Uses of antibody-drug conjugate in treating disease

Abstract

This disclosure relates to the use of an antibody-drug conjugate for the treatment of head and neck cancer. Specifically, this disclosure provides a method for using an antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate of any of the foregoing, for the treatment of head and neck cancer, as well as a use of the antibody-drug conjugate in the preparation of a medicament for the prevention and / or treatment of head and neck cancer. The method and use demonstrate superior disease control and objective response rates, meeting medical needs.

Description

[0001] USES OF ANTIBODY-DRUG CONJUGATE IN TREATING DISEASE TECHNICAL FIELD

[0002] The present application belongs to the pharmaceutical field and relates to a method for using an antibody-drug conjugate to treat a disease. Specifically, the present invention provides a method for treating cancer with an antibody -drug conjugate as well as a use of the antibody-drug conjugate in the preparation of a medicament for treating cancer.

[0003] BACKGROUND ART

[0004] According to global cancer data from 2022, head and neck squamous cell carcinoma (HNSCC) ranks 8th in new cases of malignant tumors and 9th in cancer deaths worldwide, posing a serious threat to global health. In China, there were about 85,000 new cases of HNSCC and about 48,000 deaths. More than 60% of HNSCC cases are already at a locally advanced or metastatic stage at the time of diagnosis. The recurrence rate after radical treatment is as high as 60%, and patients with advanced relapsed / metastatic HNSCC have a poor prognosis, with a 5-year survival rate of less than 5%.

[0005] First-line treatment options for relapsed / metastatic HNSCC patients are limited. In 2008, the FDA approved the addition of cetuximab to platinum-based chemotherapy combined with 5-FU (EXTREME regimen) for first-line treatment of relapsed / metastatic HNSCC patients. Compared to platinum -based chemotherapy plus 5-FU, the EXTREME regimen significantly prolonged overall survival (OS) (10.1 months vs. 7.4 months), and the regimen was approved in China in March 2020. In recent years, there have been rapid advances in the treatment of advanced HNSCC with immune checkpoint inhibitors such as anti-PD-1 monoclonal antibodies. The FDA approved pembrolizumab for first-line relapsed / metastatic HNSCC in June 2019, and it was approved for the same indication in China in December 2020, becoming a recommended first-line treatment (NCCN and CSCO guidelines).

[0006] There is currently no standard salvage treatment regimen for patients with relapsed or metastatic HNSCC who have progressed after failure of standard therapy (PD-l / PD-L1 immunotherapy and platinum-based therapy). Chemotherapy and targeted therapy not previously used are both viable options. In terms of chemotherapeutic agents, methotrexate (ORR: 3.9%; median OS: 6.7 months) and docetaxel (ORR: 6.2%; median OS: 6.0 months) have shown some therapeutic efficacy. In terms of targeted therapies, cetuximab is suitable for patients who have not been previously exposed to this drug or have a poor PS score (ORR: 13%, median OS: 5.9 months). In summary, the overall efficacy of subsequent treatment for patients with relapsed / metastatic HNSCC who have progressed after standard therapy is poor, with an ORR of 3.9% to 13% and a

[0007] 1 CIE25B0191PCTmedian OS of 5.9 to 6.7 months. This indicates a significant unmet clinical need for treatment of patients with relapsed / metastatic HNSCC who have progressed after standard therapy, and new anti-tumor drugs are urgently required.

[0008] SUMMARY OF THE INVENTION

[0009] This disclosure provides a method for the treatment of head and neck cancer with an antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of any of the foregoing, and a pharmaceutical use.

[0010] In a first aspect, this disclosure provides a use of an antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of any of the foregoing for preparing a drug for the treatment of head and neck cancer.

[0011] In another aspect, this disclosure provides an antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of any of the foregoing, for the treatment of head and neck cancer.

[0012] In another aspect, this disclosure provides an antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of any of the foregoing, for the treatment of a head and neck cancer patient.

[0013] In another aspect, this disclosure provides a method for the treatment of head and neck cancer, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of any of the foregoing.

[0014] Specifically, this disclosure provides a method for using an antibody-drug conjugate for the prevention and / or treatment of head and neck cancer, comprising administering to a patient a therapeutically effective amount of the antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of any of the foregoing, wherein the structure of the antibody-drug conjugate is shown in formula (I):

[0015]

[0016] wherein n is a decimal or integer between 1 and 10, preferably a decimal or integer between 1 and 8, more preferably a decimal or integer between 2 and 8, further preferably 3 to 8, and can be either a decimal or an integer.

[0017] Pc is an anti-B7H3 antibody or its antigen-binding fragment.

[0018] In some embodiments, the anti-B7H3 antibody or its antigen-binding fragment

[0019] 2 CIE25B0191PCTcomprises heavy chains HCDR1, HCDR2, and HCDR3 as shown in the amino acid sequences of SEQ ID NOs 01, 02, and 03, respectively, and light chains LCDR1, LCDR2, and LCDR3 as shown in the amino acid sequences of SEQ ID NOs 04, 05, and 06, respectively.

[0020] In this invention, the amino acid sequences of the CDRs listed above are all as shown in the Kabat numbering scheme. However, it is well known to those skilled in the art that antibody CDRs can be defined in various ways. Although the scope of protection claimed in this invention is based on the sequences shown in the Kabat numbering scheme, amino acid sequences defined according to other CDR numbering schemes should also fall within the scope of protection of this invention.

[0021] The CDR sequences mentioned above are shown in the table below:

[0022] Table A: CDR sequences of each heavy and light chain

[0023]

[0024] Note: The CDR sequence is derived from the Kabat numbering scheme..

[0025] Preferably, the anti-B7H3 antibody or its antigen-binding fragment is selected from humanized antibodies or fragments thereof.

[0026] In some optional embodiments, the anti-B7H3 antibody or its antigen-binding fragment described in this application is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments.

[0027] In some optional embodiments, the anti-B7H3 antibody or its antigen-binding fragment described in this application comprises a heavy chain constant region of human IgGl, IgG2, IgG3 or IgG4 isotypes, and preferably comprises a heavy chain constant region of IgGl or IgG4 isotypes.

[0028] In some optional embodiments, the anti-B7H3 antibody or its antigen-binding fragment comprises a K or light chain constant region.

[0029] In some optional embodiments, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region sequence comprises the sequence shown in SEQ ID NO: 07 or a variant thereof, and the light chain variable region sequence comprises the sequence shown in SEQ ID NO: 08 or a variant thereof.

[0030] In a preferred embodiment, the heavy chain variable region sequence of the anti-B7H3 antibody or its antigen-binding fragment is the sequence shown in SEQ ID NO:07 or a variant thereof, and the light chain variable region sequence is the sequence shown in SEQ ID NO: 08 or a variant thereof.

[0031] In a preferred embodiment, the heavy chain variable region sequence of the anti-B7H3 antibody or its antigen-binding fragment is the sequence shown in SEQ ID 3 CIE25B0191PCTNO:07, and the light chain variable region sequence is the sequence shown in SEQ ID NO:08.

[0032] The sequences of the heavy and light chain variable regions of the aforementioned anti-B7H3 antibody or its antigen-binding fragment are shown below:

[0033] Heavy chain variable region sequence OVOLVOSGGGWOPGTSLRLSCAASGFIFSSSAMHWVROAPGKGLEWVANISYDGSNKY YVDSVKGRFTISRDNSKNTLYLOMNSLRAEDTAVYYCARSARLYASFDYWGQGALVTVSS SEQ ID NO: 07 Light chain variable region sequence DTWTOEPSFSVSPGGTVTLTCGLSSGSYSYSHYPSWYOOTPGOAPRMLIYNYNYRSSGV PDRFSGSILGNKAALTITGAQADDESDYYCAYtWf YRDPYNNFGGGTKLTVL

[0034] SEQ ID NO: 08 Note: The sequence is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. Italics indicate an FR sequence, while underlining indicates a CDR sequence, wherein the CDR sequence is derived from Rabat’s numbering scheme.

[0035] In some optional embodiments, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain sequence comprises the sequence shown in SEQ ID NO: 09 or a variant thereof, and the light chain sequence comprises the sequence shown in SEQ ID NO: 10 or a variant thereof.

[0036] In a preferred embodiment, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain sequence is the sequence shown in SEQ ID NO: 09 or a variant thereof, and the light chain sequence is the sequence shown in SEQ ID NO: 10 or a variant thereof.

[0037] In a preferred embodiment, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain sequence is the sequence shown in SEQ ID NO: 09 and the light chain sequence is the sequence shown in SEQ ID NO: 10.

[0038] The sequences of the heavy and light chains of the aforementioned anti-B7H3 antibody or its antigen-binding fragment are shown below:

[0039] Heavy chain (IgGl) amino acid sequence: (SEQ ID NO: 09) QVQLVQSGGGVVQPGTSLRLSCAASGFIFSSSAMHWVRQAPGKGLEWVAVISYD GSNKYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSARLYASFDYWG QGALVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0040] Light chain ( ) amino acid sequence: (SEQ ID NO: 10) DTVVTQEPSFSVSPGGTVTLTCGLSSGSVSTSHYPSWYQQTPGQAPRMLIYNTNT RSSGVPDRFSGSILGNKAALTITGAQADDESDYYCAIHVDRDIWVFGGGTKL

[0041] 4 CIE25B0191PCTTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVET TKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTEC

[0042] In some embodiments, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal injection, and is preferably administration by intravenous injection.

[0043] In some embodiments, the frequency of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from once a week, once every two weeks, once every three weeks, once every four weeks or once every six weeks, and is preferably once every two weeks or once every three weeks.

[0044] In some embodiments, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal injection, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks or once every six weeks.

[0045] In a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, and the frequency of administration is selected from once every two weeks or once every three weeks.

[0046] In some embodiments, the amount of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing administered is selected from 0.1 mg / kg up to 20.0 mg / kg, preferably 0.5 mg / kg to 18.0 mg / kg, more preferably 1.0 mg / kg to 16.0 mg / kg, further preferably 2.0 mg / kg to 14.0 mg / kg, and still further preferably 4.0 mg / kg to 12.0 mg / kg.

[0047] In some embodiments, the amount of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing administered is selected from 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / k, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7.0 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8.0 mg / kg, 8.1 mg / kg, 8.2 mg / kg, 8.3 mg / kg, 8.4 mg / kg, 8.5 mg / kg, 8.6 mg / kg, 8.7 mg / kg, 8.8 mg / kg, 8.9 mg / kg, 9.0 mg / kg, 9.1 mg / kg, 9.2 mg / kg, 9.3 mg / kg, 9.4 mg / kg, 9.5 mg / kg, 9.6 mg / kg, 9.7 mg / kg, 9.8 mg / kg, 9.9 mg / kg, 10.0 mg / kg, 10.1 mg / kg, 10.2 mg / kg, 10.3 mg / kg, 10.4 mg / kg, 10.5 mg / kg, 10.6 mg / kg, 10.7 mg / kg, 10.8 mg / kg, 10.9 mg / kg, 11.0

[0048] 5 CIE25B0191PCTmg / kg, 11.1 mg / kg, 11.2 mg / kg, 11.3 mg / kg, 11.4 mg / kg, 11.5 mg / kg, 11.6 mg / kg, 11.7 mg / kg, 11.8 mg / kg, 11.9 mg / kg, or 12.0 mg / kg.

[0049] In a preferred embodiment, the amount of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing administered is selected from 6.0 mg / kg, 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg or 10.0 mg / kg.

[0050] In some embodiments, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, the frequency of administration is selected from once every two weeks or once every three weeks, and the amount administered is selected from 6.0 mg / kg, 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg or 10.0 mg / kg.

[0051] In some embodiments, the method of using the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing for the prevention and / or treatment of head and neck cancer comprises administering to a patient intravenously at a dose of 6.0 mg / kg, 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg, or 10.0 mg / kg every two weeks or every three weeks.

[0052] In some embodiments, the head and neck cancer is selected from head and neck squamous cell carcinoma, preferably relapsed or metastatic head and neck squamous cell carcinoma, and more preferably relapsed or metastatic head and neck squamous cell carcinoma that has progressed after standard treatment.

[0053] In some embodiments, the patient is a head and neck squamous cell carcinoma patient, preferably a patient with relapsed or metastatic head and neck squamous cell carcinoma, and more preferably a patient with relapsed or metastatic head and neck squamous cell carcinoma that has progressed after standard treatment.

[0054] In some embodiments, the standard treatment comprises platinum-based chemotherapy and PD-1 / PD-L1 immunotherapy.

[0055] In a preferred embodiment, the head and neck cancer is selected from relapsed or metastatic squamous cell carcinoma of the head and neck that has progressed after receiving platinum -based chemotherapy and PD-1 / PD-L1 immunotherapy.

[0056] In a preferred embodiment, the patient is a patient with relapsed or metastatic head and neck squamous cell carcinoma who has progressed after platinum-based chemotherapy and PD-1 / PD-L1 immunotherapy.

[0057] This disclosure also provides a use of the antibody-drug conjugate of formula (I) and its pharmaceutically acceptable salts, stereoisomers, metabolites, or solvates of any of the foregoing, in the preparation of medicaments for the prevent! on / treatm ent of head and neck cancer.

[0058] 6 CIE25B0191PCT

[0059]

[0060] wherein:

[0061] n is 1 to 10, preferably 2 to 8, more preferably 3 to 8, and is a decimal or an integer;

[0062] Pc is an anti-B7H3 antibody or its antigen-binding fragment;

[0063] In some embodiments, the anti-B7H3 antibody or its antigen-binding fragment comprises heavy chains HCDR1, HCDR2, and HCDR3 as shown in the amino acid sequences of SEQ ID NOs 01, 02, and 03, respectively, and light chains LCDR1, LCDR2, and LCDR3 as shown in the amino acid sequences of SEQ ID NOs 04, 05, and 06, respectively.

[0064] In some optional embodiments, the anti-B7H3 antibody or its antigen-binding fragment described in this application is an antigen fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2.

[0065] In some optional embodiments, the anti-B7H3 antibody or its antigen-binding fragment described in this application comprises a heavy chain constant region of human IgGl, IgG2, IgG3 or IgG4 isotypes, and preferably comprises a heavy chain constant region of IgGl or IgG4 isotypes.

[0066] In some optional embodiments, the anti-B7H3 antibody or its antigen-binding fragment comprises a K or X light chain constant region.

[0067] In some optional embodiments, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region sequence comprises the sequence shown in SEQ ID NO: 07 or a variant thereof, and the light chain variable region sequence comprises the sequence shown in SEQ ID NO: 08 or a variant thereof.

[0068] In a preferred embodiment, the heavy chain variable region sequence of the anti-B7H3 antibody or its antigen-binding fragment is the sequence shown in SEQ ID NO: 07 or a variant thereof, and the light chain variable region sequence is the sequence shown in SEQ ID NO: 08 or a variant thereof.

[0069] In a preferred embodiment, the heavy chain variable region sequence of the anti-B7H3 antibody or its antigen-binding fragment is the sequence shown in SEQ ID NO: 07, and the light chain variable region sequence is the sequence shown in SEQ ID NO: 08.

[0070] In some optional embodiments, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain sequence

[0071] 7 CIE25B0191PCTcomprises the sequence shown in SEQ ID NO: 09 or a variant thereof, and the light chain sequence comprises the sequence shown in SEQ ID NO: 10 or a variant thereof.

[0072] In a preferred embodiment, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain sequence is the sequence shown in SEQ ID NO: 09 or a variant thereof, and the light chain sequence is the sequence shown in SEQ ID NO: 10 or a variant thereof.

[0073] In a preferred embodiment, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain sequence is the sequence shown in SEQ ID NO: 09 and the light chain sequence is the sequence shown in SEQ ID NO: 10.

[0074] In some embodiments, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal injection, and is preferably administration by intravenous injection.

[0075] In some embodiments, the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is administered once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks, preferably once every two weeks or once every three weeks.

[0076] In some embodiments, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal injection, and the frequency of administration is once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks.

[0077] In a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every two weeks or once every three weeks.

[0078] In some embodiments, the amount of the the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing administered is 1.0 mg / kg to 16.0 mg / kg, preferably 2.0 mg / kg to 14.0 mg / kg, and more preferably 4.0 mg / kg to 12.0 mg / kg.

[0079] In some embodiments, the amount of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing administered is selected from 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5

[0080] 8 CIE25B0191PCTmg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7.0 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8.0 mg / kg, 8.1 mg / kg, 8.2 mg / kg, 8.3 mg / kg, 8.4 mg / kg, 8.5 mg / kg, 8.6 mg / kg, 8.7 mg / kg, 8.8 mg / kg, 8.9 mg / kg, 9.0 mg / kg, 9.1 mg / kg, 9.2 mg / kg, 9.3 mg / kg, 9.4 mg / kg, 9.5 mg / kg, 9.6 mg / kg, 9.7 mg / kg, 9.8 mg / kg, 9.9 mg / kg, 10.0 mg / kg, 10.1 mg / kg, 10.2 mg / kg, 10.3 mg / kg, 10.4 mg / kg, 10.5 mg / kg, 10.6 mg / kg, 10.7 mg / kg, 10.8 mg / kg, 10.9 mg / kg, 11.0 mg / kg, 11.1 mg / kg, 11.2 mg / kg, 11.3 mg / kg, 11.4 mg / kg, 11.5 mg / kg, 11.6 mg / kg, 11.7 mg / kg, 11.8 mg / kg, 11.9 mg / kg, or 12.0 mg / kg.

[0081] In a preferred embodiment, the amount of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing administered is selected from 6.0 mg / kg, 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg or 10.0 mg / kg.

[0082] In some embodiments, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal injection, in a frequency of once every week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks, and in a dosage selected from 6.0 mg / kg, 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg or 10.0 mg / kg.

[0083] In a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every three weeks or once every four weeks, and in a dosage selected from 6.0 mg / kg, 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg or 10.0 mg / kg.

[0084] In a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every three weeks, and in a dosage selected from 6.0 mg / kg; in a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every three weeks, and in a dosage selected from 7.0 mg / kg; in a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every three weeks, and in a dosage selected from 8.0 mg / kg; in a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every three weeks, and in a dosage selected from 9.0

[0085] 9 CIE25B0191PCTmg / kg; in a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every three weeks, and in a dosage selected from 10.0 mg / kg.

[0086] In a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every four weeks, and in a dosage selected from 6.0 mg / kg; in a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every four weeks, and in a dosage selected from 7.0 mg / kg; in a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every four weeks, and in a dosage selected from 8.0 mg / kg; in a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every four weeks, and in a dosage selected from 9.0 mg / kg; in a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every four weeks, and in a dosage selected from 10.0 mg / kg.

[0087] In a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every two weeks, and in a dosage selected from 6.0 mg / kg; in a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every two weeks, and in a dosage selected from 7.0 mg / kg; in a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every two weeks, and in a dosage selected from 8.0 mg / kg; in a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or

[0088] 10 CIE25B0191PCTthe solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every two weeks, and in a dosage selected from 9.0 mg / kg; in a preferred embodiment, the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous injection, in a frequency of once every two weeks, and in a dosage selected from 10.0 mg / kg.

[0089] In some embodiments, the head and neck cancer is selected from head and neck squamous cell carcinoma, preferably relapsed or metastatic head and neck squamous cell carcinoma, and more preferably relapsed or metastatic head and neck squamous cell carcinoma that has progressed after standard treatment.

[0090] In some embodiments, the patient is a head and neck squamous cell carcinoma patient, preferably a patient with relapsed or metastatic head and neck squamous cell carcinoma, and more preferably a patient with relapsed or metastatic head and neck squamous cell carcinoma that has progressed after standard treatment.

[0091] In some embodiments, the standard treatment comprises platinum-based chemotherapy and PD-1 / PD-L1 immunotherapy.

[0092] In a preferred embodiment, the head and neck cancer is selected from relapsed or metastatic squamous cell carcinoma of the head and neck that has progressed after receiving platinum -based chemotherapy and PD-1 / PD-L1 immunotherapy.

[0093] In a preferred embodiment, the patient is a patient with relapsed or metastatic head and neck squamous cell carcinoma who has progressed after platinum-based chemotherapy and PD-1 / PD-L1 immunotherapy.

[0094] In some embodiments, the patient exhibits an improved result after administration. In some embodiments, exhibiting an improved result after administration is exhibiting an improved objective response rate (ORR), an improved disease control rate (DCR), an improved progression-free survival (PFS) or an improved overall survival (OS) after administration.

[0095] In some embodiments, the prevention and / or treatment comprises administering to the patient a therapeutically effective amount of the anti-B7H3 antibody-drug conjugate of formula (I), the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing.

[0096] In some embodiments, the anti-B7H3 antibody-drug conjugate of formula (I), the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is available in an injectable form, such as subcutaneously or intravenously, wherein the preferred injectable form is an injection solution or lyophilized powder for injection comprising the anti-B7H3 antibody-drug conjugate of formula (I), the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing, as well as buffers, stabilizers, pH regulators and optionally present surfactants.

[0097] 11 CIE25B0191PCTThe drug load (DAR) of the injectable anti-B7H3 antibody drug conjugate in this invention is about 2, 4, 6 or 8, preferably about 4 or 6, and more preferably 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3 or 6.4.

[0098] The preparation of the injectable anti-B7H3 antibody-drug conjugate in this invention was carried out according to the production method described in WO 2020063673, using hl702DS (anti-B7H3 antibody) and an exatecan analogue to prepare the anti-B7H3 antibody-drug conjugate having the structure shown below. The mean as calculated by the HIC technique was n = 4.1, i.e., FADC-2. The heavy chain sequence of hl702DS is shown in SEQ ID NO: 09, and the light chain sequence is shown in SEQ ID NO: 10.

[0099]

[0100] FADC-2

[0101] In another aspect of the present invention there is further provided a pharmaceutical composition comprising the aforementioned antibody-drug conjugate and one or more pharmaceutically acceptable excipients.

[0102] The anti-B7H3 antibody-drug conjugate provided by this invention significantly inhibited the proliferation of head and neck cancer cells Detroit 562 and CAL33. In xenograft models of pleural effusion metastasis of pharyngeal carcinoma (Detroit 562) and squamous cell carcinoma of the human tongue (CAL33), the antitumor effect was significant and showed a good dose-response relationship, and the treatment was well tolerated by all animals. In BALB / c nude mice bearing human tongue squamous cell carcinoma cells (CAL33), the drug was found to be mainly distributed in the blood after a single intravenous injection, with the highest distribution in the tumor, lung, and bladder tissues, and the lowest distribution in the brain tissue, indicating that the drug does not easily cross the blood-brain barrier.

[0103] The anti-B7H3 antibody-drug conjugate provided by this invention exhibited a definite anti-tumor effect for the treatment of head and neck squamous cell carcinoma in clinical trials, and has the potential to be more effective than other same-line therapeutic agents. With good safety and reduced drug toxicity, it can effectively improve patient objective response rates (ORR), and holds exceptional promise for clinical application.

[0104] 12 CIE25B0191PCTDESCRIPTION OF THE DRAWINGS

[0105] FIG. 1 : Optimal depth of response of target lesions in head and neck squamous cell carcinoma

[0106] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0107] Terms

[0108] To facilitate understanding of this disclosure, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0109] This disclosure hereby incorporates application WO 2020063673 in its entirety into the present application.

[0110] The term “antibody-drug conjugate” refers to an antibody linked to a biologically active drug via a stable linker unit. For the purposes of this disclosure, an “antibodydrug conjugate” refers to a monoclonal antibody or antibody fragment that is linked to a biologically active toxic drug via a stable linker unit.

[0111] The term “antibody” refers to an immunoglobulin, which are tetrapeptide chains composed of two identical heavy chains and two identical light chains linked by disulfide bonds. The amino acid composition and sequence of the heavy chain constant region differ among immunoglobulins, thus their antigenicity also varies. Based on this, immunoglobulins can be classified into five classes, or isotypes of immunoglobulins, IgM, IgD, IgG, IgA and IgE, the corresponding heavy chains of which are the p chain, 5 chain, y chain, a chain, and a chain, respectively. Ig of the same type may be further divided into different subclasses based on differences in the amino acid composition of their hinge region and the number and position of disulfide bonds in their heavy chain, For example, IgG can be divided into IgGl, IgG2, IgG3, and IgG4. Light chains may be K chain or chain depending on their constant region. Each of the five classes of Ig may possess either a K chain or a chain.

[0112] The about 110 amino acids at the N terminus of the antibody heavy and light chain which vary considerably in their sequence constitute the variable region (Fv region), while the remaining amino acids at the C terminus are relatively stable in sequence and constitute the constant region. The variable region includes three hypervariable regions (HVRs) and four relatively conserved framework regions (FRs). The three hypervariable regions determine the specificity of the antibody and are also known as the complementarity-determining regions (CDRs). Each light chain variable region (LCVR) and heavy chain variable region (HCVR) are composed of three CDRs and four FRs, arranged as follows in order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDRs of the light chain are LCDR1, LCDR2 and LCDR3, while the three CDRs of the heavy chain are HCDR1,

[0113] 13 CIE25B0191PCTHCDR2 and HCDR3.

[0114] In the present disclosure, the amino acid sequences of the aforementioned CDRs are all derived according to the Kabat numbering scheme. However, it is well known to one skilled in the art that antibody CDRs can be defined in various ways, such as the Chothia scheme based on the 3D structure and CDR ring topology of the antibody (Chothia et al. (1989) Nature 342:877-883, Al-Lazikani et al., “Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927-948 (1997)), the Kabat scheme based on antibody sequence variability (Kabat et al. Sequences of Proteins of Immunological Interest, 4thEdition, U.S. Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), the international ImMunoGeneTics database (IMGT) (imgt.cines.fr / ), and the North CDR definition based on affinity propagation clustering using a large number of crystal structures. Those skilled in the art will understand that, unless otherwise specified, the terms “CDR” and “complementarity-determining region” for a given antibody or its region (e.g., the variable region) should be understood to encompass complementarity-determining regions defined as described in any of the known schemes described herein. While the scope of protection claimed by this invention is based on the sequence shown in the Kabat numbering scheme, amino acid sequences corresponding to other CDR numbering scheme shall also fall within the protective scope of this invention.

[0115] The term “antigen-binding fragment” refers to one or more fragments of an antibody that maintain the ability to specifically bind to an antigen. It has been shown that fragments of full-length antibodies can be used for antigen-binding function. Examples of binding fragments included in “antigen-binding fragments” include (i) Fab fragments, monovalent fragments consisting of VL, VH, CL, and CHI domains; (ii) F(ab')2 fragments, bivalent fragments comprising two Fab fragments linked by disulfide bridges on hinge regions; (iii) Fd fragments consisting of VH and CHI domains; (iv) Fv fragments consisting of VH and VL domains of a single arm of the antibody; (v) single-domain or dAb fragments (Ward et al., (1989) Nature 341: 544-546) consisting of a VH domain; and (vi) separate complementarity-determining regions (CDRs) or (vii) combinations of two or more separate CDRs optionally linked by synthetic linkers.

[0116] The term “drug load” refers to the average amount of cytotoxic drug loaded onto each ligand in the molecule of formula (I), which can also be expressed as the ratio of amount of drug to amount of antibody . The drug load can range from each antibody (Pc) linking to 0-12, preferably 1-10, cytotoxic drugs (D). In embodiments of this disclosure, the drug load is expressed as n, also known as the DAR, and exemplarily is a mean value of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. The average number of drug molecules per ADC molecule after the coupling reaction can be identified using conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA, and HPLC.

[0117] 14 CIE25B0191PCTThe drug load or DAR of the injectable anti-B7H3 antibody drug conjugate of the present application is about 2, 4, 6 or 8, preferably about 4 or 6, and more preferably 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3 or 6.4.

[0118] The terms “administer” and “treat” when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. “Administer” and “treat” can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Cellular treatment includes contact between a reagent and cells, as well as contact between a reagent and a fluid, wherein the fluid is in contact with the cells. “Administering” and “treating” also mean, for example, the treatment of cells in vitro and ex vivo with a reagent, diagnostic agent, conjugate composition, or another cell. When applied to humans, veterinary, or research subjects, “treating” refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic applications.

[0119] The term “therapy” means administering an oral or topical therapeutic agent, such as a composition comprising any of the compounds disclosed herein, to a patient who has symptoms of one or more diseases, where the therapeutic agent is known to have a therapeutic effect on these symptoms. Typically, a therapeutic agent is administered in a treated patient or population in an amount that effectively relieves symptoms of one or more diseases to induce the regression of such symptoms or inhibit their progression to any clinically measurable extent. The amount of a therapeutic agent that effectively relieves any specific disease symptom (also referred to as a “therapeutically effective amount”) can vary depending on a variety of factors, such as the patient’s disease status, age, and weight, and the ability of the drug to produce the desired therapeutic effect in the patient. Whether or not the disease symptoms have been relieved can be evaluated using any clinical testing method commonly used by a physician or other healthcare professional to assess the severity or progression of the symptoms. Although the embodiments of this disclosure (e.g., therapeutic methods or products) may be ineffective in alleviating every symptom of the target disease, they should reduce symptoms of the target disease in a statistically significant number of patients, as determined by any statistical test known in the art, such as the Student / -test, chi-square test, / -test according to Mann and Whitney, Kruskal -Wallis test ( / / -test), Jonckheere-Terpstra test, and Wilcoxon test.

[0120] An “effective amount” includes the amount sufficient to improve or prevent the symptoms or condition of a medically diagnosed disease. An effective amount also means the amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the patient’s overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the

[0121] 15 CIE25B0191PCTmaximum dose or administration regimen that avoids significant side effects or toxicity. The term “patient” as used in this disclosure refers to a human being.

[0122] The term “pharmaceutical composition” refers to a product that optionally comprises one or more active ingredients (e.g., antibodies, antibody-drug conjugates, small molecule drugs) in optional, specific amounts, as well as any product directly or indirectly produced by combining one or more active ingredients in optional, specific amounts. These compositions may also optionally comprise suitable pharmaceutical excipients, such as pharmaceutical carriers, pharmaceutical vehicles, including buffers, known in the art. The different active ingredients in a pharmaceutical composition may be administered independently in separate formulations, including synergistic administration at simultaneous or different time points. In this disclosure, “pharmaceutical composition” and “pharmaceutical formulation” are not mutually exclusive.

[0123] The term “pharmaceutically acceptable salt” refers to those salts of the antibodydrug conjugates of this invention which are safe and effective when used in mammals and possess the intended biological activity. The antibody-drug conjugates of this invention contain at least one amino group, and therefore can form salts with acids. Non-limiting examples of pharmaceutically acceptable salts include: hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, sorbate, hydrogen phosphate, dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, and -toluenesulfonate. “Pharmaceutically acceptable salt” and “pharmaceutical salt” are used interchangeably herein.

[0124] The term “solvent compound” refers to the antibody-drug conjugate compound of the present invention forming a pharmaceutical solvent compound with one or more solvent molecules, non-limiting examples of which include water, ethanol, acetonitrile, isopropanol, and ethyl acetate.

[0125] The term “drug load” (DAR) is denoted by y, which is the average number of cytotoxic drugs per antibody in formula (I). The drug load range in the present invention can be 1-20 cytotoxic drugs (D) per antibody. Antibody-drug conjugates of general formula (A) are collections of antibodies conjugated with a range of cytotoxic drugs (1-20). The drug load (DAR) in antibody-drug conjugates from the conjugation reaction can be characterized by conventional methods such as mass spectrometry, HPLC, and ELISA. These methods allow for the quantitative distribution of the antibody-drug conjugate on the -value.

[0126] In one embodiment of this disclosure, a cytotoxic drug is coupled to the N-terminal amino group, the s-amino group of a lysine residue, and / or the thiol group of an antibody or its antigen-binding fragment via a linker unit. Generally, the number of drug molecules that can be coupled to the antibody in the coupling reaction will be less

[0127] 16 CIE25B0191PCTthan the theoretical maximum value.

[0128] The load of cytotoxic drugs can be controlled using the following non-limiting methods, including:

[0129] (1) Controlling the molar ratio of the ligation reagent and the monoclonal antibody. (2) Controlling the reaction time and temperature.

[0130] (3) Choosing different reaction reagents.

[0131] “Optional” or “optionally” means that the event or circumstances described thereafter may, but do not have to, occur, including the circumstances in which the event or circumstances may or may not occur. For example, “optionally comprises 1-3 antibody heavy chain variable regions” means that the antibody heavy chain variable regions of a particular sequence may, but do not have to, be present.

[0132] The term “overall survival (OS)” refers to the period from randomization to death from any cause. For subjects still alive at the final follow-up, their OS is censored as of time of the final follow-up. For subjects lost to follow-up, their OS is censored as of the time of the last confirmed survival prior to loss to follow-up. Data censored OS is defined as the time from randomization to censoring.

[0133] The term “objective response rate (ORR)” refers to the proportion of patients whose tumors shrink to a certain extent and remain so for a certain period of time, including cases of CR and PR. The RECIST 1.1 criteria for evaluating response in solid tumors are used to assess objective response. Subjects must have measurable tumor lesions at baseline. The efficacy assessment criteria, according to RECIST 1.1, are categorized as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).

[0134] The term “complete response (CR)” means that all target lesions have disappeared and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10 mm.

[0135] The term “partial response (PR)” refers to a reduction of at least 30% in the sum of the diameters of the target lesions compared to the baseline level.

[0136] The term “progressive disease (PD)” refers to a relative increase of at least 20% in the sum of the diameters of all target lesions measured throughout the entire experimental study, taking as reference the smallest sum of the diameters (or the baseline value if this is the smallest); in addition, the absolute value of the sum of the diameters must increase by at least 5 mm (the appearance of one or more new lesions is also considered progressive disease).

[0137] The term “stable disease (SD)” refers to a state in which the reduction in target lesions does not reach the PR level, nor does the increase reach the PD level, instead falling between the two. The smallest sum of diameters can serve as a reference while under study.

[0138] The term “progression-free survival (PFS)” refers to the time from randomization to the date of first recorded objective tumor progression or to death from any cause,

[0139] 17 CIE25B0191PCTwhichever comes first. Assessed according to RECIST 1.1 criteria, analysis of this endpoint includes tumor evaluation results during study treatment and follow-up. If a patient has several endpoints that qualify as PD, such as recurrence, new lesions, or death, the earliest endpoint is used in the PFS analysis. Switching to other treatment regimens or targeted anti-tumor therapy is also considered tumor progression and is treated as censored data.

[0140] The term “time to treatment failure (TTF)” refers to the time from randomization until disease progression or death or termination of the study due to toxicity, including patient withdrawal.

[0141] The present application will be explained in more detail herein with reference to examples. The examples of the present application are only used to illustrate the technical solutions of the present application and are not intended to limit the substance and scope of the present application.

[0142] Example 1. Phase II clinical study of the efficacy and safety of injectable anti-B7H3 antibody-drug conjugates in patients with solid tumors such as head and neck squamous cell carcinoma.

[0143] 1. Investigational drug

[0144] Anti-B7H3 antibody-drug conjugate for injection. Production date: Mar 8, 2023, Expiry date: Mar 7, 2025, Lot no.: P2304, Dosage form: powder for injection, Strength: o.i g.

[0145] 2. Subject inclusion criteria

[0146] Males or females aged 18 years or older (>18 years). Pathologically confirmed relapsed / metastatic squamous cell carcinoma of the head and neck progressing after or unable to tolerate standard treatment. Subjects were required to have at least one target lesion according to RECIST 1.1.

[0147] 3. Administration regimen

[0148] The drug was administered via intravenous infusion at a dose of 8.0 mg / kg. The initial infusion was given over at least 90 minutes (including flushing). Subsequent infusions could be adjusted based on the subject’s tolerance, but could not last less than 30 minutes (including flushing).

[0149] Treatment duration: once every 3 weeks, with 21 days as one treatment cycle, until objective disease progression or other criteria for termination of study treatment as specified in the protocol were met.

[0150] 4. Study endpoints

[0151] Primary study endpoint:

[0152] 18 CIE25B0191PCTTumor imaging assessments were performed every 6 weeks for the first 24 weeks after initial administration, and every 12 weeks starting from week 25, until disease progression or other criteria for discontinuing study treatment were met. Objective response rate (ORR) was assessed according to RECIST 1.1 criteria.

[0153] Secondary study endpoints:

[0154] Tumor imaging assessments were performed every 6 weeks for the first 24 weeks after initial administration, and every 12 weeks starting from week 25, until disease progression or other criteria for discontinuing study treatment were met. Disease control rate (DCR), duration of response (DoR), and progression-free survival (PFS) were assessed according to RECIST 1.1 criteria.

[0155] Safety of the intravenously injected anti-B7H3 antibody-drug conjugate throughout the entire study period, up until 90 days after the patient’s final dose.

[0156] 5. Study results

[0157] A total of 43 patients with head and neck squamous cell carcinoma were enrolled from the first informed consent on December 4, 2023 up to August 23, 2024. All subjects had previously received platinum-based chemotherapy and PD-1 / PD-L1 immunotherapy, with a median of two lines of anti-tumor therapy. All enrolled subjects were intravenously administered 8 mg / kg of anti-B7H3 antibody-drug conjugate, with 36 subjects completing at least one efficacy evaluation.

[0158] The efficacy results are shown in Figure 1. The bars represent the optimal depth of response at the target lesion in 36 subjects. Statistical analysis revealed 12 cases of PR, 17 cases of SD, and 7 cases of PD (including two cases with new lesions). ORR was 33.3%, DCR 80.6%, 3-month DOR 100%, 6-month OS 70.1%, and median PFS 2.9 months. A definite antitumor effect was observed in patients with relapsed or metastatic head and neck squamous cell carcinoma.

[0159] Safety: The safety analysis set included 43 patients with head and neck squamous cell carcinoma. The most common (overall incidence >15%) adverse events related to the study drug were, in descending order: anemia (55.8%), decreased white blood cell count (51.2%), decreased neutrophil count (44.2%), decreased appetite (27.9%), decreased lymphocyte count (25.6%), hypoalbuminemia (23.3%), nausea (23.3%), fever (23.3%), asthenia (20.9%), and elevated serum alkaline phosphatase (16.3%). The main adverse events primarily involved hematological toxicity, metabolic toxicity, and nutritional toxicity. Overall safety was manageable, and safety events were predictable and manageable.

[0160] Example 2. Phase III clinical study of the efficacy and safety of injectable anti-B7H3 antibody-drug conjugates in patients with solid tumors such as head and neck squamous cell carcinoma.

[0161] 19 CIE25B0191PCT1. Investigational drug

[0162] Trial group: Anti-B7H3 antibody-drug conjugate for injection. Dosage form: Injection (lyophilized powder), Strength: 100 mg / vial, packaged in 20 mL borosilicate glass vials.

[0163] Control group: cetuximab, methotrexate, or docetaxel monotherapy; see the corresponding drug package inserts for details of dosage form / strengths.

[0164] 2. Subject inclusion criteria

[0165] (1) Males or females aged 18 years or older (>18 years of age).

[0166] (2) Pathologically confirmed relapsed / metastatic squamous cell carcinoma of the head and neck. Specific requirements were as follows:

[0167] a. Relapsed or metastatic disease not suited to radical therapy;

[0168] b. Primary tumor located in the oral cavity, oropharynx, hypopharynx, or larynx; c. Relapsed or metastatic disease progressing after receiving standard treatment that included platinum-based chemotherapy and PD-1 / PD-L1 immunotherapy. For patients receiving platinum-based chemotherapy or PD-1 / PD-L1 immunotherapy as part of multimodal therapy for locally advanced tumors, if disease progression occurred within 6 months of the last platinum-based chemotherapy or PD-1 / PD-L1 immunotherapy, this was regarded as having received platinum-based chemotherapy or PD-1 / PD-L1 immunotherapy and counted as a line of treatment. The total number of lines of treatment for relapsed or metastatic disease could not exceed two.

[0169] (3) Subjects having at least one target lesion according to RECIST 1.1, the criteria for a target lesion being: a measurable lesion that has not undergone local treatment such as irradiation, or has clearly progressed after local treatment, with a baseline longest diameter >10 mm (or a highest short diameter >15 mm for lymph nodes). Brain lesions alone were not accepted as target lesions.

[0170] 3. Administration regimen

[0171] Trial group (anti-B7H3 antibody-drug conjugate)

[0172] Subjects received intravenous infusion of the anti-B7H3 antibody-drug conjugate at a dose of 8.0 mg / kg once every 3 weeks (Q3W), with each treatment cycle lasting 21 days, until objective disease progression or other prescribed criteria for discontinuation of study treatment were met.

[0173] According to the recommended dosage adjustment principles, a dose reduction was implemented if the criteria for dose reduction were met, where the levels of dose reduction were: 8.0 mg / kg initial dose, reduced at first to 7.0 mg / kg, and then again to 6.0 mg / kg (the lowest reduced dose).

[0174] Control group (receiving a therapeutic agent chosen by the investigator)

[0175] Subjects received an investigator-selected therapeutic agent (cetuximab,

[0176] 20 CIE25B0191PCTmethotrexate, or docetaxel monotherapy) continuously until disease progression or other criteria for discontinuation of treatment were met. The specific regimen and duration of treatment followed the package inserts of the investigator-selected treatment.

[0177] 4. Study endpoints

[0178] Primary study endpoint:

[0179] Overall survival (OS) of patients receiving injectable anti-B7H3 antibody-drug conjugate versus an investigator-selected treatment in relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) that progresses after standard therapy.

[0180] Secondary study endpoints:

[0181] Other endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and progression -free survival (PFS) of patients receiving injectable anti-B7H3 antibody-drug conjugate versus an investigator-selected treatment in relapsed or metastatic HNSCC that progressed after standard therapy.

[0182] Safety of injectable anti-B7H3 antibody-drug conjugates compared with investigator- selected treatments in patients with relapsed or metastatic HNSCC that progressed after standard therapy.

[0183] All references cited herein are incorporated by reference as if each individual publication, patent application, or patent were expressly and individually indicated by reference. References herein do not imply an admission that the references are relevant prior art, nor do they constitute any admission of the content or dates of such publications or documents. To the extent that the definitions of terms provided in the references conflict with those provided in the description of this invention, the definitions provided in the description shall be used to interpret the claimed invention.

[0184] 21 CIE25B0191PCT

Claims

Claims1. A use as shown in either (1) or (2) below:(1) an antibody-drug conjugate being used for the prevention and / or treatment of head and neck cancer;(2) a use of an antibody-drug conjugate for preparing a drug for the treatment of head and neck cancer;the use comprising administering to a patient a therapeutically effective amount of the antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of any of the foregoing, wherein the antibody-drug conjugate has the structure shown in formula (I):wherein:n is 1 to 10, preferably 2 to 8, more preferably 3 to 8, and is a decimal or an integer.Pc is anti-B7H3 antibody or its antigen-binding fragment.

2. The use as recited in claim 1, wherein the anti-B7H3 antibody or its antigenbinding fragment comprises heavy chains HCDR1, HCDR2, and HCDR3 as shown in the amino acid sequences of SEQ ID NOs 01, 02, and 03, respectively, and light chains LCDR1, LCDR2, and LCDR3 as shown in the amino acid sequences of SEQ ID NOs 04, 05, and 06, respectively.

3. The use as recited in claim 1 or 2, wherein the anti-B7H3 antibody or its antigenbinding fragment is selected from humanized antibodies or fragments thereof.

4. The use as recited in claim 3, the anti-B7H3 antibody or its antigen-binding fragment comprising a human IgGl, IgG2, IgG3, or IgG4 isotype heavy chain constant region, and a K or / light chain constant region; preferably, the anti-B7H3 antibody or its antigen-binding fragment comprises an IgGl or IgG4 isotype heavy chain constant region.

5. The use as recited in claim 3, wherein the anti-B7H3 antibody or its antigenbinding fragment comprises a heavy chain variable region and a light chain variable22 CIE25B0191PCTregion, wherein the heavy chain variable region sequence comprises the sequence shown in SEQ ID NO: 07 or a variant thereof, and the light chain variable region sequence comprises the sequence shown in SEQ ID NO: 08 or a variant thereof.

6. The use as recited in any one of claims 1 to 5, wherein the anti-B7H3 antibody or its anti gen -binding fragment comprises a heavy chain and a light chain, wherein the heavy chain sequence comprises the sequence shown in SEQ ID NO: 09 or a variant thereof, and the light chain sequence comprises the sequence shown in SEQ ID NO: 10 or a variant thereof.

7. The use as recited in any one of claims 1-6, wherein the route of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from administration by intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal injection, and is preferably administration by intravenous injection.

8. The use as recited in any one of claims 1-6, wherein the frequency of administration of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing is selected from once a week, once every two weeks, once every three weeks, once every four weeks or once every six weeks, and is preferably once every two weeks or once every three weeks.

9. The use as recited in any one of claims 1-6, wherein the amount of the antibodydrug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing administered is 1.0 mg / kg to 16.0 mg / kg, preferably 2.0 mg / kg to 14.0 mg / kg, and more preferably 4.0 mg / kg to 12.0 mg / kg.

10. The use as recited in claim 9, wherein the amount of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing administered is selected from 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7.0 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8.0 mg / kg, 8.1 mg / kg, 8.2 mg / kg, 8.3 mg / kg, 8.4 mg / kg, 8.5 mg / kg, 8.6 mg / kg, 8.7 mg / kg, 8.8 mg / kg, 8.9 mg / kg, 9.0 mg / kg, 9.1 mg / kg, 9.2 mg / kg, 9.3 mg / kg, 9.4 mg / kg, 9.5 mg / kg, 9.6 mg / kg, 9.7 mg / kg, 9.8 mg / kg, 9.9 mg / kg, 10.0 mg / kg, 10.1 mg / kg, 10.2 mg / kg, 10.3 mg / kg, 10.4 mg / kg, 10.5 mg / kg, 10.6 mg / kg, 10.7 mg / kg, 10.8 mg / kg,23 CIE25B0191PCT10.9 mg / kg, 11.0 mg / kg, 11.1 mg / kg, 11.2 mg / kg, 11.3 mg / kg, 11.4 mg / kg, 11.5 mg / kg, 11.6 mg / kg, 11.7 mg / kg, 11.8 mg / kg, 11.9 mg / kg, or 12.0 mg / kg, preferably 6.0 mg / kg, 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg or 10.0 mg / kg.

11. The use as recited in any of claims 7-10, wherein a patient is administered an intravenous injection of 6.0 mg / kg, 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg or 10.0 mg / kg of the antibody-drug conjugate, the pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or the solvate of any of the foregoing once every two or three weeks.

12. The use as recited in any of claims 1-11, wherein the head and neck cancer is selected from head and neck squamous cell carcinoma, preferably relapsed or metastatic head and neck squamous cell carcinoma, and more preferably relapsed or metastatic head and neck squamous cell carcinoma that has progressed after standard treatment.

13. The use as recited in any one of claims 1-11, wherein the patient is a patient with head and neck squamous cell carcinoma, preferably a patient with relapsed or metastatic head and neck squamous cell carcinoma, and more preferably a patient with relapsed or metastatic head and neck squamous cell carcinoma that has progressed after standard treatment.

14. The use as recited in claim 12 or 13, wherein the standard treatment comprises platinum-based chemotherapy and PD-1 / PD-L1 immunotherapy.

15. The use as recited in any one of claims 1-14, wherein the patient exhibits an improved result after administration;preferably, said exhibiting an improved result after administration is exhibiting an improved objective response rate (ORR), an improved disease control rate (DCR), an improved progress! on -free survival (PFS) or an improved overall survival (OS) after administration.24 CIE25B0191PCT

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