513, Podocarpusflavone A, indimitecan, lurtotecan, TP3011 or 10-hydroxycamptothecin, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), mertansine (DM1), an anthracycline, a pyrrolobenzodiazepine, an α-amanitin, a tubulysin, a benzodiazepine, erlotinib, bortezomib, fulvestrant, sunitinib, letrozole, imatinib mesylate, PTK787 / ZK 222584, oxaliplatin, leucovorin, rapamycin, lapatinib, lonafarnib (SARASAR, SCH 66336), 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine, 5-fluorouracil, gemcitabine,66336), sorafenib, gefitinib, AG1478, AG1571, alkylating agents, alkyl sulfonates, aziridines, ethylenimines, methylamelamines, acetogenins, camptothecins, bryostatin, callystatin, CC-1065, cryptophycins, dolastatins, duocarmycins, eleutherobins, pancratistatin, sarcodictyin, spongistatins, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, calicheamicin, dynemicin, clodronate, esperamicin, neocarzinostatin, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, dactinomycin C(cactinomycin), carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalarnycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin;acid), nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, ro dorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, 5-fluorouracil (5-FU), denopterin, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, aminoglutethimide, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elformithine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidamide, mitoguazone, mitomycin, mopidamol, nitracine, pentostatin, phenamet, pirarubicin, podophyllinic acid, 2-ethylhydrazide, procarbazine, PSK®, razoxane, sizofiran, spirogermanium, tenuazonic acid, triaziquone, 2,2',2'-trichlorotriethylamine, urethan, vindesine, dacarbazine, mannosulfan, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside ("Ara-C"), cyclophosphamide ("CTX"), thiotepa, busulfan, carmustine, chlorambucil, cisplatin, and melphalan.acid), eniluracil, amsacrine, bestrabucil, bisantrene, edatrexate, defofamine, demecolcine, diaziquone, elformithine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, lo soxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonic acid, triaziquone, 2, 2, 2- trichloroethylhydroxylamine, urogenital, puramycin A and the like.acid), triaziquone, 2,2',2"-trichlorotriethylamine, trichothecene, urethan, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, taxoid, paclitaxel, doxetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, cisplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, topoisomerase inhibitors, difluoromethylornithine (DMFO), retinoid, or capecitabine.

12. A pharmaceutical composition comprising the antibody drug conjugate of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier, or excipient.

13. The pharmaceutical composition of claim 12, further comprising an additional anti-cancer agent.

14. A method of treating cancer in a patient, comprising administering to the patient in need thereof an effective amount of the antibody drug conjugate of claim 1 and a pharmaceutically acceptable carrier, or the pharmaceutical composition of claim 12.

15. The method of claim 14, wherein the cancer is a TROP2-expressing cancer selected from the group consisting of lung cancer, breast cancer, head and neck cancer, esophageal cancer, gastric cancer, bladder cancer, pancreatic cancer, colorectal cancer, cervical cancer, endometrial cancer, ovarian cancer, laryngeal cancer, prostate cancer, thyroid cancer, and oral cancer.

16. The method of claim 14, further comprising administering to the patient an additional anti-cancer agent.

17. The method of claim 16, wherein the combination of the antibody drug conjugate and the additional anti-cancer agent provides a synergistic or additive effect in cancer treatment to enhance therapeutic efficacy.

18. A method of inducing or enhancing an immune response in a patient in need thereof, comprising administering an effective amount of the pharmaceutical composition of claim 12, and performing one or more steps selected from the group consisting of: (a) administering the pharmaceutical composition two or more times; (b) adjusting the time interval between two consecutive administrations and / or the dosing regimen; ​ ​ (c) adjusting the route of administration and / or changing the site of administration; or (d) administering an additional anti-cancer agent.

19. The method of claim 18, wherein the administration is altered and / or supplemented by the addition of an immune response enhancer.

20. The method of claim 14 or 18, wherein the effective amount is 0.001 pg to 250 mg per kg of body weight of the patient.

21. The method of claim 18, wherein the method comprises administering an additional anti-cancer agent, and the combination of the pharmaceutical composition and the additional anti-cancer agent is synergistic or additive in inducing or enhancing the immune response.

22. Use of the antibody drug conjugate of claim 1 in the manufacture of a medicament for treating cancer in combination with an effective amount of an additional agent selected from the group consisting of an anti-cancer agent, an immunosuppressive agent, and an anti-infective agent, and the cancer is selected from lung cancer, breast cancer, head and neck cancer, esophageal cancer, gastric cancer, bladder cancer, pancreatic cancer, colorectal cancer, cervical cancer, endometrial cancer, ovarian cancer, laryngeal cancer, prostate cancer, thyroid cancer, or oral cancer.

23. A method of selecting a patient for cancer treatment by imaging, wherein the method comprises: (a) administering to the patient an effective amount of the antibody drug conjugate of claim 1 ; and (b) detecting a reporter signal of an imaging agent in the patient; wherein the imaging agent is a fluorescent substance, a dye, a nuclear magnetic resonance contrast agent, or a radionuclide; and wherein the reporter signal is detected visually or by an instrument.

24. The method of claim 23, wherein the patient has detectable cancer, and the method further detects metastasis of the cancer.

25. An antibody drug conjugate (ADC) that binds to TROP2, comprising: (a) an antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises: i. a first heavy chain complementarity determining region (HCDR1) having the amino acid sequence of SEQ ID NO: 1 ; ii. a second heavy chain complementarity determining region (HCDR2) having the amino acid sequence of SEQ ID NO: 2; iii. a third heavy chain complementarity determining region (HCDR3) having the amino acid sequence of SEQ ID NO: 3; wherein the light chain variable domain comprises: iv. a first light chain complementarity determining region (LCDR1) having the amino acid sequence of SEQ ID NO: 4; v. a second light chain complementarity determining region (LCDR2) having the amino acid sequence of SEQ ID NO: 5; vi. a third light chain complementarity determining region (LCDR3) having the amino acid sequence of SEQ ID NO: 6; (b) a drug unit; and (c) a linking molecule.

26. The antibody drug conjugate of claim 25, wherein the antibody further comprises: (a) a heavy chain variable domain comprising an amino acid sequence that is 90% to 100% identical to the amino acid sequence of SEQ ID NO: 7; and (b) a heavy chain variable domain comprising an amino acid sequence that is 90% to 100% identical to the amino acid sequence of SEQ ID NO:

7. (b) a heavy chain variable domain comprising an amino acid sequence that is 90% to 100% identical to the amino acid sequence of SEQ ID NO:

7. (b) a heavy chain variable domain comprising an amino

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