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EP-4740956-A1 - PHARMACEUTICAL COMBINATION FOR SUBCUTANEOUS ADMINISTRATION AND USE THEREOF

EP4740956A1EP 4740956 A1EP4740956 A1EP 4740956A1EP-4740956-A1

Abstract

A pharmaceutical combination for subcutaneous administration and use thereof are provided. The pharmaceutical combination for subcutaneous administration comprises a hyaluronidase and an antibody-drug conjugate. The pharmaceutical combination can enable administration in a greater volume or at a higher dose, without worsened adverse effects.

Inventors

  • LIU, YANJUN

Assignees

  • Shanghai Bao Pharmaceuticals Co., Ltd.

Dates

Publication Date
20260513
Application Date
20250208

Claims (20)

  1. A pharmaceutical combination, comprising a hyaluronidase and an antibody-drug conjugate.
  2. The pharmaceutical combination according to claim 1, wherein the pharmaceutical combination is administered subcutaneously.
  3. The pharmaceutical combination according to claim 1 or 2, wherein the antibody-drug conjugate comprises a fragment of a bioactive molecule.
  4. The pharmaceutical combination according to claim 3, wherein the bioactive molecule is a bioactive molecule with moderate toxicity.
  5. The pharmaceutical combination according to claim 3 or 4, wherein the bioactive molecule is a topoisomerase I inhibitor.
  6. The pharmaceutical combination according to claim 5, wherein the topoisomerase I inhibitor is a camptothecin-based topoisomerase I inhibitor.
  7. The pharmaceutical combination according to claim 6, wherein the topoisomerase I inhibitor is selected from camptothecin (CPT), hydroxycamptothecin (HCPT), 9-aminocamptothecin (9-AC), 7-ethyl-10-hydroxycamptothecin (SN-38), exatecan derivative (Dxd or DX-8951 derivative), irinotecan (CPT-11), topotecan, lurtotecan, belotecan, or exatecan.
  8. The pharmaceutical combination according to claim 6 or 7, wherein the topoisomerase I inhibitor is selected from any one of the following:
  9. The pharmaceutical combination according to any one of claims 1-8, wherein the antibody-drug conjugate is selected from: 9MW-2921, A-315, ACR-246, ADC-2154, AZD-9592, AZD-9829, BIO-201, BLB-01D1, BSI-04702, CUSP-06, DAN-311, DB-1303, DB-1311, GPCR-targeted Project 010, HDP-201, HLX-42, HLX-43, IBI-354, IM-1021, JSKN-033, M-9140, MABS-01, MBK-101, MBK-102, MBK-105, NV-104, OBI-902, OBI-904, OBI-905, PRO-1102, DS-6000, IMMU-132, SMP-190, TQB-2102, DS-8201, DS-1062, DS-7300, U3-1402, XB-033, YL-201, YL-202, ZW-191, ZW-220, or ZW-251.
  10. The pharmaceutical combination according to any one of claims 1-9, wherein the hyaluronidase is a mammalian hyaluronidase.
  11. The pharmaceutical combination according to any one of claims 1-10, wherein the hyaluronidase comprises a catalytic domain of hyaluronidases PH-20, HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1.
  12. The pharmaceutical combination according to any one of claims 1-11, wherein the hyaluronidase is selected from HuPH20, HYAL1, HYAL2, HYAL3, or HYAL4, or any variant thereof, or any isotype thereof.
  13. The pharmaceutical combination according to any one of claims 1-12, wherein the hyaluronidase is a hyaluronidase set forth in any one of SEQ ID NOs: 1-3 or a fragment thereof.
  14. The pharmaceutical combination according to any one of claims 1-13, wherein the pharmaceutical combination is selected from the group consisting of: rHuPH20 and DS-8201, rHuPH20 and IMMU-132, rHuPH20 and DS-1062, rHuPH20 and DS-7300, rHuPH20 and U3-1402, and PH20 variant 1 and DS-8201.
  15. The pharmaceutical combination according to any one of claims 1-14, wherein the antibody-drug conjugate is administered at a concentration of about 2 - 100 mg/mL; and the hyaluronidase is administered at a concentration of about 100 - 5000 IU/mL; optionally, the antibody-drug conjugate is administered at a concentration of about 2 mg/mL, 6 mg/mL, 8 mg/mL, 10 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL, 80 mg/mL, or 100 mg/mL; the hyaluronidase is administered at a concentration of about 100 IU/mL, 150 IU/mL, 200 IU/mL, 500 IU/mL, 1000 IU/mL, 2000 IU/mL, 3000 IU/ml, or 4000 IU/mL; optionally, the antibody-drug conjugate is administered at a concentration of about 20 mg/mL, and the hyaluronidase is administered at a concentration of about 500 IU/mL.
  16. The pharmaceutical combination according to any one of claims 1-14, wherein the antibody-drug conjugate and the hyaluronidase are administered in a dose ratio of about 2 - 100 mg : 100 - 5000 IU; optionally, the antibody-drug conjugate and the hyaluronidase are administered in a dose ratio of about 3 - 60 mg : 100-3000 IU; optionally, the antibody-drug conjugate is administered at a dose of 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 10 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, or 60 mg/mL; optionally, the hyaluronidase is administered at a dose of 100 IU/mL, 150 IU/mL, 200 IU/mL, 500 IU/mL, 1000 IU/mL, 2000 IU/mL, or 3000 IU/mL; optionally, a ratio of the antibody-drug conjugate to the hyaluronidase is about 20 mg : 500 IU.
  17. The pharmaceutical combination according to any one of claims 1-16, wherein the antibody-drug conjugate is DS-8201.
  18. The pharmaceutical combination according to any one of claims 1-17, wherein the pharmaceutical combination is: rHuPH20 and DS-8201; wherein DS-8201 is administered at a concentration of about 20 mg/mL, and rHuPH20 is administered at a concentration of about 500 IU/mL.
  19. The pharmaceutical combination according to any one of claims 1-18, wherein the pharmaceutical combination is: rHuPH20 and DS-8201; wherein DS-8201 and rHuPH20 are administered in a dose ratio of about 20 mg : 500 IU.
  20. A pharmaceutical composition for subcutaneous administration, comprising: the pharmaceutical combination according to any one of claims 1-19 and a pharmaceutically acceptable excipient.

Description

PRIORITY CLAIM This application is a Continuation of International Patent Application No. PCT/CN2025/076396 filed on Feb. 8, 2025, which claims priority to International Patent Application No. PCT/CN2024/076995 entitled "SUBCUTANEOUS ANTIBODY-DRUG CONJUGATES", filed on Feb. 8, 2024, and International Patent Application No. PCT/CN2024/112586 entitled "PHARMACEUTICAL COMBINATIONS FOR SUBCUTANEOUS ADMINISTRATION AND USES THEREOF", filed on Aug. 16, 2024, which are incorporated herein by reference in their entireties. TECHNICAL FIELD The present disclosure relates to the field of biopharmaceuticals, and in particular, to a pharmaceutical combination for subcutaneous administration and use thereof. BACKGROUND TECHNOLOGY Existing antibody-drug conjugates are administered by intravenous (IV) injection. However, the IV administration faces a series of clinical challenges. For example, for patients with poor venous access, IV treatments may result in the loss of treatment opportunity. Injections need to be performed in an outpatient setting, which increases the risk of hospital-acquired infections. The need for long-term infusion and accompaniment may lead to the loss of laborers and additional medical insurance expenses such as hospitalization consumables and interventions for complications, increasing the complexity of drug formulation processes and the difficulty of quality and safety management. Moreover, the prolonged infusion time may also lead to a low patient turnover. Very few cytotoxic agents can be administered subcutaneously for the treatment of cancers, as most known anti-cancer cytotoxic agents may cause local damage in the subcutaneous or dermal tissues after extravasation. In Chinese Patent No. CN110352201A, the local toxicity of ADCs is controlled by optimizing the dosage and time. However, subcutaneous formulations generally require higher doses relative to intravenous injections, which in turn require higher injection volumes and/or drug concentrations. Although a variety of FDA-approved antibodies have been developed as subcutaneous formulations, subcutaneous (sc) administration is difficult for antibody-drug conjugates (ADCs) since immune cells in the skin may respond to cytotoxic loads and mediate off-target effects, leading to toxic effects such as the local deposition of cytotoxic substances (Lucas AT, Price LSL, Schorzman AN, et al. Factors Affecting the Pharmacology of Antibody-Drug Conjugates. Antibodies (Basel, Switzerland). 2018 Feb; 7(1):E10. DOI: 10.3390/antib7010010.). Also, as the volume of a conventional subcutaneous dose is generally less than 2 mL, formulations with a high concentration are required for ADCs. ADCs generally have higher hydrophobicity after the drug load is conjugated. Therefore, the development and production of pharmaceutical ADC formulations are also challenging, and the development of subcutaneous formulations with a high concentration is even more difficult. Due to the large variety of substances in conjugate products, the sample complexity makes the preparation of non-specific ADCs extremely difficult. In addition, the drugs and the linkers in ADCs also increase the complexity of preparing ADCs. During the conjugation of ADCs, aggregation-prone regions in the antibody backbone may be exposed, or the aggregation between antibodies may be caused by drug-mediated interactions, which greatly limits the ability to prepare high-stability and high-concentration ADC treatments. Therefore, there is an urgent clinical need to develop ADC composition/combinations that enable safe and efficient subcutaneous administration. CONTENT OF THE INVENTION In some aspects of the present disclosure, provided is a pharmaceutical combination comprising a hyaluronidase and an antibody-drug conjugate. In some embodiments, the pharmaceutical combination disclosed herein is administered subcutaneously. In some embodiments, the antibody-drug conjugate in the pharmaceutical combination disclosed herein comprises a bioactive molecule fragment. In some embodiments, the bioactive molecule described herein is a bioactive molecule with moderate toxicity. In some embodiments, the bioactive molecule described herein is a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor described herein is a camptothecin-based topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor described herein is selected from camptothecin (CPT), hydroxycamptothecin (HCPT), 9-aminocamptothecin (9-AC), 7-ethyl-10-hydroxycamptothecin (SN-38), exatecan derivative (Dxd or DX-8951 derivative), irinotecan (CPT-11), topotecan, lurtotecan, belotecan, and exatecan. In some embodiments, the topoisomerase I inhibitor described herein is selected from any one of the following: In some embodiments, the antibody-drug conjugate described herein is selected from: 9MW-2921, A-315, ACR-246, ADC-2154, AZD-9592, AZD-9829, BIO-201, BLB-01D1, BSI-04702, CUSP-06, DAN-311, DB-1303, DB-1311, GPCR-ta