Combination therapy for cancer treatment

Abstract

The present invention provides a combination of: (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof. The present invention provides use of the combination in treating cancer, in particular endometrial cancer.

Description

[0001] COMBINATION THERAPY FOR CANCER TREATMENT

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a combination for use in treating cancer, in particular endometrial cancer.

[0004] BACKGROUND TO THE INVENTION

[0005] Epidermal growth factor receptor 2 (EGFR2 or HER2) has shown gene amplification / over-expression in more than 30% of all human cancers, including breast cancer, gastric, colon, salivary gland, bladder, and uterine serous carcinoma and its overexpression in tumours is associated with poor prognosis.

[0006] The clinical application of HER2-targeted therapy has improved the outcome of patients that have HER2 amplified / overexpressing tumours. However, not all patients with HER2 positive tumours respond well to current therapies. Resistance towards HER2-targeting therapies is common, occurring as either intrinsic or acquired resistance. Furthermore, the current approved drugs mainly focus on breast cancer and gastric cancer and for HER2 positive cancers beyond breast cancer and gastric cancer including heavily treated patients, there is no HER2-targeting drug approved and still lacks effective treatment.

[0007] Endometrial cancer is one of the most common cancers of the female genital tract. According to the GLOBOCAN cancer statistics, in 2020, there are an estimated 417,367 new cases and 97,370 deaths attributed to endometrial cancer worldwide. Once disease relapses, the prognosis is poor, with a 5-year survival rate of less than 50% for patients with lymph node metastases and less than 20% for patients with peritoneal or distant metastases. HER2 overexpression and / or gene amplification is present in approximately 25% to 30% of endometrial serous carcinomas. Uterine serous carcinoma (USC) is an aggressive type of endometrial cancer, and accounts for 10% to 15% of endometrial cancer. In about one-third of women with USC, their tumour cells overproduce HER2.

[0008] There remains an unmet need for safe and effective treatments, and novel treatment approaches are needed for HER2-expressing cancers, for example endometrial cancer.SUMMARY OF THE INVENTION

[0009] The present invention provides a combination therapy which has particularly advantageous and surprising properties. In particular, the combination therapy according to the invention may be particularly effective at treating cancers, such as HER2-expressing cancers, for example endometrial cancer.

[0010] In one aspect, the present invention provides a combination of: (a) an anti-HER2 antibodydrug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

[0011] In another aspect, the present invention provides a combination of: (a) an anti-HER2 antibodydrug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof, for use in therapy.

[0012] In another aspect, the present invention provides a combination of: (a) an anti-HER2 antibodydrug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof, for use in treating cancer.

[0013] In another aspect, the present invention provides an anti-HER2 antibody-drug conjugate for use in therapy, wherein the use comprises administering to a subject: (a) the anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

[0014] In another aspect, the present invention provides an anti-HER2 antibody-drug conjugate for use in treating cancer in a subject, wherein the use comprises administering to the subject: (a) the anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

[0015] In another aspect, the present invention provides an anti-PD-1 / PD-L1 antibody or fragment thereof for use in therapy, wherein the use comprises administering to a subject: (a) an anti-HER2 antibody-drug conjugate; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof.

[0016] In another aspect, the present invention provides an anti-PD-1 / PD-L1 antibody or fragment thereof for use in treating cancer in a subject, wherein the use comprises administering to the subject: (a) an anti-HER2 antibody-drug conjugate; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof.

[0017] In another aspect, the present invention provides use of a combination of (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof, in the manufacture of a medicament.In another aspect, the present invention provides use of a combination of (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof, in the manufacture of a medicament for treating cancer.

[0018] In another aspect, the present invention provides use of an anti-HER2 antibody-drug conjugate in the manufacture of a medicament, the use comprising administering to a subject: (a) the anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

[0019] In another aspect, the present invention provides use of an anti-HER2 antibody-drug conjugate in the manufacture of a medicament for treating cancer in a subject, the use comprising administering to the subject: (a) the anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

[0020] In another aspect, the present invention provides use of an anti-PD-1 / PD-L1 antibody or fragment thereof in the manufacture of a medicament, the use comprising administering to a subject: (a) an anti-HER2 antibody-drug conjugate; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof.

[0021] In another aspect, the present invention provides use of an anti-PD-1 / PD-L1 antibody or fragment thereof in the manufacture of a medicament for treating cancer in a subject, the use comprising administering to the subject: (a) an anti-HER2 antibody-drug conjugate; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof.

[0022] In another aspect, the present invention provides use of a combination of (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof in therapy.

[0023] In another aspect, the present invention provides use of a combination of (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof in treating cancer.

[0024] In another aspect, the present invention provides use of an anti-HER2 antibody-drug conjugate in therapy, the use comprising administering to a subject: (a) the anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

[0025] In another aspect, the present invention provides use of an anti-HER2 antibody-drug conjugate in treating cancer in a subject, the use comprising administering to the subject: (a)the anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

[0026] In another aspect, the present invention provides use of an anti-PD-1 / PD-L1 antibody or fragment thereof in therapy, the use comprising administering to a subject: (a) an anti-HER2 antibody-drug conjugate; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof.

[0027] In another aspect, the present invention provides use of an anti-PD-1 / PD-L1 antibody or fragment thereof in treating cancer in a subject, the use comprising administering to the subject: (a) an anti-HER2 antibody-drug conjugate; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof.

[0028] In another aspect, the present invention provides a method of treating cancer in a subject, the method comprising administering to the subject: (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

[0029] In another aspect, the present invention provides a kit-of-parts comprising (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

[0030] In another aspect, the present invention provides a composition comprising (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

[0031] The anti-HER2 antibody-drug conjugate and the anti-PD-1 / PD-L1 antibody or fragment thereof may be any described herein.

[0032] In some embodiments, the anti-HER2 antibody-drug conjugate has a structure shown as formula (I):

[0033]

[0034] (i)or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0035] q is a connection number and is an integer from 1 to 16;

[0036] L is -La-Lb-Lc-;

[0037] La- is

[0038] - Lb- is:

[0039] H? H?

[0040] N A N A N N H H

[0041]

[0042] -Lc- is -CH2-;

[0043] U is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0044] V is selected from the group consisting of: (C1-6) alkylene, (C3-10) cycloalkylene, or (C1-6) alkylene-(C3-10) cycloalkylene;

[0045] R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; and

[0046] each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

[0047] In some embodiments, the anti-HER2 antibody-drug conjugate has a structure shown as formula (II):Trastuzumabb

[0048]

[0049] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0050] the connection number q is an integer from 1 to 16;

[0051] I— iS -La-Lb-Lc”,

[0052] La- is

[0053]

[0054] -Lc- is -CH2-;

[0055] X1is saturated C, and X1is substituted with Rn;

[0056] ring A is selected from the group consisting of: 3-10 membered saturated or partially unsaturated heterocyclyl and 3-10 membered saturated or partially unsaturated carbocyclyl, wherein ring A is substituted with 0 or at least 1 substituent R1a;

[0057] when ring A is 3-10 membered saturated or partially unsaturated carbocyclyl, ring A is substituted with p L2, and L2is not Rn;

[0058] or, when ring A is 3-10 membered saturated or partially unsaturated heterocyclyl, ring A is substituted with p L2;

[0059] L2is -R2-L3-, and R2is used for direct or indirect linking of a ligand;

[0060] L3is -(C(R3a)(R3b))m-, wherein when L3comprises a methylene unit, 0 or at least 1 methylene unit of L3is independently replaced by -N(R4)C(O)-, -C(O)N(R4)-, -C(O)-, -OC(O)-, -C(O)O-, -NR4-, -0-, -S-, -SO-, -SO2-, -P(R4)-, -P(=O)(R4)-, -N(R4)SO2-, -SO2N(R4)-, -C(=S)-, -C(=NR4)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;

[0061] R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0062] L1is -(C(R5a)(R5b))n-, wherein when L1comprises a methylene unit, 0 or at least 1 methylene unit of L1is independently replaced by -N(R6)C(O)-, -C(O)N(R6)-, -C(O)-, -OC(O)-, -C(O)O-, -NR6-, -O-, -S-, -SO-, -SO2-, -P(R6)-, -P(=O)(R6)-, -N(R6)SO2-, -SO2N(R6)-, -C(=S)-, -C(=NR6)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;

[0063] wherein each R1a, each R2a, each R3a, each R3b, each R4, each R5a, each R5b, each R6and each Rnare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a Ci-6aliphatic group optionally substituted with R;

[0064] wherein each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6 aliphatic group; and m and n are each independently selected from the group consisting of integers > 0, and p is an integer ≥ 1.

[0065] In some embodiments, the anti-HER2 antibody-drug conjugate has the structure represented by formula (III):

[0066] Trastuzumab

[0067]

[0068] (HI) wherein the connection number q is an integer from 1 to 16;

[0069] R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0070] R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6 aliphatic group optionally substituted with R; andeach R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

[0071] In some embodiments, the anti-HER2 antibody-drug conjugate has the structure represented by formula (IV):

[0072] Trastuzumab

[0073]

[0074] (IV) wherein the connection number q is an integer from 1 to 16. In some embodiments, is an integer from 4 to 12, preferably wherein q is an integer from 6 to 10, more preferably wherein q is an integer from 7 to 9. In some embodiments, the anti-HER2 antibody-drug conjugate is in the form of a composition comprising one or more anti-HER2 antibody-drug conjugates.

[0075] In some embodiments, the anti-HER2 antibody-drug conjugate is trastuzumab pamirtecan, also known as BNT323 or DB-1303.

[0076] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is not a bispecific antibody comprising (i) an antibody or fragment thereof that specifically binds to PD-L1 and (i) an antibody or fragment thereof that specifically binds to VEGF. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is not a bispecific antibody comprising (i) an antibody or fragment thereof that specifically binds to PD-1 or PD-L1 and (ii) an antibody or fragment thereof that specifically binds to VEGF. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is not a bispecific antibody comprising an antibody or fragment thereof that specifically binds to VEGF.

[0077] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment is selected from: dostarlimab or a fragment thereof, pembrolizumab or a fragment thereof, nivolumab or a fragment thereof, cemiplimab or a fragment thereof, atezolizumab or a fragment thereof, durvalumab or a fragment thereof, or avelumab or a fragment thereof.In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment is an anti-PD-1 antibody or fragment thereof.

[0078] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof comprises: (i) a heavy chain variable region comprising: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 21; and a light chain variable region comprising: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 23; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, wherein the CDRs are defined according to the Kabat numbering system; and / or (ii) a heavy chain variable region comprising: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 25; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and a light chain variable region comprising: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 28; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 30, wherein the CDRs are defined according to the IMGT numbering system.

[0079] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof comprises: (i) a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 31 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and (ii) a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 32 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

[0080] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof comprises: (i) a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 35 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and (ii) a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

[0081] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof comprises two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 35; and two light chains comprising or consisting of the amino acid sequence of SEQ ID NO: 36.In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is dostarlimab.

[0082] In some embodiments, the anti-HER2 antibody-drug conjugate has the structure represented by formula (IV):

[0083] Trastuzumab

[0084]

[0085] (IV) wherein the connection number q is an integer from 1 to 16. In some embodiments, is an integer from 4 to 12, preferably wherein q is an integer from 6 to 10, more preferably wherein q is an integer from 7 to 9; and the anti-PD-1 / PD-L1 antibody or fragment thereof comprises two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 35; and two light chains comprising or consisting of the amino acid sequence of SEQ ID NO: 36.

[0086] In some embodiments, the anti-HER2 antibody-drug conjugate is trastuzumab pamirtecan and the anti-PD-1 / PD-L1 antibody or fragment thereof is dostarlimab.

[0087] The anti-HER2 antibody-drug conjugate and anti-PD-1 / PD-L1 antibody or fragment thereof may be administered to any subject in need thereof. In some embodiments, the subject is a human subject. In some embodiments, the subject is an adult human subject. In some embodiments, the subject may suffer from and / or have been diagnosed with one or more cancer(s). In some embodiments, the one or more cancers are HER2-expressing cancers. In some embodiments, the one or more cancers are selected from endometrial cancer, lung cancer, kidney cancer, urinary tract carcinoma, colorectal cancer, prostatic cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, and esophageal cancer. In preferred embodiments, the cancer is endometrial cancer. In preferred embodiments, the cancer is proficient mismatch repair (pMMR) endometrial cancer. In preferred embodiments, the cancer is recurrent or primary advanced endometrial cancer. In more preferred embodiments, the cancer is pMMR, recurrent or primary advanced HER2-expressing endometrial cancer. In some embodiments, the subject has been previously treated for the cancer. In some embodiments, the subject hasbeen previously treated for the cancer with carboplatin, paclitaxel, and a PD-1 / PD-L1 inhibitor (e.g. dostarlimab). In some embodiments, following treatment with carboplatin, paclitaxel, and a PD-1 / PD-L1 inhibitor (e.g. dostarlimab) the subject achieved complete response (CR), partial response (PR), or stable disease (SD), for example determined by imaging, according to RECIST version 1.1.

[0088] The anti-HER2 antibody-drug conjugate and anti-PD-1 / PD-L1 antibody or fragment thereof may be administered by any suitable route and in any suitable dosage. In some embodiments, the anti-HER2 antibody-drug conjugate and anti-PD-1 / PD-L1 antibody or fragment thereof are administered separately. In some embodiments, the anti-HER2 antibody-drug conjugate and anti-PD-1 / PD-L1 antibody or fragment thereof are each administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, excipients or diluents. In some embodiments, the anti-HER2 antibody-drug conjugate is administered intravenously, preferably wherein the anti-HER2 antibody-drug conjugate is administered by IV infusion. In some embodiments, the anti-HER2 antibody-drug conjugate is administered every 3 weeks. In some embodiments, the anti-HER2 antibody-drug conjugate is administered in a dosage of from 2.2 mg / kg to 12.0 mg / kg, preferably from 6.0 mg / kg to 10.0 mg / kg, or about 8.0 mg / kg. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is administered intravenously, preferably wherein the anti-PD-1 / PD-L1 antibody or fragment thereof is administered by IV infusion. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is administered every 6 weeks. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is administered in a dosage of from 500 mg to 2000 mg, preferably from 800 mg to 1200 mg, or about 1000 mg.

[0089] BRIEF DESCRIPTION OF THE DRAWINGS

[0090] Figure 1 - Schematic flow diagram of Phase III, randomized, double-blind trial of Compound 1 plus dostarlimab versus placebo plus dostarlimab in participants with pMMR, recurrent or primary advanced HER2-expressing endometrial cancer. Participants can receive Compound 1 or placebo + dostarlimab for up to 24 months. Continued treatment beyond 24 months will be at the discretion of the investigator and sponsor. Abbreviations: BICR = blinded independent central review; CR = complete response; DoR = duration of response; HER2 = human epidermal growth factor receptor 2; IHC = immunohistochemistry; n = number of participants; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; pMMR = mismatch repair-proficient; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumours; SD = stable disease.DETAILED DESCRIPTION OF THE INVENTION

[0091] General Definitions

[0092] This disclosure is not limited by the exemplary methods and materials disclosed herein, and any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of this disclosure.

[0093] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0094] The terms "comprising", "comprises" and "comprised of" as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The terms "comprising", "comprises" and "comprised of" also include the term "consisting of".

[0095] Numeric ranges are inclusive of the numbers defining the range. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within this disclosure. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within this disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in this disclosure.

[0096] In the context of the present disclosure, the term "about" denotes an interval of accuracy that the person of ordinary skill will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value by ±10%, such as ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, and for example ±0.01%. As will be appreciated by the person of ordinary skill, the specific such deviation for a numerical value for a given technical effect will depend on the nature of the technical effect. For example, a natural or biological technical effect may generally have a larger such deviation than one for a man-made or engineering technical effect. The term “about” allows to account for technicalmeasurement uncertainty and variations when referring for example to a particular quantity or concentration.

[0097] The term “polypeptide” is used in the conventional sense to mean a series of amino acids, typically L-amino acids, connected one to the other, typically by peptide bonds between the a-amino and carboxyl groups of adjacent amino acids. The term “polypeptide” is used interchangeably with the terms “amino acid sequence”, “peptide” and / or “protein”. The term “residues” is used to refer to amino acids in an amino acid sequence. Unless otherwise indicated, amino acid sequences are written left to right in amino to carboxy orientation, respectively.

[0098] In the present application, the term "aliphatic group" generally refers to a linear hydrocarbon, branched hydrocarbon or cyclic hydrocarbon having 1 to 12 carbon atoms, and the hydrocarbon may be either a fully saturated hydrocarbon or a hydrocarbon with one or more unsaturated units, but the unsaturated units are not aromatic groups. For example, suitable aliphatic groups may include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl, as defined herein. For example, aliphatic groups have 1 to 12, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms.

[0099] The term "alkyl" refers to a monoradical of a saturated straight or branched hydrocarbon. Preferably, the alkyl group comprises from 1 to 40, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40, carbon atoms, such as 1 to 30, such as 1 to 20 carbon atoms, such as 1 to 12 carbon atoms, such as 1 to 10 carbon atoms, such as 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, iso-propyl (also called 2-propyl or 1 methylethyl), butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2-dimethylpropyl, iso-amyl, n-hexyl, iso-hexyl, sec-hexyl, n-heptyl, iso-heptyl, n-octyl, 2-ethyl-hexyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-icosyl, n-triacontyl, n-tetracontyl, and the like.

[0100] The term "alkylene" refers to a diradical of a saturated straight or branched hydrocarbon. Preferably, the alkylene group comprises from 1 to 40, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40, carbon atoms, such as 1 to 30, such as 1 to 20 carbon atoms, such as 1 to 12 carbon atoms, such as 1 to 10 carbon atoms, such as 1 to 8 carbon atoms, such as 1 to 6 or1 to 4 carbon atoms. Exemplary alkylene groups include methylene, ethylene ( / .e., 1,1-ethylene, 1,2-ethylene), propylene ( / .e., 1,1 -propylene, 1,2-propylene (-CH(CH3)CH2-), 2,2-propylene (-C(CH3)2-), and 1,3-propylene), the butylene isomers (e.g., 1,1-butylene, 1,2-butylene, 2,2-butylene, 1,3-butylene, 2,3-butylene (c / s or trans or a mixture thereof), 1,4-butylene, 1,1 -iso-butylene, 1,2-iso-butylene, and 1,3-iso-butylene), the pentylene isomers (e.g., 1,1 -pentylene, 1,2-pentylene, 1,3-pentylene, 1,4-pentylene, 1,5-pentylene, 1,1-iso-pentylene, 1,1 -sec-pentyl, 1,1-neo-pentyl), the hexylene isomers (e.g., 1,1 -hexylene, 1,2-hexylene, 1,3-hexylene, 1,4-hexylene, 1,5-hexylene, 1,6-hexylene, and 1,1 -isohexylene), the heptylene isomers (e.g., 1,1 -heptylene, 1,2-heptylene, 1,3-heptylene, 1,4-heptylene, 1,5-heptylene, 1,6-heptylene, 1,7-heptylene, and 1,1 -isoheptylene), the octylene isomers (e.g., 1,1 -octylene, 1,2-octylene, 1,3-octylene, 1,4-octylene, 1,5-octylene, 1,6-octylene, 1,7-octylene, 1,8-octylene, and 1,1 -isooctylene), and the like. The straight alkylene moieties having at least 3 carbon atoms and a free valence at each end can also be designated as a multiple of methylene (e.g., 1,4-butylene can also be called tetramethylene). Generally, instead of using the ending "ylene" for alkylene moieties as specified above, one can also use the ending "diyl" (e.g., 1,2-butylene can also be called butan-1,2-diyl).

[0101] The term "alkenyl" refers to a monoradical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Generally, the maximal number of carboncarbon double bonds in the alkenyl group can be equal to the integer which is calculated by dividing the number of carbon atoms in the alkenyl group by 2 and, if the number of carbon atoms in the alkenyl group is uneven, rounding the result of the division down to the next integer. For example, for an alkenyl group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenyl group has 1 to 6 (such as 1 to 4), / .e., 1, 2, 3, 4, 5, or 6, carbon-carbon double bonds. Preferably, the alkenyl group comprises from 2 to 40 carbon atoms, such as 2 to 30 carbon atoms, such as 2 to 20 carbon atoms, such as 2 to 12 carbon atoms, such as 2 to 10 carbon atoms, such as 2 to 8 carbon atoms, such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, the alkenyl group comprises from 2 to 40, such as 2 to 30, such as 2 to 20, such as 2 to 12, such as 2 to 10 carbon atoms and 1, 2, 3, 4, 5, or 6 (e.g., 1, 2, 3, 4, or 5) carbon-carbon double bonds, such as comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds, such as 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon double bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon double bond(s) may be in cis (Z) or trans (E) configuration. Exemplary alkenyl groups include vinyl, 1 -propenyl, 2-propenyl ( / .e., allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1 -pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1 -octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1 -decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1 -undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1 -dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, 11-dodecenyl, and the like.

[0102] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon moiety having at least one carbon-carbon triple bond in which the total carbon atoms may be six to forty, such as six to thirty, typically six to twenty, such as six to eighteen. Alkynyl groups can optionally have one or more carbon-carbon triple bonds. Generally, the maximal number of carboncarbon triple bonds in the alkynyl group can be equal to the integer which is calculated by dividing the number of carbon atoms in the alkynyl group by 2 and, if the number of carbon atoms in the alkynyl group is uneven, rounding the result of the division down to the next integer. For example, for an alkynyl group having 9 carbon atoms, the maximum number of carbon-carbon triple bonds is 4. Preferably, the alkynyl group has 1 to 6 (such as 1 to 4), i.e., 1, 2, 3, 4, 5, or 6, more preferably 1 or 2 carbon-carbon triple bonds.

[0103] The term “carbocyclyl” refers to any group containing a ring of atoms, all of which are carbon atoms. Examples include cycloalkyl groups, as defined herein, and aryl groups, as defined herein.

[0104] The terms "cycloalkyl" represents cyclic non-aromatic versions of "alkyl" with preferably 3 to 40, such as 3 to 30, such as 3 to 20, such as 3 to 14 carbon atoms, such as 3 to 12 or 3 to 10 carbon atoms, i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 3 to 7 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and adamantyl. The cycloalkyl group may consist of one ring (monocyclic), two rings (bicyclic), or more than two rings (polycyclic).

[0105] The term "cycloalkylene" represents cyclic non-aromatic versions of "alkylene" with preferably 3 to 40, such as 3 to 30, such as 3 to 20, such as 3 to 14 carbon atoms, such as 3 to 12 or 3 to 10 carbon atoms, i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 3 to 7 carbon atoms. Exemplary cycloalkylene groups include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene.The term "heterocyclyl" or "heterocyclic ring" means a cycloalkyl group as defined above in which from 1, 2, 3, or 4 carbon atoms in the cycloalkyl group are replaced by heteroatoms of oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur, preferably O, S, or N. A heterocyclyl group has preferably 1 or 2 rings containing from 3 to 10, such as 3, 4, 5, 6, or 7, ring atoms. Preferably, in each ring of the heterocyclyl group the maximum number of O atoms is 1, the 5 maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. The term "heterocyclyl" is also meant to encompass partially or completely hydrogenated forms (such as dihydro, tetrahydro or perhydro forms) of the above-mentioned heteroaryl groups. Exemplary heterocyclyl groups include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl (also called piperidyl), piperazinyl, di- and tetrahydrofuranyl, di- and tetrahydrothienyl, di- and tetrahydropyranyl, urotropinyl, lactones, lactams, cyclic imides, and cyclic anhydrides.

[0106] The term "halogen" generally refers to fluorine, chlorine, bromine or iodine, and it may be, for example, refer to fluorine or chlorine.

[0107] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that such publications constitute prior art to the claims appended hereto.

[0108] Combination therapy

[0109] The present invention provides a combination of: (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

[0110] The combination may be used in therapy. Each component of the combination, i.e., the anti-HER2 antibody-drug conjugate and the anti-PD-1 / PD-L1 antibody or fragment thereof may be administered separately. For example, the combination can be administered sequentially in this order, in reverse order, concomitantly, or combinations thereof.

[0111] In some aspects of the invention, there is provided a combination of: (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof, for use in therapy, the use comprising administering to a subject: (a) the anti-HER2 antibody-drug conjugate; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof.

[0112] In some aspects of the invention, there is provided an anti-HER2 antibody-drug conjugate for use in therapy, the use comprising administering to a subject: (a) the anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.In some aspects of the invention, there is provided an anti-PD-1 / PD-L1 antibody or fragment thereof for use in therapy, the use comprising administering to a subject: (a) an anti-HER2 antibody-drug conjugate; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof.

[0113] Antibodies

[0114] “Antibodies” are glycoproteins belonging to the immunoglobulin superfamily. The term "full-length antibody" may refer to an immunoglobulin molecule that binds to a target molecule and contains four peptide chains: two heavy chains and two light chains which are connected to each other through disulfide bonds.

[0115] Antibodies may comprise several “regions” or “domains” and the terms may be used interchangeably herein. An antibody may recognise an antigen via the fragment antigenbinding (Fab) variable region. The fragment crystallizable region (Fc region) is the tail region of an antibody that may allow antibodies to activate the immune system. The hinge region is a stretch of heavy chains linking the Fab and Fc regions. The heavy chain and light chain may each comprise a variable domain and one or more constant domains. For example, in IgG antibodies, a heavy chain comprises a variable domain (VH) and three constant domains (CH1, CH2, and CH3) and a light chain comprises a variable domain (VL) and one constant domain (CL). Example antibodies include a human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, a monoclonal antibody, and a polyclonal antibody.

[0116] Antibodies described herein include IgA antibodies such as lgA1 or lgA2, IgG antibodies such as lgG1, lgG2, lgG3, or lgG4, IgE antibodies, IgM antibodies, and IgD antibodies. In various embodiments, the antibody is an lgG1 antibody, more particularly an lgG1, kappa or lgG1, lambda isotype (i.e. lgG1, K, A), an lgG2a antibody (e.g. lgG2a, K, A), an lgG2b antibody (e.g. lgG2b, K, A), an lgG3 antibody (e.g. lgG3, K, A) or an lgG4 antibody (e.g. lgG4, K, A). An antibody may be of any species (for example human, monkey, camel, llama, goat, sheep, rabbit, mouse, rat, mouse, hamster or chicken) or it may be a hybrid derived from more than one species. It may be naturally occurring or it may be non-naturally occurring (i.e. an isolated antibody). An antibody may be created by genetic engineering (for example a chimeric antibody, humanised antibody, camelised antibody, intrabody, bispecific antibody).

[0117] The term “antibody fragment” may refer to a fragment of an antibody, or a genetically engineered product of one of more fragments of an antibody, which fragment is involved in binding with the target molecule.Examples of antibody fragments include an antigen-binding fragment (Fab), a Fab', a Fab'-SH, a fragment antibody (F(ab’)2), a variable region (Fv), a single chain variable fragment (scFv), a single-domain antibody (sdAb), a nanobody, a VHH, and a camelid antibody. The term “Antigen-binding fragment” or “Fab” refers to a region of an antibody that binds to antigens and is composed of one constant and one variable region of each of the heavy and the light chain. The term “fragment antibody” or “F(ab’)2” refers to a region of an antibody that remains following digestion of the Fc region while leaving intact some of the hinge region. The term “Fab”’ refers to a fragment formed by the reduction of a F(ab')2 fragment. The term “Fab’-SH” refers to a Fab’ fragment with a free sulfhydryl group. The term “variable region (Fv)” or “Fv” may refer to a region of an antibody consisting of a light chain variable region and a heavy chain variable region. The term “Single chain variable fragment” or “scFv” refers to an engineered antibody consisting of a light chain variable region and a heavy chain variable region which are connected to each other.

[0118] The term “heavy chain” refers to a large protein subunit of an immunoglobulin. Heavy chains can be of any immunoglobulin isotype (for example IgG, IgE, IgM, IgD, IgA or IgY), subtype (for example lgG1, lgG2, lgG2a, lgG2b, lgG2c, lgG3, lgG4, lgA1 or lgA2) or allotype. The term “light chain” refers to a small protein subunit of an immunoglobulin. Light chains can be of any type (for example kappa or lambda), subtype or allotype.

[0119] “Variable regions” as used herein means a segment of an antibody which contains three CDRs, designated CDR1, CDR2 and CDR3. A “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable region of the heavy chain may be referred to as “VH.” The variable region of the light chain may be referred to as “VL.” Typically, the variable regions of both the heavy and light chains comprise three hypervariable regions, the CDRs, which are located within relatively conserved framework regions (FR). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. In general, from N-terminal to C-terminal, both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0120] “CDR” or “CDRs” means complementarity determining region(s) in an immunoglobulin variable region. The variable regions of the heavy and light chains each contain three CDRs, designated CDR1, CDR2 and CDR3. The precise boundaries of these CDRs can be defined according to various numbering systems known in the art (see e.g. Dondelinger, M., et al., 2018. Frontiers in immunology, 9, p.2278), such as the Kabat numbering system (Kabatetal.,Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991; Kabat et al., 1992, Sequences of Proteins of Immunological Interest, DIANE Publishing: 2719), the Chothia numbering system (Chothia & Lesk (1987) J. Mol. Biol. 196:901-917; Chothia etal. (1989) Nature 342:878-883) orthe lMGT numbering system (Lefranc et al., Dev. Comparat.lmmunol.27:55-77, 2003; Ehrenmann F, Kaas Q, Lefranc M P. Nucleic acids research, 2009;38(suppl_1): D301-D307). For a given antibody, those skilled in the art will readily identify the CDRs defined by each numbering system. Also, the correspondence between different numbering systems is well known to those skilled in the art (e.g. see Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003).

[0121] In some embodiments, the CDRs disclosed herein are defined according to the Kabat numbering system. “Kabat,” as used herein, means an immunoglobulin alignment and numbering system pioneered by Elvin Kabat ((1991) Sequences of Proteins of Immunological Interest 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.). In other embodiments, the CDRs disclosed herein are defined according to the IMGT numbering system. The IMGT unique numbering has been defined by Marie-Paule Lefranc, in order to easily compare sequences of IG and TR from all vertebrates species, and, by extension, sequences with an immunoglobulin-like domain (see Lefranc et al., Dev. Comparat. Immunol.27:55-77, 2003).

[0122] “Chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in an antibody derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in an antibody derived from another species (e.g., mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.

[0123] “Humanized antibody” refers to forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence.“Human antibody” refers to an antibody that comprises human immunoglobulin protein sequences only. A human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell. Similarly, “mouse antibody” or “rat antibody” refer to an antibody that comprises only mouse or rat immunoglobulin sequences, respectively.

[0124] The term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies. The individual antibodies composing the population may be identical except for possible naturally occurring mutations, which may be present in minor amounts. Monoclonal antibodies are highly specific and target a single antigenic epitope. In contrast, polyclonal antibody preparations typically include a large number of antibodies which are specific for different epitopes.

[0125] A “single domain antibody” (sdAb) is an antibody composed of a single variable domain (e.g., heavy chain variable region) composed of antibody fragments. Typically, a single domain antibody, domain antibody or nanobody consists of 4 framework regions and 3 complementarity determining regions, the 4 framework regions are respectively FR1-FR4, and the 3 complementarity determining regions are respectively CDR1-CDR3. In certain embodiments, the single domain antibody of the present application may have a structure of FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. These antibodies do not require light chain variable regions to bind antigens with high affinity and specificity. Examples of single-domain antibodies include, but are not limited to, VHH fragments, and VNAR fragments.

[0126] The term “monospecific antibody” refers to antibodies which recognise only one antigen or one epitope. In some embodiments, a “monospecific antibody” refers to an antibody which specifically binds to only one antigen (e.g. PD-1 or PD-L1).

[0127] The term “multispecific antibody” refers to antibodies which recognise two or more epitopes located on the same or distinct targets. Formats of multispecific antibodies can be divided into two broad categories: IgG-like antibody formats, with an Fc domain, and non-IgG-like antibody formats, without an Fc domain (see e.g. Elshiaty, M., et al., 2021. International journal of molecular sciences, 22(11), p.5632). Examples of multispecific antibodies include bispecific and trispecific antibodies.

[0128] Example anti-HER2 and anti-PD-1 / PD-L1 antibody CDRs, variable region sequences, and heavy and light chain sequences are described herein.An “anti-HER2 antibody or fragment thereof” may refer to an antibody or antibody fragment that specifically binds HER2.

[0129] An “anti-PD-1 / PD-L1 antibody or fragment thereof” may refer to an antibody or antibody fragment that specifically binds PD-1 or PD-L1. The term “an anti-PD-1 / PD-L1 antibody or fragment thereof” may refer to “an anti-PD-1 antibody or fragment thereof or an anti-PD-L1 antibody or fragment thereof”, and these terms may be used interchangeably.

[0130] An “anti-PD-1 antibody or fragment thereof” may refer to an antibody or antibody fragment that specifically binds PD-1.

[0131] An “anti-PD-L1 antibody or fragment thereof” may refer to an antibody or antibody fragment that specifically binds PD-L1.

[0132] The terms “selectively binds / selectively binding” and “specifically binds / specifically binding” may be used interchangeably herein. In some embodiments, it will be understood herein that “specifically binds to” refers to the antibody-like binding of the antibody or fragment thereof, which may be via heavy chain complementarity determining regions (HCDRs) 1-3 and light chain complementarity determining regions (LCDRs) 1-3, to the target. Thus, in some embodiments, it will be understood herein that the term “specifically” does not exclude the binding molecule from having other targets.

[0133] An antibody that “specifically binds to” a specified target protein may refer to an antibody that exhibits preferential binding to that target as compared to other proteins, but this specificity does not require absolute binding specificity. An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g., without producing undesired results such as false positives. Antibodies, or fragments thereof, useful in the present invention may bind to the target protein with an affinity that is at least two-fold greater, preferably at least ten times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with non-target proteins. As used herein, an antibody may bind specifically to a polypeptide comprising a given amino acid sequence if it binds to polypeptides comprising that sequence but does not bind to polypeptides lacking that sequence.

[0134] Suitable assays and techniques for measuring / quantifying binding activity of the antibody or fragment thereof as defined herein may include, but are not limited to, ELISA, surface plasmon resonance (SPR), bio-layer interferometry (BLI), quartz crystal microbalance (QCM),bioluminescence assays and flow cytometry. Binding affinity (e.g. a KD value) may be quantitatively determined or measured using methods know in the art, such as by surface plasmon resonance (SPR), for example by using the Biacore® system (e.g. Biacore T200). In addition to the equilibrium dissociation constant (KD), the association rate constant (Ka (1 / Ms)), and the dissociation rate constant (Kd (1 / s)) may also be determined.

[0135] Anti-HER2 antibody-drug conjugates

[0136] The combination therapy of the present invention comprises an antibody-drug conjugate comprising an anti-HER2 antibody or fragment thereof.

[0137] ADCs are a class of targeted therapeutics that improves both the selectivity and the cytotoxic activity of drugs, such as cancer drugs, by targeting the drugs to specific targets such as cancer cells. In general, ADCs comprise three main components: (i) an antibody (such as a monoclonal antibody) conjugated to (ii) a linker, which in turn is also conjugated to (iii) a cargo or payload (such as a cytotoxic or chemotherapeutic drug). A cytotoxic or chemotherapeutic drug may refer to a drug that reduces or eliminates the viability of a cell. Suitable cytotoxic or chemotherapeutic drugs will be known in the art.

[0138] The antibody component and the linker-payload drug component of the antibody-drug conjugate are linked (i.e. conjugated) to each other via the linker as defined herein. Such linkers typically have chemically reactive groups at each end. These linkers can form a covalent attachment between two molecules, e.g. the antibody and the drug. Thus, the antibody and the drug are typically covalently linked via a linker. Suitably, one region of the linker may bind to the antibody and another region of the linker may bind to the drug. In some embodiments, the linker may be a cleavable linker. In some embodiments, the linker may be a maleimide tetrapeptide-based cleavable linker.

[0139] It will be understood by the person skilled in the art that all references in this specification to the term “antibody-drug conjugate” will also include compositions comprising mixtures of antibody-drug conjugates, each which may have different drug-antibody ratios (DARs). These are described in more detail below with reference to compositions. The drug-antibody ratio (DAR) of the antibody-drug conjugates as described herein may vary. Consequently, the composition may comprise a mixture of antibody-drug conjugates having a number of different DARs, and may therefore have an average DAR which is non-integral. In this specification, the terms “DAR” and “connection number” are synonymous, and the terms “average DAR” and “average connection number” are synonymous.It will be understood that the term “DAR” or “connection number” when referring to a specific antibody-drug conjugate refers to the number of drug molecules connected (e.g. conjugated) to the antibody, optionally via linkers, in any single antibody-drug conjugate. Thus, the connection number (referred to herein as “q”) can be considered as the specific number of linker-payload structures conjugated to the antibody in a given antibody-drug conjugate. The number of drug molecules per antibody molecule, also referred to herein as the drug-antibody ratio (DAR), can be characterized by conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA assays and HPLC.

[0140] Suitably, the anti-HER2 antibody-drug conjugate has a structure shown as formula (l-A):

[0141] HO’

[0142]

[0143] q

[0144] (l-A)

[0145] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0146] Ab is trastuzumab;

[0147] q is a connection number and is an integer from 1 to 16;

[0148] L is -La-Lb-Lc‘

[0149] La- is

[0150] o

[0151]

[0152] - Lb- is:

[0153]

[0154] -Lc- is -CH2-;

[0155] U is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0156] V is selected from the group consisting of: (C1-6) alkylene, (C3-10) cycloalkylene, or (C1-6) alkylene-(C3-10) cycloalkylene;

[0157] R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; and

[0158] each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

[0159] In some embodiments, the anti-HER2 antibody-drug conjugate has the structure represented

[0160]

[0161] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0162] Ab is trastuzumab;the connection number q is an integer from 1 to 16;

[0163] L is -La_Lb_Lc",

[0164] La- is

[0165]

[0166] -Lc- is -CH2-;

[0167] X1is saturated C, and X1is substituted with Rn;

[0168] ring A is selected from the group consisting of: 3-10 membered saturated or partially unsaturated heterocyclyl and 3-10 membered saturated or partially unsaturated carbocyclyl, wherein ring A is substituted with 0 or at least 1 substituent R1a;

[0169] when ring A is 3-10 membered saturated or partially unsaturated carbocyclyl, ring A is substituted with p L2, and L2is not Rn;

[0170] or, when ring A is 3-10 membered saturated or partially unsaturated heterocyclyl, ring A is substituted with p L2;

[0171] L2is -R2-L3-, and R2is used for direct or indirect linking of a ligand;

[0172] L3is -(C(R3a)(R3b))m-, wherein when L3comprises a methylene unit, 0 or at least 1 methylene unit of L3is independently replaced by -N(R4)C(O)-, -C(O)N(R4)-, -C(O)-, -OC(O)-, -C(O)O-, -NR4-, -O-, -S-, -SO-, -SO2-, -P(R4)-, -P(=O)(R4)-, -N(R4)SO2-, -SO2N(R4)-, -C(=S)-, -C(=NR4)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;

[0173] R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0174] L1is -(C(R5a)(R5b))n-, wherein when L1comprises a methylene unit, 0 or at least 1 methylene unit of L1is independently replaced by -N(R6)C(O)-, -C(O)N(R6)-, -C(O)-, -OC(O)-, -C(O)O-, -NR6-, -O-, -S-, -SO-, -SO2-, -P(R6)-, -P(=O)(R6)-, -N(R6)SO2-, -SO2N(R6)-, -C(=S)-, -C(=NR6)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;

[0175] wherein each R1a, each R2a, each R3a, each R3b, each R4, each R5a, each R5b, each R6and each Rnare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R;wherein each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6 aliphatic group; and m and n are each independently selected from the group consisting of integers > 0, and p is an integer ≥ 1.

[0176] In some embodiments, the anti-HER2 antibody-drug conjugate has the structure represented by formula (lll-A):

[0177]

[0178] (lll-A) or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0179] Ab is trastuzumab;

[0180] q is a connection number, and is an integer from 1 to 16;

[0181] R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0182] R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6 aliphatic group optionally substituted with R; and

[0183] wherein each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

[0184] In some embodiments, the anti-HER2 antibody-drug conjugate has the structure represented by formula (IV-A):

[0185]

[0186] (IV-A) or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0187] Ab is trastuzumab; and

[0188] q is a connection number, and is an integer from 1 to 16.

[0189] In other embodiments, the anti-HER2 antibody-drug conjugate has a structure represented by formula (V-A):

[0190]

[0191] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0192] Ab is an anti-HER2 antibody or a fragment thereof as defined herein (e.g. trastuzumab); and q is a connection number, and is an integer from 1 to 16.

[0193] In one embodiment, the antibody-drug conjugate is a pharmaceutically acceptable salt thereof. It will be understood that the term “pharmaceutically acceptable salt” has the generally known meaning of an ionic assembly of anions and cations, where one of the ions is the compound used in the present invention and the other ion is a non-toxic counter-ion. Examples ofpharmaceutically acceptable salts are defined herein. In some embodiments, the pharmaceutically acceptable salt may be a sodium salt or a potassium salt. In some embodiments, the pharmaceutically acceptable salt may be a sodium salt. In some embodiments, the pharmaceutically acceptable salt may be a potassium salt.

[0194] In one embodiment, the antibody component and the payload-linker component may take the structures shown herein. In another embodiment, the antibody component and the payloadlinker component of the antibody-drug conjugate may take the form of a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer of any of the structures shown.

[0195] As used herein, the connection number q is an integer from 1 to 16. In some embodiments, the connection number q is selected from the group of integers of: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0196] In some embodiments, the connection number q is an integer from 2 to 16. In some embodiments, the connection number q is an integer from 3 to 15. In some embodiments, the connection number q is an integer from 4 to 14. In some embodiments, the connection number q is an integer from 4 to 13. In some embodiments, the connection number q is an integer from 4 to 12. In some embodiments, the connection number q is an integer from 5 to 11. In some embodiments, the connection number q is an integer from 6 to 10. In some embodiments, the connection number q is an integer from 7 to 9. In some embodiments, the connection number q is 8.

[0197] Human epidermal growth factor receptor 2 (HER2)

[0198] HER2 is a protein that in humans is encoded by the ERBB2 gene and which may also be known as human epidermal growth factor receptor 2 (EGFR2), Receptor tyrosine-protein kinase erbB-2 and CD340 (Cluster of Differentiation 340).

[0199] The HER2 receptor has an important role in normal cell growth and differentiation. However, amplification of the HER2 gene leads to overexpression of the receptor, which is linked to the development of many types of human cancers. When HER2 is overexpressed multiple HER2 heterodimers are formed and cell signalling is stronger, resulting in enhanced responsiveness to growth factors and malignant growth (see Rubin, I. and Yarden, Y., 2001. Annals of oncology, 12, pp. S3-S8).Suitably, the HER2 may be human HER2 (hHER2). An example amino acid sequence for human HER2 is provided by Uniprot reference P04626. In some embodiments, human HER2 comprises or consists of the amino acid sequence of SEQ ID NO: 49:

[0200] MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQV VQGNLELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNY ALAVLDNGDPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILW KDIFHKNNQLALTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGC ARCKGPLPTDCCHEQCAAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFE SMPNPEGRYTFGASCVTACPYNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCS KPCARVCYGLGMEHLREVRAVTSANIQEFAGCKKIFGSLAFLPESFDGDPASNTAP LQPEQLQVFETLEEITGYLYISAWPDSLPDLSVFQNLQVIRGRILHNGAYSLTLQGLG ISWLGLRSLRELGSGLALIHHNTHLCFVHTVPWDQLFRNPHQALLHTANRPEDECV GEGLACHQLCARGHCWGPGPTQCVNCSQFLRGQECVEECRVLQGLPREYVNAR HCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARCPSGVKPDLSYMPI WKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSIISAWGILLVWLGVV FGILIKRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETELRKVKVLG SGAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANKEILDEAYVMAGVGSPYVSRL LGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLEDVRL VHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRR FTHQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIM VKCWMIDSECRPRFRELVSEFSRMARDPQRFWIQNEDLGPASPLDSTFYRSLLED DDMGDLVDAEEYLVPQQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLTLGLEP SEEEAPRSPLAPSEGAGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPL PSETDGYVAPLTCSPQPEYVNQPDVRPQPPSPREGPLPAARPAGATLERPKTLSP GKNGWKDVFAFGGAVENPEYLTPQGGAAPQPHPPPAFSPAFDNLYYWDQDPPE RGAPPSTFKGTPTAENPEYLGLDVPV

[0201] Example human HER2 amino acid sequence (SEQ ID NO: 49)

[0202] Anti-HER2 antibodies and fragments thereof

[0203] In some embodiments, the anti-HER2 antibody-drug conjugate comprises an anti-HER2 antibody or fragment thereof.

[0204] The anti-HER2 antibody or fragment thereof may specifically bind HER2. The anti-HER2 antibody may be a monoclonal antibody. In some embodiments, the anti-HER2 antibody or fragment thereof is a humanized antibody. In some embodiments, the anti-HER2 antibody or fragment thereof is a monoclonal humanized antibody. In some embodiments, the anti-HER2antibody or fragment thereof is a monoclonal humanized I gG 1 antibody. The fragment thereof may be any antigen-binding fragment thereof, for example a Fab, a Fab', a F(ab')2, a Fv, a scFv, a Fab'-SH, an sdAb, or a VHH. In some embodiments, the anti-HER2 antibody or fragment thereof is a full-length anti-HER2 antibody.

[0205] The anti-HER2 antibody or fragment thereof may comprise a variable region that specifically binds HER2. In some embodiments, the anti-HER2 antibody or fragment thereof comprises a heavy chain variable region and / or a light chain variable region. In some embodiments, the anti-HER2 antibody or fragment thereof comprises a heavy chain variable region and a light chain variable region. In some embodiments, the anti-HER2 antibody or fragment thereof comprises a constant region, preferably derived from a human antibody, optionally the constant region is selected from the constant region of human lgG1, lgG2, lgG3 or lgG4. In some embodiments, the constant region is the constant region of a human IgG 1 antibody. In some embodiments, the anti-HER2 antibody or fragment thereof comprises a heavy chain and / or a light chain. In some embodiments, the anti-HER2 antibody or fragment thereof comprises a heavy chain and a light chain. In some embodiments, the anti-HER2 antibody or fragment thereof comprises or consists of two heavy chains and two light chains.

[0206] In some embodiments, the anti-HER2 antibody or fragment thereof is trastuzumab or a fragment thereof. In some embodiments, the anti-HER2 antibody or fragment thereof is trastuzumab. Trastuzumabb (also known as Herceptin®) is an lgG1 humanized monoclonal anti-HER2 antibody. Example trastuzumab CDRs, variable region sequences, and heavy and light chain sequences are provided below.

[0207] Kabat HCDR1 DTYIH (SEQ ID NO: 1)

[0208] Kabat HCDR2 RIYPTNGYTRYADSVKG (SEQ ID NO: 2)

[0209] Kabat HCDR3 WGGDGFYAMDY (SEQ ID NO: 3)

[0210] Kabat LCDR1 RASQDVNTAVA (SEQ ID NO: 4)

[0211] Kabat LCDR2 SASFLYS (SEQ ID NO: 5)

[0212] Kabat LCDR3 QQHYTTPPT (SEQ ID NO: 6)

[0213] IMGT HCDR1 GFNIKDTY (SEQ ID NO: 7)

[0214] IMGT HCDR2 IYPTNGYT (SEQ ID NO: 8)

[0215] IMGT HCDR3 SRWGGDGFYAMDY (SEQ ID NO: 9)

[0216] IMGT LCDR1 QDVNTA (SEQ ID NO: 10)

[0217] IMGT LCDR2 SAS (SEQ ID NO: 11)

[0218] IMGT LCDR3 QQHYTTPPT (SEQ ID NO: 12)

[0219] VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVA RIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRW GGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 13)

[0220] VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYS ASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQ

[0221]

[0222] GTKVEIK (SEQ ID NO: 14)CH human ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV igGl HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 15)

[0223] CL kappa RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC (SEQ ID NO: 16)

[0224] Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVA RIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRW GGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPG (SEQ ID NO: 17)

[0225] Light chain DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYS ASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQ GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL

[0226]

[0227] SSPVTKSFNRGEC (SEQ ID NO: 18)

[0228] In some embodiments, a heavy chain variable region of the anti-HER2 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 1, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 2, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat numbering system.

[0229] In some embodiments, a light chain variable region of the anti-HER2 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat numbering system.In some embodiments, a heavy chain variable region of the anti-HER2 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 1, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 2, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, or a variant thereof having up to three amino acid substitutions, additions or deletions; and a light chain variable region of the anti-HER2 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat numbering system.

[0230] In some embodiments, a heavy chain variable region of the anti-HER2 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 8, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 9, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT numbering system.

[0231] In some embodiments, a light chain variable region of the anti-HER2 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 10, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 11; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 12, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT numbering system.

[0232] In some embodiments, a heavy chain variable region of the anti-HER2 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO:8, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 9, or a variant thereof having up to three amino acid substitutions, additions or deletions; and a light chain variable region of the anti-HER2 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 10, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 11, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 12, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT numbering system.

[0233] In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0234] In some embodiments, a heavy chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 13, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ I D NO: 13.

[0235] In some embodiments, a light chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 14.

[0236] In some embodiments, a heavy chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 13, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity theretoand / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0237] In some embodiments, a heavy chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 13, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 1; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and a light chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6.

[0238] In some embodiments, a heavy chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 13, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 7; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 8; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; and a light chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consistingof the amino acid sequence of SEQ ID NO: 10; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 11; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 12.

[0239] In some embodiments, a heavy chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 13, or an amino acid sequence having at least 98% identity thereto, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 1; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and a light chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 98% identity thereto, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6.

[0240] In some embodiments, a heavy chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 13, or an amino acid sequence having at least 98% identity thereto, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 7; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 8; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; and a light chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 98% identity thereto, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 11; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 12.

[0241] In some embodiments, a heavy chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 13; and a light chain variable region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 14. In some embodiments, a heavy chain variable region of the anti-HER2 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 13; and a light chain variable region of the anti-HER2 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 14.In some embodiments, a heavy chain constant region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 15, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. In some embodiments, a heavy chain constant region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 15.

[0242] In some embodiments, a light chain constant region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto. In some embodiments, a light chain constant region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 16.

[0243] In some embodiments, a heavy chain constant region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 15, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and a light chain constant region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

[0244] In some embodiments, a heavy chain constant region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 15; and a light chain constant region of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 16. In some embodiments, a heavy chain constant region of the anti-HER2 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 15; and a light chain constant region of the anti-HER2 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 16.

[0245] In some embodiments, a heavy chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 17, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 17.

[0246] In some embodiments, a light chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ I D NO: 18.

[0247] In some embodiments, a heavy chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 17, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0248] In some embodiments, a heavy chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 17, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 1; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and a light chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6.

[0249] In some embodiments, a heavy chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 17, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 7; a HCDR2 comprisingor consisting of the amino acid sequence of SEQ ID NO: 8; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; and a light chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 11; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 12.

[0250] In some embodiments, a heavy chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 17, or an amino acid sequence having at least 98% identity thereto, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 1; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and a light chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence having at least 98% identity thereto, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6.

[0251] In some embodiments, a heavy chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 17, or an amino acid sequence having at least 98% identity thereto, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 7; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 8; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; and a light chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence having at least 98% identity thereto, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 11; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 12.In some embodiments, a heavy chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 17; and a light chain of the anti-HER2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 18. In some embodiments, a heavy chain of the anti-HER2 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 17; and a light chain of the anti-HER2 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 18.

[0252] In some embodiments, the anti-HER2 antibody or fragment thereof comprises or consists of two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 17; and two light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-HER2 antibody or fragment thereof comprises or consists of two heavy chains consisting of the amino acid sequence of SEQ ID NO: 17; and two light chains consisting of the amino acid sequence of SEQ ID NO: 18.

[0253] In some embodiments, the anti-HER2 antibody-drug conjugate has a structure shown as

[0254]

[0255] (l)

[0256] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0257] q is a connection number and is an integer from 1 to 16;

[0258] L is -La-Lb-Lc-;

[0259] La- is

[0260]

[0261] -Lc- is -CH2-;

[0262] U is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0263] V is selected from the group consisting of: (C1-6) alkylene, (C3-10) cycloalkylene, or (C1-6) alkylene-(C3-10) cycloalkylene;

[0264] R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; and

[0265] each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

[0266] In preferred embodiments, the antibody-drug conjugate has the structure represented by

[0267]

[0268] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0269] the connection number q is an integer from 1 to 16;

[0270] L is -La-Lb-Lc-;

[0271] La- is

[0272] N

[0273] - Lb- is:

[0274] H N J? L H?

[0275] N N. JL N

[0276] H H

[0277]

[0278] -Lc- is -CH2-;

[0279] X1is saturated C, and X1is substituted with Rn;

[0280] ring A is selected from the group consisting of: 3-10 membered saturated or partially unsaturated heterocyclyl and 3-10 membered saturated or partially unsaturated carbocyclyl, wherein ring A is substituted with 0 or at least 1 substituent R1a;

[0281] when ring A is 3-10 membered saturated or partially unsaturated carbocyclyl, ring A is substituted with p L2, and L2is not Rn;

[0282] or, when ring A is 3-10 membered saturated or partially unsaturated heterocyclyl, ring A is substituted with p L2;

[0283] L2is -R2-L3-, and R2is used for direct or indirect linking of a ligand;

[0284] L3is -(C(R3a)(R3b))m-, wherein when L3comprises a methylene unit, 0 or at least 1 methylene unit of L3is independently replaced by -N(R4)C(O)-, -C(O)N(R4)-, -C(O)-, -OC(O)-, -C(O)O-, -NR4-, -O-, -S-, -SO-, -SO2-, -P(R4)-, -P(=O)(R4)-, -N(R4)SO2-, -SO2N(R4)-, -C(=S)-, -C(=NR4)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;

[0285] R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0286] L1is -(C(R5a)(R5b))n-, wherein when L1comprises a methylene unit, 0 or at least 1 methylene unit of L1is independently replaced by -N(R6)C(O)-, -C(O)N(R6)-, -C(O)-, -OC(O)-, -C(O)O-, -NR6-, -O-, -S-, -SO-, -SO2-, -P(R6)-, -P(=O)(R6)-, -N(R6)SO2-, -SO2N(R6)-, -C(=S)-, -C(=NR6)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;

[0287] wherein each R1a, each R2a, each R3a, each R3b, each R4, each R5a, each R5b, each R6and each Rnare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R;wherein each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6 aliphatic group; and m and n are each independently selected from the group consisting of integers > 0, and p is an integer ≥ 1.

[0288] In preferred embodiments, the antibody-drug conjugate has the structure represented by formula (III):

[0289] Trastuzumab

[0290]

[0291] (HI) or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0292] wherein:

[0293] q is a connection number, and is an integer from 1 to 16;

[0294] R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0295] R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6 aliphatic group optionally substituted with R; and

[0296] wherein each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

[0297] In preferred embodiments, the antibody-drug conjugate has the structure represented by formula (IV):

[0298]

[0299] (IV) or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0300] wherein q is a connection number, and is an integer from 1 to 16.

[0301] In other embodiments, the antibody-drug conjugate has a structure represented by formula (V):

[0302]

[0303] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0304] wherein q is a connection number, and is an integer from 1 to 16.

[0305] Linker-payload, linker and payload moieties

[0306] The moiety of the anti-HER2 antibody-drug conjugate comprises a linker, which is a chemical structural fragment, which is linked to the anti-HER2 antibody or fragment thereof at one end and linked to a cytotoxic drug at the other end, or linked to other linkers and then linked to the cytotoxic drug. The direct or indirect linking of a ligand may mean that the group is directlylinked to the ligand via a covalent bond, and may also be linked to the ligand via a linker structure.

[0307] In some embodiments, the linker is a cleavable linker. In some embodiments, the linker is a maleimide tetrapeptide-based cleavable linker. The linker structure may be a structure shown as -La-Lb-Lc- as defined herein.

[0308] In one embodiment, -La-Lb-Lc- is

[0309]

[0310] The moiety of the anti-HER2 antibody-drug conjugate of formula (II) above contains a drug linked to the anti-HER2 antibody or fragment thereof via linker L. The remaining moieties of the anti-HER2 antibody-drug conjugate, i.e. all those structures including L2and all structures to the right of it in formula (II), are termed “the drug moiety” or “the payload moiety”. In use, the bond between L and L2is cleaved, and L2and all structures to the right of it are released in vivo.

[0311] In some embodiments, X1is saturated C.

[0312] In some embodiments, ring A is 3-10 membered saturated carbocyclyl.

[0313] In some embodiments, ring A is 3-6 membered saturated carbocyclyl.

[0314] In some embodiments, ring A is a 4 membered saturated carbocyclyl.

[0315] In some embodiments, ring A is cis- 1,3-cyclobutyl.

[0316] In some embodiments, ring A is substituted with 0 substituent R1a.

[0317] In some embodiments, n is 1, and L1is -C(R5a)(R5b)-.

[0318] In some embodiments, 1 methylene unit of L1is replaced by -N(R6)C(O)-, -C(O)N(R6)-, -C(O)-, -OC(O)-, -C(O)O-, -NR6-, -O-, -S-, -SO-, -SO2-, -P(R6)-, -P(=O)(R6)-, -N(R6)SO2-, -SO2N(R6)-, -C(=S)-, -C(=NR6)-, -N=N-, -C=N-, -N=C- or-C(=N2)-.In some embodiments, 1 methylene unit of L1is replaced by -C(O)-.

[0319] In some embodiments, n is 1, and 1 methylene unit of L1is replaced by -C(O)-.

[0320] In some embodiments, R2is selected from the group consisting of: -O-, -(R2a)N- and –S-. In some embodiments, R2is -O-.

[0321] In some embodiments, p is 1.

[0322] In some embodiments, R1ais H.

[0323] In some embodiments, R1bis H.

[0324] In some embodiments, R2ais H.

[0325] In some embodiments, R3aand R3bare each independently H.

[0326] In some embodiments, R4is H.

[0327] In some embodiments, R5aand R5bare each independently H.

[0328] In some embodiments, R6is H.

[0329] In some embodiments, Rnis H.

[0330] In some embodiments, R is H.

[0331] In some embodiments, Rais H.

[0332] In some embodiments, Rbis H.

[0333] In some embodiments, ring A is substituted with 1 L2.

[0334] In some embodiments, m is 0, and L3is a covalent bond.In some embodiments, n is 1, and L1is -C(R5a)(R5b)- wherein 1 methylene unit of L1may be replaced by -C(O)-.

[0335] In some embodiments, the drug moiety may have the following partial structure:

[0336]

[0337] wherein R2is as defined above, either in its broadest aspect or a preferred aspect.

[0338] In some embodiments, R2is -O- or –S-. In some embodiments, R2is -O-.

[0339] In some embodiments, the drug moiety (or payload moiety) is Compound 2, having the following structure:

[0340]

[0341] Compound 2 is disclosed as compound P-ll-3 and general and specific methods for its synthesis are disclosed in WO2022 / 068878 and published national applications derived therefrom.

[0342] Example antibody-drug conjugates

[0343] In preferred embodiments, the anti-HER2 antibody-drug conjugate has the structural formula (IV):Trastuzumab

[0344]

[0345] (IV) wherein, q is a connection number and q is selected from the group consisting of integers from 1 to 16, preferably integers from 4 to 12, for example, q is an integer from 6 to 10, for example, n is an integer from 7 to 9, such as 7, 8 or 9, preferably 8.

[0346] An antibody-drug conjugate of formula (IV) where q is 8 may be referred to herein as “Compound 1” and is also known as trastuzumab pamirtecan, DB-1303 and BNT323. It is disclosed as compound ADC-ll-9 in WO2022 / 068878 and national applications deriving therefrom. In one embodiment, the anti-HER2 antibody-drug conjugate is Compound 1. Compound 1 has demonstrated a manageable safety profile and promising antitumour activity, with high disease control in patients with advanced / metastatic endometrial cancer (see Moore, K., et al, 2023. International Journal of Gynecologic Cancer 2023;33: A9-A10).

[0347] In other embodiments, the antibody-drug conjugate has a structure shown as formula (V)

[0348]

[0349] (V) wherein, q is a connection number and q is selected from the group consisting of integers from 1 to 16, preferably integers from 4 to 12, for example, q is an integer from 6 to 10, for example, n is an integer from 7 to 9, such as 7, 8 or 9, preferably 8.An antibody-drug conjugate of formula (V) where q is 8 is also known as trastuzumab deruxtecan, Enhertu®, or DS-8201 (see e.g. Modi, S., et al., 2020. NEJM, 382(7), pp.610-621). In one embodiment, the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan. Trastuzumabb deruxtecan has been shown to have efficacy in patients with uterine carcinosarcoma (UCS) (see e.g. Nishikawa, T., et al. Journal of Clinical Oncology, 41(15), pp.2789-2799) and in patients with HER2-expressing tumours, including endometrial (see e.g. Meric-Bernstam, F., et al., 2024. Journal of Clinical Oncology, 42(1), pp.47-58).

[0350] Antibody-drug conjugate compositions

[0351] The anti-HER2 antibody-drug conjugates may be in the form of a composition. It will be understood by the person skilled in the art that the composition may comprise multiple anti-HER2 antibody-drug conjugates as defined herein, and that the drug-antibody ratio (as defined herein) of each anti-HER2 antibody-drug conjugate may be the same or different.

[0352] In contrast to the term “connection number” when used alone, it will be understood that the term “average connection number” in the context of a composition containing antibody-drug conjugates refers to the average number of drug molecules connected (e.g. conjugated) to the antibody in all of the ADCs present in the composition. As the skilled person will readily understand, the average connection number (defined as q’ when referred to in the context of a composition containing multiple ADCs) may therefore be an integer or be non-integral.

[0353] Thus, the average connection number q’ can be considered as the number of linker-payload moieties (e.g. cytotoxic drugs attached via a linker) per antibody when expressed as an average across the whole of the composition. It will also be understood that the average connection number q’ can affect the safety and therapeutic effectiveness of the antibody-drug conjugate. The number of drug molecules per antibody molecule can be characterized by conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA assays and HPLC.

[0354] In one embodiment, the term “average” may refer to the arithmetic mean, which is calculated as the sum of the connection numbers in all ADCs present in the composition divided by the number of ADCs present. In one embodiment, the term “average” may refer to the median, which is calculated as the middle value separating the greater and lesser halves of the connection numbers in all ADCs present in the composition. In one embodiment, the term “average” may refer to the mode, which is calculated as most frequent value of the connection number in all ADCs present in the composition. In one embodiment, the term “average” mayrefer to the mid-range, which is calculated as the arithmetic mean of the highest and lowest values of the connection number in all ADCs present in the composition. Preferably, the term “average” refers to the arithmetic mean.

[0355] As used herein, the average connection number q’ is an integer or a decimal from 1 to 16. In some embodiments, the average connection number q’ is selected from the group of integers or decimals of about: 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, or 16.0.

[0356] In some embodiments, the average connection number q’ is selected from the group of integers or decimals of about: 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0.

[0357] In some embodiments, the average connection number q’ is an integer or a decimal from 1 to 16, from 2 to 14, from 6 to 10, or from 7 to 9. In some embodiments, the average connection number q’ is selected from the group of integers or decimals of about: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, or 9.0.

[0358] In some embodiments, the average connection number q’ is an integer or a decimal from 2.0 to 16.0. In some embodiments, the average connection number q’ is an integer or a decimal from 3.0 to 15.0. In some embodiments, the average connection number q’ is an integer or a decimal from 4.0 to 14.0. In some embodiments, the average connection number q’ is an integer or a decimal from 4.0 to 13.0. In some embodiments, the average connection number q’ is an integer or a decimal from 4.0 to 12.0. In some embodiments, the average connection number q’ is an integer or a decimal from 5.0 to 11.0. In some embodiments, the average connection number q’ is an integer or a decimal from 6.0 to 10.0. In some embodiments, the average connection number q’ is an integer or a decimal from 7.0 to 9.0.In some embodiments, the average connection number q’ is about 7.0. In some embodiments, the average connection number q’ is about 7.1. In some embodiments, the average connection number q’ is about 7.2. In some embodiments, the average connection number q’ is about 7.3. In some embodiments, the average connection number q’ is about 7.4. In some embodiments, the average connection number q’ is about 7.5. In some embodiments, the average connection number q’ is about 7.6. In some embodiments, the average connection number q’ is about 7.7. In some embodiments, the average connection number q’ is about 7.8. In some embodiments, the average connection number q’ is about 7.9. In some embodiments, the average connection number q’ is about 8.0. In some embodiments, the average connection number q’ is about 8.1. In some embodiments, the average connection number q’ is about 8.2. In some embodiments, the average connection number q’ is about 8.3. In some embodiments, the average connection number q’ is about 8.4. In some embodiments, the average connection number q’ is about 8.5. In some embodiments, the average connection number q’ is about 8.6. In some embodiments, the average connection number q’ is about 8.7. In some embodiments, the average connection number q’ is about 8.8. In some embodiments, the average connection number q’ is about 8.9. In some embodiments, the average connection number q’ is about 9.0.

[0359] In some embodiments, the average connection number q’ is an integer or a decimal from 7 to 8. In some embodiments, the average connection number q’ is an integer or a decimal from 7.5 to 8. In some embodiments, the average connection number q’ is an integer or a decimal from 7.6 to 8. In some embodiments, the average connection number q’ is selected from the group of integers or decimals of about: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0.

[0360] In some embodiments, the anti-HER2 antibody-drug conjugate is in the form of a composition comprising one or more anti-HER2 antibody-drug conjugates having the structure shown as formula (I’-A):

[0361]

[0362] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0363] Ab is trastuzumab;

[0364] q’ is an average connection number and is an integer or decimal from 1 to 16;

[0365] L is -La-Lb-Lc-;

[0366] La- is

[0367] o

[0368] - Lb- is:

[0369]

[0370] -Lc- is -CH2-;

[0371] U is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0372] V is selected from the group consisting of: (C1-6) alkylene, (C3-10) cycloalkylene, or (C1-6) alkylene-(C3-10) cycloalkylene;

[0373] R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; and

[0374] each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.In some embodiments, the anti-HER2 antibody-drug conjugate is in the form of a composition comprising one or more anti-HER2 antibody-drug conjugates having the structure shown as formula (ll’-A):

[0375]

[0376] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0377] Ab is trastuzumab;

[0378] q’ is an average connection number and is an integer or decimal from 1 to 16;

[0379] L is -La-Lb-Lc-;

[0380] La- is

[0381]

[0382] -Lc- is -CH2-;

[0383] X1is saturated C, and X1is substituted with Rn;

[0384] ring A is selected from the group consisting of: 3-10 membered saturated or partially unsaturated heterocyclyl and 3-10 membered saturated or partially unsaturated carbocyclyl, wherein ring A is substituted with 0 or at least 1 substituent R1a;when ring A is 3-10 membered saturated or partially unsaturated carbocyclyl, ring A is substituted with p L2, and L2is not Rn;

[0385] or, when ring A is 3-10 membered saturated or partially unsaturated heterocyclyl, ring A is substituted with p L2;

[0386] L2is -R2-L3-, and R2is used for direct or indirect linking of a ligand;

[0387] L3is -(C(R3a)(R3b))m-, wherein when L3comprises a methylene unit, 0 or at least 1 methylene unit of L3is independently replaced by -N(R4)C(O)-, -C(O)N(R4)-, -C(O)-, -OC(O)-, -C(O)O-, -NR4-, -O-, -S-, -SO-, -SO2-, -P(R4)-, -P(=O)(R4)-, -N(R4)SO2-, -SO2N(R4)-, -C(=S)-, -C(=NR4)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;

[0388] R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0389] L1is -(C(R5a)(R5b))n-, wherein when L1comprises a methylene unit, 0 or at least 1 methylene unit of L1is independently replaced by -N(R6)C(O)-, -C(O)N(R6)-, -C(O)-, -OC(O)-, -C(O)O-, -NR6-, -O-, -S-, -SO-, -SO2-, -P(R6)-, -P(=O)(R6)-, -N(R6)SO2-, -SO2N(R6)-, -C(=S)-, -C(=NR6)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;

[0390] wherein each R1a, each R2a, each R3a, each R3b, each R4, each R5a, each R5b, each R6and each Rnare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a Ci-6aliphatic group optionally substituted with R;

[0391] wherein each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6 aliphatic group; and m and n are each independently selected from the group consisting of integers > 0, and p is an integer ≥ 1.

[0392] In some embodiments, the anti-HER2 antibody-drug conjugate is in the form of a composition comprising one or more anti-HER2 antibody-drug conjugates having the structure shown as formula (IH’-A):

[0393]

[0394] q' (lll'-A) or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0395] Ab is trastuzumab;

[0396] q’ is an average connection number and is an integer or decimal from 1 to 16;

[0397] R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0398] R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; and

[0399] each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

[0400] In some embodiments, the anti-HER2 antibody-drug conjugate is in the form of a composition comprising one or more anti-HER2 antibody-drug conjugates having the structure shown as formula (IV’-A):

[0401]

[0402] (IV'-A)or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0403] Ab is trastuzumab; and

[0404] q’ is an average connection number and is an integer or decimal from 1 to 16.

[0405] In some embodiments, the anti-HER2 antibody-drug conjugate is in the form of a composition comprising one or more anti-HER2 antibody-drug conjugates having the structure shown as formula (V’-A):

[0406]

[0407] (V’-A) or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0408] Ab is an anti-HER2 antibody or a fragment thereof as defined herein (e.g. trastuzumab); and q’ is an average connection number and is an integer or decimal from 1 to 16.

[0409] In some embodiments, the anti-HER2 antibody-drug conjugate is in the form of a composition comprising one or more anti-HER2 antibody-drug conjugates having the structure shown as formula (I’):Trastuzumabb

[0410]

[0411] (I')

[0412] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0413] q’ is an average connection number and is an integer or decimal from 1 to 16;

[0414] L is -La-Lb-Lc-;

[0415] La- is

[0416] o

[0417] - Lb- is:

[0418]

[0419] -Lc- is -CH2-;

[0420] U is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0421] V is selected from the group consisting of: (C1-6) alkylene, (C3-10) cycloalkylene, or (C1-6) alkylene-(C3-10) cycloalkylene;

[0422] R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; and

[0423] each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.In some embodiments, the anti-HER2 antibody-drug conjugate is in the form of a composition comprising one or more anti-HER2 antibody-drug conjugates having the structure shown as

[0424]

[0425] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0426] q’ is an average connection number and is an integer or decimal from 1 to 16;

[0427] L is -La-Lb-Lc-;

[0428] La- is

[0429] o

[0430] - Lb- is:

[0431]

[0432] -Lc- is -CH2-;

[0433] X1is saturated C, and X1is substituted with Rn;

[0434] ring A is selected from the group consisting of: 3-10 membered saturated or partially unsaturated heterocyclyl and 3-10 membered saturated or partially unsaturated carbocyclyl, wherein ring A is substituted with 0 or at least 1 substituent R1a;

[0435] when ring A is 3-10 membered saturated or partially unsaturated carbocyclyl, ring A is substituted with p L2, and L2is not Rn;or, when ring A is 3-10 membered saturated or partially unsaturated heterocyclyl, ring A is substituted with p L2;

[0436] L2is -R2-L3-, and R2is used for direct or indirect linking of a ligand;

[0437] L3is -(C(R3a)(R3b))m-, wherein when L3comprises a methylene unit, 0 or at least 1 methylene unit of L3is independently replaced by -N(R4)C(O)-, -C(O)N(R4)-, -C(O)-, -OC(O)-, -C(O)O-, -NR4-, -O-, -S-, -SO-, -SO2-, -P(R4)-, -P(=O)(R4)-, -N(R4)SO2-, -SO2N(R4)-, -C(=S)-, -C(=NR4)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;

[0438] R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0439] L1is -(C(R5a)(R5b))n-, wherein when L1comprises a methylene unit, 0 or at least 1 methylene unit of L1is independently replaced by -N(R6)C(O)-, -C(O)N(R6)-, -C(O)-, -OC(O)-, -C(O)O-, -NR6-, -O-, -S-, -SO-, -SO2-, -P(R6)-, -P(=O)(R6)-, -N(R6)SO2-, -SO2N(R6)-, -C(=S)-, -C(=NR6)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;

[0440] wherein each R1a, each R2a, each R3a, each R3b, each R4, each R5a, each R5b, each R6and each Rnare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a Ci-6aliphatic group optionally substituted with R;

[0441] wherein each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6 aliphatic group; and m and n are each independently selected from the group consisting of integers > 0, and p is an integer ≥ 1.

[0442] In some embodiments, the anti-HER2 antibody-drug conjugate is in the form of a composition comprising one or more anti-HER2 antibody-drug conjugates having the structure shown as formula (III’):

[0443] Trastuzumab

[0444]

[0445] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0446] q’ is an average connection number and is an integer or decimal from 1 to 16;

[0447] R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0448] R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; and

[0449] each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

[0450] In some embodiments, the anti-HER2 antibody-drug conjugate is in the form of a composition comprising one or more anti-HER2 antibody-drug conjugates having the structure shown as formula (IV’):

[0451] Trastuzumab

[0452]

[0453]

[0454] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0455] q’ is an average connection number and is an integer or decimal from 1 to 16.

[0456] In some embodiments, the anti-HER2 antibody-drug conjugate is in the form of a composition comprising one or more anti-HER2 antibody-drug conjugates having the structure shown as formula (V’):,0

[0457] , MH.,0

[0458]

[0459] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0460] q’ is an average connection number and is an integer or decimal from 1 to 16.

[0461] Anti-PD-1 / PD-L1 antibodies and fragments thereof

[0462] The combination therapy of the present invention comprises an anti-PD-1 / PD-L1 antibody or fragment thereof. In certain embodiments, the combination therapy of the present invention comprises an anti-PD-1 antibody or fragment thereof.

[0463] Programmed cell death protein 1 (PD-1) is a protein that in humans is encoded by the PDCD1 gene and which may also be known as CD279 (Cluster of Differentiation 279). Programmed death-ligand 1 (PD-L1) is a protein that in humans is encoded by the CD274 gene and which may also be known as CD274 (Cluster of Differentiation 274) or B7 homolog 1 (B7-H1).

[0464] The pathway consisting of the programmed cell death 1 (PD-1) receptor and its ligands PD-L1 and PD-L2 plays an important role in the induction and maintenance of peripheral tolerance and for the maintenance of the stability and the integrity of T cells. However, the PD-1: PD-L1 / L2 pathway also mediates potent inhibitory signals to hinder the proliferation and function of T effector cells and have inimical effects on antiviral and antitumour immunity. Therapeutic targeting of this pathway has resulted in successful enhancement of T cell immunity against viral pathogens and tumours (see Bardhan, K., et al., 2016. Frontiers in immunology, 7, p.550).

[0465] Suitably, the PD-1 may be human PD-1 (hPD-1). An example amino acid sequence for human PD-1 is provided by Uniprot reference Q15116. In some embodiments, human PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 50:MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLWTEGDNATFTC SFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHM SVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAG QFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFS VDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQ PLRPEDGHCSWPL

[0466] Example human PD-1 amino acid sequence (SEQ ID NO: 50)

[0467] Suitably, the PD-L1 may be human PD-L1 (hPD-1). An example amino acid sequence for human PD-L1 is provided by Uniprot reference Q9NZQ7. In some embodiments, human PD-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 51:

[0468] MRIFAVFIFMTYWHLLNAFTVTVPKDLYWEYGSNMTIECKFPVEKQLDLAALIVYWE MEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELP LAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLE ET

[0469] Example human PD-L1 amino acid sequence (SEQ ID NO: 51)

[0470] The anti-PD-1 / PD-L1 antibody or fragment thereof may specifically bind PD-1 or PD-L1. The anti-PD-1 / PD-L1 antibody may be a monoclonal antibody. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is a humanized or human antibody. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is a monoclonal humanized or human antibody. The fragment thereof may be any antigen-binding fragment thereof, for example a Fab, a Fab', a F(ab')2, a Fv, a scFv, a Fab'-SH, an sdAb, or a VHH. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is a full-length anti-PD-1 / PD-L1 antibody.

[0471] The anti-PD-1 / PD-L1 antibody or fragment thereof may comprise a variable region that specifically binds PD-1 or PD-L1. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof comprises a heavy chain variable region and / or a light chain variable region. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof comprises a heavy chain variable region and a light chain variable region. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof comprises a constant region, preferably derived from a human antibody, optionally the constant region is selected from the constant region of human lgG1, lgG2, lgG3 or lgG4. In some embodiments, the constant region is the constant region of a human lgG4 antibody. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragmentthereof comprises a heavy chain and / or a light chain. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof comprises a heavy chain and a light chain. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof comprises or consists of two heavy chains and two light chains. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof consists of two heavy chains and two light chains.

[0472] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof comprises a variable fragment (Fv) that specifically binds PD-1 or PD-L1. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof comprises an antigen-binding fragment (Fab) that specifically binds PD-1 or PD-L1.

[0473] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is an anti-PD-1 antibody or fragment thereof or a monospecific anti-PD-L1 antibody or fragment thereof. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is a monospecific anti-PD-1 / PD-L1 antibody or fragment thereof. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is a monospecific anti-PD-1 / PD-L1 antibody.

[0474] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is not a bispecific antibody comprising an antibody or fragment thereof that specifically binds to VEGF. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is not a bispecific antibody comprising an anti-VEGF or fragment thereof, and an antagonist of the PD1 / PD-L1 interaction and / or a PD-1 or PD-L1 blocking antibody. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is not a bispecific antibody comprising an anti-VEGF antibody or fragment thereof, and a PD-1 or PD-L1 blocking antibody. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is not a bispecific antibody comprising an anti-VEGF antibody (e.g., anti-VEGF-A antibody) or fragment thereof, and an anti-PD-1 or anti-PD-L1 antibody or fragment thereof.

[0475] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is not a bispecific antibody comprising (a) an antibody or fragment thereof that specifically binds to PD-L1 and (b) an antibody or fragment thereof that specifically binds to VEGF. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is not a bispecific antibody comprising (a) an antibody or fragment thereof that specifically binds to PD-1 or PD-L1 and (b) an antibody or fragment thereof that specifically binds to VEGF.

[0476] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is not a bispecific anti-PD-L1 antibody. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereofis not a bispecific anti-PD-1 / PD-L1 antibody. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is not a multispecific anti-PD-L1 antibody. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is not a multispecific anti-PD-1 / PD-L1 antibody.

[0477] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is selected from: dostarlimab or a fragment thereof, pembrolizumab or a fragment thereof, nivolumab or a fragment thereof, cemiplimab or a fragment thereof, atezolizumab or a fragment thereof, durvalumab or a fragment thereof, or avelumab or a fragment thereof.

[0478] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is selected from: dostarlimab, pembrolizumab, nivolumab, cemiplimab, atezolizumab, durvalumab, or avelumab.

[0479] Anti-PD-1 antibodies and fragments thereof

[0480] In some preferred embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is an anti-PD-1 antibody or fragment thereof.

[0481] The anti-PD-1 antibody or fragment thereof may specifically bind PD-1. The anti-PD-1 antibody may be a monoclonal antibody. In some embodiments, the anti-PD-1 antibody or fragment thereof is a humanized or human antibody. In some embodiments, the anti-PD-1 antibody or fragment thereof is a monoclonal humanized or human lgG4 antibody. In some embodiments, the anti-PD-1 antibody or fragment thereof is a monoclonal humanized or human antibody. The fragment thereof may be any antigen-binding fragment thereof, for example a Fab, a Fab', a F(ab')2, a Fv, a scFv, a Fab'-SH, an sdAb, or a VHH. In some embodiments, the anti-PD-1 antibody or fragment thereof is a full-length anti-PD-1 antibody.

[0482] The anti-PD-1 antibody or fragment thereof may comprise a variable region that specifically binds PD-1. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a heavy chain variable region and / or a light chain variable region. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a heavy chain variable region and a light chain variable region. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a constant region, preferably derived from a human antibody, optionally the constant region is selected from the constant region of human lgG1, lgG2, lgG3 or lgG4. In some embodiments, the constant region is the constant region of a human lgG4 antibody. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a heavy chainand / or a light chain. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a heavy chain and a light chain. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains and two light chains. In some embodiments, the anti-PD-1 antibody or fragment thereof consists of two heavy chains and two light chains.

[0483] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a variable fragment (Fv) that specifically binds PD-1. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises an antigen-binding fragment (Fab) that specifically binds PD-1.

[0484] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is a monospecific anti-PD-1 antibody or fragment thereof. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is a monospecific anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody or fragment thereof is not a bispecific anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody or fragment thereof is not a multispecific anti-PD-1 antibody.

[0485] The biological activity of the anti-PD-1 antibody or fragment thereof also can be assessed by determining its binding affinity to a PD-1 protein or an epitope thereof. The term "affinity" may refer to the equilibrium constant for the reversible binding of two agents and may be expressed as the dissociation constant (KD). In some embodiments, the anti-PD-1 antibody or fragment thereof can bind to a PD-1 protein with a KD less than or equal to 1 nanomolar (e.g., 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM, 0.05 nM, 0.025 nM, 0.01 nM, 0.001 nM, or a range defined by any two of the foregoing values). In some embodiments, the anti-PD-1 antibody or fragment thereof can bind to a PD-1 protein with a KD less than or equal to 200 pM (e.g., 190 pM, 175 pM, 150 pM, 125 pM, 110 pM, 100 pM, 90 pM, 80 pM, 75 pM, 60 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM, 10 pM, 5 pM, 1 pM, or a range defined by any two of the foregoing values).

[0486] In some embodiments, the anti-PD-1 antibody or fragment binds to human PD-1 with a KD of less than or equal to 1 nanomolar, less than or equal to 0.9 nM, less than or equal to 0.8 nM, less than or equal to 0.7 nM, less than or equal to 0.6 nM, less than or equal to 0.5 nM, less than or equal to 0.4 nM, or less than or equal to 0.3 nM, for example as determined by surface plasmon resonance (SPR).

[0487] Exemplary anti-PD-1 antibodies include, without limitation, BGB-A317 (BeiGene; see US 8,735,553, WO 2015 / 035606 and US 2015 / 0079109), cemiplimab (Regeneron; see WO 2015 / 112800) and lambrolizumab (e.g., disclosed as hPD109A and its humanized derivativesh409A1, h409A16 and h409A17 in WO2008 / 156712), AB137132 (Abeam), EH12.2H7 and RMP1-14 (#BE0146; Bioxcell Lifesciences Pvt. LTD.), MIH4 (Affymetrix eBioscience), nivolumab (OPDIVO, BMS-936558; Bristol Myers Squibb; see WO 2006 / 121168), pembrolizumab (KEYTRUDA; MK-3475; Merck; see WO 2008 / 156712), pidilizumab (CT-011; CureTech; see Hardy et al., 1994, Cancer Res., 54(22):5793-6 and WO 2009 / 101611), PDR001 (Novartis; see WO 2015 / 112900), MEDI0680 (AMP-514; AstraZeneca; see WO 2012 / 145493), TSR-042 (see WO 2014 / 179664), REGN-2810 (H4H7798N; cf. US 2015 / 0203579), JS001 (TAIZHOU JUNSHI PHARMA; see Si-Yang Liu et al., 2007, J. Hematol. Oncol. 70: 136), AMP-224 (GSK-2661380; cf. Li et al., 2016, Int J Mol Sci 17(7): 1151 and WO 2010 / 027827 and WO 2011 / 066342), PF-06801591 (Pfizer), BGB-A317 (BeiGene; see WO 2015 / 035606 and US 2015 / 0079109), Bl 754091, SHR-1210 (see WO2015 / 085847), and antibodies 17D8, 2D3, 4H1, 4A11, 7D3, and 5F4 as described in WO 2006 / 121168, INCSHR1210 (Jiangsu Hengrui Medicine; also known as SHR-1210; see WO 2015 / 085847), TSR-042 (Tesaro Biopharmaceutical; also known as ANB011; see W02014 / 179664), GLS-010 (Wuxi / Harbin Gloria Pharmaceuticals; also known as WBP3055; see Si-Yang et al., 2017, J. Hematol. Oncol. 70: 136), STI-1110 (Sorrento Therapeutics; see WO 2014 / 194302), AGEN2034 (Agenus; see WO 2017 / 040790), MGA012 (Macrogenics; see WO 2017 / 019846), IBI308 (Innovent; see WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825, and WO 2017 / 133540), anti-PD-1 antibodies as described, e.g., in US 7,488,802, US 8,008,449, US 8,168,757, WO 03 / 042402, WO 2010 / 089411 (further disclosing anti-PD-L1 antibodies), WO 2010 / 036959, WO 2011 / 159877 (further disclosing antibodies against TIM-3), WO 2011 / 082400, WO 2011 / 161699, WO 2009 / 014708, WO 03 / 099196, WO 2009 / 114335, WO 2012 / 145493 (further disclosing antibodies against PD-L1), WO 2015 / 035606, WO 2014 / 055648 (further disclosing anti-KIR antibodies), US 2018 / 0185482 (further disclosing anti-PD-L1 and anti-TIGIT antibodies), US 8,008,449, US 8,779,105, US 6,808,710, US 8,168,757, US 2016 / 0272708, and US 8,354,509.

[0488] In certain embodiments, the anti-PD-1 antibody or fragment thereof comprises dostarlimab (JEMPERLI; TSR-042; WBP-285), nivolumab (OPDIVO; BMS-936558), pembrolizumab (KEYTRUDA; MK-3475), cemiplimab (LIBTAYO, REGN2810), pidilizumab (CT-011), spartalizumab (PDR001), MEDI0680 (AMP-514), cetrelimab (JNJ 63723283), toripalimab (JS001), AMP-224 (GSK-2661380), PF-06801591, tislelizumab (BGB-A317), ABBV-181, Bl 754091, SHR-1210, or fragments thereof.

[0489] In some embodiments, the anti-PD-1 antibody or fragment thereof is selected from: dostarlimab or a fragment thereof, pembrolizumab or a fragment thereof, nivolumab or a fragment thereof, or cemiplimab or a fragment thereof.In some embodiments, the anti-PD-1 antibody or fragment thereof is selected from: dostarlimab, pembrolizumab, nivolumab, or cemiplimab.

[0490] Example anti-PD-1 antibody CDRs, variable region sequences, and heavy and light chain sequences are provided below.

[0491] Example anti-PD-1 antibody sequences 1 - dostarlimab

[0492] In some preferred embodiments, the anti-PD-1 antibody or fragment thereof is dostarlimab or a fragment thereof. In some more preferred embodiments, the anti-PD-1 antibody or fragment thereof is dostarlimab.

[0493] Dostarlimab (also known as Jemperli) is a humanized lgG4 monoclonal anti-PD-1 antibody. Dostarlimab is described in WO2014 / 179664 and WO 2018 / 085468. Dostarlimab is approved in the US for adults with mismatch repair deficient (dMMR) recurrent or advanced solid tumours that have progressed on or following prior treatment and who lack satisfactory alternative treatment option. Dostarlimab, in combination with carboplatin and paclitaxel, followed by single-agent dostarlimab, is approved for primary advanced or recurrent dMMR endometrial cancer (see e.g. Mirza, M. R., et al., 2023. NEJM, 388(23), pp.2145-2158).

[0494] Kabat HCDR1 SYDMS (SEQ ID NO: 19)

[0495] Kabat HCDR2 TISGGGSYTYYQDSVKG (SEQ ID NO: 20)

[0496] Kabat HCDR3 PYYAMDY (SEQ ID NO: 21)

[0497] Kabat LCDR1 KASQDVGTAVA (SEQ ID NO: 22)

[0498] Kabat LCDR2 WASTLHT (SEQ ID NO: 23)

[0499] Kabat LCDR3 QHYSSYPWT (SEQ ID NO: 24)

[0500] IMGT HCDR1 GFTFSSYD (SEQ ID NO: 25)

[0501] IMGT HCDR2 ISGGGSYT (SEQ ID NO: 26)

[0502] IMGT HCDR3 ASPYYAMDY (SEQ ID NO: 27)

[0503] IMGT LCDR1 QDVGTA (SEQ ID NO: 28)

[0504] IMGT LCDR2 WAS (SEQ ID NO: 29)

[0505] IMGT LCDR3 QHYSSYPWT (SEQ ID NO: 30)

[0506] VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWV STISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAS PYYAMDYWGQGTTVTVSS (SEQ ID NO: 31)

[0507] VL DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYW ASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQ GTKLEIK (SEQ ID NO: 32)

[0508] CH human ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV lgG4 HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE

[0509]

[0510] GNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 33)CL kappa RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC (SEQ ID NO: 34)

[0511] Heavy chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWV STISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAS PYYAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0512] (SEQ ID NO: 35)

[0513] Light chain DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYW ASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQ GTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL

[0514]

[0515] SSPVTKSFNRGEC (SEQ ID NO: 36)

[0516] In some embodiments, a heavy chain variable region of the anti-PD-1 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 19, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 20, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 21, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat numbering system.

[0517] In some embodiments, a light chain variable region of the anti-PD-1 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 22, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 23, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat numbering system.

[0518] In some embodiments, a heavy chain variable region of the anti-PD-1 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 19, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 20, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 21, or avariant thereof having up to three amino acid substitutions, additions or deletions; and a light chain variable region of the anti-PD-1 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 22, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 23, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat numbering system.

[0519] In some embodiments, a heavy chain variable region of the anti-PD-1 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 26, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 27, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT numbering system.

[0520] In some embodiments, a light chain variable region of the anti-PD-1 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 28, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 30, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT numbering system.

[0521] In some embodiments, a heavy chain variable region of the anti-PD-1 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 26, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 27, or a variant thereof having up to three amino acid substitutions, additions or deletions; and a light chain variable region of the anti-PD-1 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 28, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a LCDR2 comprising orconsisting of the amino acid sequence of SEQ ID NO: 29, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 30, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT numbering system.

[0522] In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0523] In some embodiments, a heavy chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 31, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 31.

[0524] In some embodiments, a light chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 32 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 32.

[0525] In some embodiments, a heavy chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 31, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 32 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.In some embodiments, a heavy chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 31, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 21; and a light chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 32 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 23; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 24.

[0526] In some embodiments, a heavy chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 31, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 25; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and a light chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 32 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 28; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 30.

[0527] In some embodiments, a heavy chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 31, or an amino acid sequence having at 98% identity thereto, wherein the heavy chain variable region comprises:a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 21; and a light chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 32 or an amino acid sequence having at least 98% identity thereto, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 23; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 24.

[0528] In some embodiments, a heavy chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 31, or an amino acid sequence having at least 98% identity thereto, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 25; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and a light chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 32 or an amino acid sequence having at least 98% identity thereto, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 28; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 30.

[0529] In some embodiments, a heavy chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 31; and a light chain variable region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 32. In some embodiments, a heavy chain variable region of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 31; and a light chain variable region of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 32.

[0530] In some embodiments, a heavy chain constant region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 33, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain constantregion of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 33.

[0531] In some embodiments, a light chain constant region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 34 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain constant region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 34.

[0532] In some embodiments, a heavy chain constant region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 33, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain constant region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 34 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0533] In some embodiments, a heavy chain constant region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 33; and a light chain constant region of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 34. In some embodiments, a heavy chain constant region of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 33; and a light chain constant region of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 34.

[0534] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 35, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 35.In some embodiments, a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 36.

[0535] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 35, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0536] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 35, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 21; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 23; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 24.

[0537] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 35, or an amino acid sequence havingat least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 25; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 28; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 30.

[0538] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 35, or an amino acid sequence having at least 98% identity thereto, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 21; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence having at least 98% identity thereto, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 23; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 24.

[0539] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 35, or an amino acid sequence having at least 98% identity thereto, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 25; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence having at least 98% identity thereto, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence ofSEQ ID NO: 28; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 30.

[0540] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 35; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 36. In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 35; and a light chain of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 36.

[0541] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 35; and two light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 36.

[0542] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains consisting of the amino acid sequence of SEQ ID NO: 35; and two light chains consisting of the amino acid sequence of SEQ ID NO: 36.

[0543] Example anti-PD-1 antibody sequences 2 - pembrolizumab

[0544] In some embodiments, the anti-PD-1 antibody or fragment thereof is pembrolizumab or a fragment thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof is pembrolizumab. Pembrolizumab (also known as Keytruda) is a humanized lgG4 monoclonal anti-PD-1 antibody.

[0545] Heavy chain QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWM GGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCAR RDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGLTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[0546] (SEQ ID NO: 37)

[0547] Light chain EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRL LIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH

[0548]

[0549] QGLSSPVTKSFNRGEC (SEQ ID NO: 38)In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 37, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 37.

[0550] In some embodiments, a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 38 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 38.

[0551] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 37, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 38 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0552] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 37; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 38. In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 37; and a light chain of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 38.

[0553] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 37; and two light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 38.In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains consisting of the amino acid sequence of SEQ ID NO: 37; and two light chains consisting of the amino acid sequence of SEQ ID NO: 38.

[0554] A further example heavy chain is provided below:

[0555] QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGT NFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN VFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 52)

[0556] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 52, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 52.

[0557] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 52, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 38 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0558] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 52; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 38. In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereofconsists of the amino acid sequence of SEQ ID NO: 52; and a light chain of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 38.

[0559] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 52; and two light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 38.

[0560] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains consisting of the amino acid sequence of SEQ ID NO: 52; and two light chains consisting of the amino acid sequence of SEQ ID NO: 38.

[0561] Example anti-PD-1 antibody sequences 3 - nivolumab

[0562] In some embodiments, the anti-PD-1 antibody or fragment thereof is nivolumab or a fragment thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof is nivolumab. Nivolumab (also known as Opdivo) is a human lgG4 monoclonal anti-PD-1 antibody.

[0563] Heavy chain QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWV AVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCAT NDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV DHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 39)

[0564] Light chain EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDA SNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQG TKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS

[0565]

[0566] SPVTKSFNRGEC (SEQ ID NO: 40)

[0567] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 39, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 39.

[0568] In some embodiments, a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 40 or an amino acid sequence havingat least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 40.

[0569] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 39, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 40 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0570] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 39; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 40. In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 39; and a light chain of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 40.

[0571] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 39; and two light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 40.

[0572] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains consisting of the amino acid sequence of SEQ ID NO: 39; and two light chains consisting of the amino acid sequence of SEQ ID NO: 40.

[0573] A further example heavy chain is provided below:

[0574] QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEVWAVIWYDGSKRY YADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMH EALHNHYTQKSLSLSLGK (SEQ ID NO: 53)

[0575] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 53, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 53.

[0576] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 53, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 40 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0577] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 53; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 40. In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 53; and a light chain of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 40.

[0578] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 53; and two light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 40.

[0579] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains consisting of the amino acid sequence of SEQ ID NO: 53; and two light chains consisting of the amino acid sequence of SEQ ID NO: 40.Example anti-PD-1 antibody sequences 4 – cemiplimab

[0580] In some embodiments, the anti-PD-1 antibody or fragment thereof is cemiplimab or a fragment thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof is cemiplimab. Cemiplimab (also known as Libtayo) is a human lgG4 monoclonal anti-PD-1 antibody.

[0581] Heavy chain EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWV SGISGGGRDTYFADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVK WGNIYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[0582] (SEQ ID NO: 41)

[0583] Light chain DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAPNLLIYAAS SLHGGVPSRFSGSGSGTDFTLTIRTLQPEDFATYYCQQSSNTPFTFGPGT VVDFRRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS

[0584]

[0585] SPVTKSFNRGEC (SEQ ID NO: 42)

[0586] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 41.

[0587] In some embodiments, a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 42 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 42.

[0588] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain of the anti-PD-1 antibodyor fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 42 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0589] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 41; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 42. In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 41; and a light chain of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 42.

[0590] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 41; and two light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 42.

[0591] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains consisting of the amino acid sequence of SEQ ID NO: 41; and two light chains consisting of the amino acid sequence of SEQ ID NO: 42.

[0592] A further example heavy chain is provided below:

[0593] EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWVSGISGGGRDTY FADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSSAS TKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWS VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSC SVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 54)

[0594] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 54, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 54.In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 54, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 42 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0595] In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 54; and a light chain of the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 42. In some embodiments, a heavy chain of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 54; and a light chain of the anti-PD-1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 42.

[0596] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 54; and two light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 42.

[0597] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of two heavy chains consisting of the amino acid sequence of SEQ ID NO: 54; and two light chains consisting of the amino acid sequence of SEQ ID NO: 42.

[0598] Anti-PD-L1 antibodies and fragments thereof

[0599] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is an anti-PD-L1 antibody or fragment thereof.

[0600] The anti-PD-L1 antibody or fragment thereof may specifically bind PD-L1. The anti-PD-L1 antibody may be a monoclonal antibody. In some embodiments, the anti-PD-L1 antibody or fragment thereof is a humanized or human antibody. In some embodiments, the anti-PD-L1 antibody or fragment thereof is a monoclonal humanized or human lgG1 antibody. In some embodiments, the anti-PD-L1 antibody or fragment thereof is a monoclonal humanized or human antibody. The fragment thereof may be any antigen-binding fragment thereof, for example a Fab, a Fab', a F(ab')2, a Fv, a scFv, a Fab'-SH, an sdAb, or a VHH. In some embodiments, the anti-PD-L1 antibody or fragment thereof is a full-length anti-PD-L1 antibody.pThe anti-PD-L1 antibody or fragment thereof may comprise a variable region that specifically binds PD-L1. In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises a heavy chain variable region and / or a light chain variable region. In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises a heavy chain variable region and a light chain variable region. In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises a constant region, preferably derived from a human antibody, optionally the constant region is selected from the constant region of human lgG1, lgG2, lgG3 or lgG4. In some embodiments, the constant region is the constant region of a human IgG 1 antibody. In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises a heavy chain and / or a light chain. In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises a heavy chain and a light chain. In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises or consists of two heavy chains and two light chains. In some embodiments, the anti-PD-L1 antibody or fragment thereof consists of two heavy chains and two light chains.

[0601] In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises a variable fragment (Fv) that specifically binds PD-L1. In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises an antigen-binding fragment (Fab) that specifically binds PD-L1.

[0602] In some embodiments, the anti-PD-L1 antibody or fragment thereof is a monospecific anti-PD-L1 antibody or fragment thereof. In some embodiments, the anti-PD-L1 antibody or fragment thereof is a monospecific anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody or fragment thereof is not a bispecific antibody comprising (a) an antibody or fragment thereof that specifically binds to PD-L1 and (b) an antibody or fragment thereof that specifically binds to VEGF. In some embodiments, the anti-PD-L1 antibody or fragment thereof is not a bispecific anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody or fragment thereof is not a multispecific anti-PD-L1 antibody.

[0603] The biological activity of the anti-PD-L1 antibody or fragment thereof also can be assessed by determining its binding affinity to a PD-L1 protein or an epitope thereof. In some embodiments, the anti-PD-L1 antibody or fragment thereof can bind to a PD-L1 protein with a KD less than or equal to 1 nanomolar (e.g., 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM, 0.05 nM, 0.025 nM, 0.01 nM, 0.001 nM, or a range defined by any two of the foregoing values). In some embodiments, the anti-PD-L1 antibody or fragment thereof can bind to a PD-L1 protein with a KD less than or equal to 200 pM (e.g., 190 pM, 175 pM, 150pM, 125 pM, 110 pM, 100 pM, 90 pM, 80 pM, 75 pM, 60 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM, 10 pM, 5 pM, 1 pM, or a range defined by any two of the foregoing values).

[0604] Exemplary anti-PD-L1 antibodies include, without limitation, MEDI4736 (durvalumab; AstraZeneca; see WO 2011 / 066389), MSB-0010718C (see US 2014 / 0341917), YW243.55. S70 (see SEQ ID NO: 20 of WO 2010 / 077634 and US 8,217,149), MIH1 (Affymetrix eBioscience; cf. EP 3 230 319), MDX-1105 (Roche / Genentech; see W02013019906 and US 8,217,149) STI-1014 (Sorrento; see W02013 / 181634), CK-301 (Checkpoint Therapeutics), KN035 (3D Med / Alphamab; see Zhang et al., 2017, Cell Discov.

[0605] 3:17004), atezolizumab (TECENTRIQ; RG7446; MPDL3280A; R05541267; see US 9,724,413), BMS-936559 (Bristol Myers Squibb; see US 7,943,743, WO 2013 / 173223), avelumab (bavencio; cf. US 2014 / 0341917), LY3300054 (Eli Lilly Co.), CX-072 (Proclaim-CX-072; also called CytomX; see WO2016 / 149201), FAZ053, KN035 (see WO2017 / 020801 and WO2017 / 020802), MDX-1105 (see US 2015 / 0320859), anti-PD-L1 antibodies disclosed in US 7,943,743, including 3G10, 12A4 (also referred to as BMS-936559), 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, anti-PD-L1 antibodies as described in WO 2010 / 077634, US 8,217,149, WO 2010 / 036959, WO 2010 / 077634, WO 2011 / 066342, US 8,217,149, US 7,943,743, WO 2010 / 089411, US 7,635,757, US 8,217,149, US 2009 / 0317368, WO 2011 / 066389, WO2017 / 034916, WO2017 / 020291, WO2017 / 020858, WO2017 / 020801, WO2016 / 111645, WO2016 / 197367, WO2016 / 061142, WO2016 / 149201, WO2016 / 000619, WO2016 / 160792, WO2016 / 022630, WO2016 / 007235, WO2015 / 179654, WO2015 / 173267, WO2015 / 181342, WO2015 / 109124, WO 2018 / 222711, WO2015 / 112805, WO2015 / 061668, WO2014 / 159562, WO2014 / 165082, WO2014 / 100079.

[0606] In certain embodiments, the anti-PD-L1 antibody or fragment thereof comprises atezolizumab (TECENTRIQ; RG7446; MPDL3280A; R05541267), durvalumab (IMFINZI; MEDI4736), avelumab (BAVENCIO; MSB0010718C), BMS-936559, lodapolimab (LY3300054), CX-072 (Proclaim-CX-072), FAZ053, KN035, MDX-1105, or fragments thereof.

[0607] In some embodiments, the anti-PD-L1 antibody or fragment thereof is selected from: atezolizumab or a fragment thereof, durvalumab or a fragment thereof, or avelumab or a fragment thereof.

[0608] In some embodiments, the anti-PD-L1 antibody or fragment thereof is selected from: atezolizumab, durvalumab, or avelumab.Example anti-PD-L1 antibody CDRs, variable region sequences, and heavy and light chain sequences are provided below.

[0609] Example anti-PD-L1 antibody sequences 1 – atezolizumab

[0610] In some embodiments, the anti-PD-L1 antibody or fragment thereof is atezolizumab or a fragment thereof. In some embodiments, the anti-PD-L1 antibody or fragment thereof is atezolizumab. Atezolizumab (also known as Tecentriq) is a humanized lgG1 monoclonal anti-PD-L1 antibody.

[0611] Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEVW AWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCAR RHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP KDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY ASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP

[0612] G (SEQ ID NO: 43)

[0613] Light chain DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYS ASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQ GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL

[0614]

[0615] SSPVTKSFNRGEC (SEQ ID NO: 44)

[0616] In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 43.

[0617] In some embodiments, a light chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 44.In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0618] In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 43; and a light chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 44. In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 43; and a light chain of the anti-PD-L1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 44.

[0619] In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises or consists of two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 43; and two light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 44.

[0620] In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises or consists of two heavy chains consisting of the amino acid sequence of SEQ ID NO: 43; and two light chains consisting of the amino acid sequence of SEQ ID NO: 44.

[0621] A further example heavy chain is provided below:

[0622] EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEVWAWISPYGGSTY YADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 55)In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 55, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 55.

[0623] In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 55, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0624] In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 55; and a light chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 44. In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 55; and a light chain of the anti-PD-L1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 44.

[0625] In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises or consists of two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 55; and two light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 44.

[0626] In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises or consists of two heavy chains consisting of the amino acid sequence of SEQ ID NO: 55; and two light chains consisting of the amino acid sequence of SEQ ID NO: 44.

[0627] Example anti-PD-L1 antibody sequences 2 – durvalumab

[0628] In some embodiments, the anti-PD-L1 antibody or fragment thereof is durvalumab or a fragment thereof. In some embodiments, the anti-PD-L1 antibody or fragment thereof isdurvalumab. Durvalumab (also known as Imfinzi) is a human IgG1κ monoclonal anti-PD-L1 antibody.

[0629] Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEVW ANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR EGGWFGELAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLF PPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK (SEQ ID NO: 45)

[0630] Light chain EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYD ASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQ GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL

[0631]

[0632] SSPVTKSFNRGEC (SEQ ID NO: 46)

[0633] In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 45.

[0634] In some embodiments, a light chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 46 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 46.

[0635] In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 46 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0636] In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 45; and a light chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 46. In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 45; and a light chain of the anti-PD-L1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 46.

[0637] In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises or consists of two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 45; and two light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 46.

[0638] In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises or consists of two heavy chains consisting of the amino acid sequence of SEQ ID NO: 45; and two light chains consisting of the amino acid sequence of SEQ ID NO: 46.

[0639] Example anti-PD-L1 antibody sequences 3 – avelumab

[0640] In some embodiments, the anti-PD-L1 antibody or fragment thereof is avelumab ora fragment thereof. In some embodiments, the anti-PD-L1 antibody or fragment thereof is avelumab. Avelumab (also known as Bavencio) is a human lgG1 monoclonal anti-PD-L1 antibody.

[0641] Heavy chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVS SIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKL GTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0642] (SEQ ID NO: 47)

[0643] Light chain QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMI YDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRV FGTGTKVTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVA WKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVT

[0644]

[0645] HEGSTVEKTVAPTECS (SEQ ID NO: 48)

[0646] In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 47, or an amino acidsequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 47.

[0647] In some embodiments, a light chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 48 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, a light chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 48.

[0648] In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 47, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and a light chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 48 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof.

[0649] In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 47; and a light chain of the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 48. In some embodiments, a heavy chain of the anti-PD-L1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 47; and a light chain of the anti-PD-L1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 48.

[0650] In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises or consists of two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 47; and two light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 48.In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises or consists of two heavy chains consisting of the amino acid sequence of SEQ ID NO: 47; and two light chains consisting of the amino acid sequence of SEQ ID NO: 48.

[0651] Example combinations

[0652] The combination of the present invention may comprise any (a) anti-HER2 antibody-drug conjugate; and (b) anti-PD-1 / PD-L1 antibody or fragment thereof described herein. Specific examples of combinations of the present invention are provided below.

[0653] In some embodiments:

[0654] (a) the anti-HER2 antibody-drug conjugate has a structure shown as formula (I):

[0655]

[0656] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0657] q is a connection number and is an integer from 1 to 16;

[0658] L is -La-Lb-Lc-;

[0659] La- is

[0660]

[0661]

[0662] -Lc- is -CH2-;

[0663] U is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0664] V is selected from the group consisting of: (C1-6) alkylene, (C3-10) cycloalkylene, or (C1-6) alkylene-(C3-10) cycloalkylene;

[0665] R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; and

[0666] each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group; and

[0667] (b) the anti-PD-1 / PD-L1 antibody or fragment thereof comprises:

[0668] (i) a heavy chain variable region comprising: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 21; and a light chain variable region comprising: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 23; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, wherein the CDRs are defined according to the Kabat numbering system; and / or

[0669] (ii) a heavy chain variable region comprising: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 25; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and a light chain variable region comprising: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 28; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 30, wherein the CDRs are defined according to the IMGT numbering system.

[0670] In preferred embodiments:

[0671] (a) the anti-HER2 antibody-drug conjugate has a structure shown as formula (II):Trastuzumabb

[0672]

[0673] or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0674] the connection number q is an integer from 1 to 16;

[0675] L is-La-Lb-Lc-,

[0676] La- is

[0677] o

[0678] - Lb- is:

[0679]

[0680] -Lc- is -CH2-;

[0681] X1is saturated C, and X1is substituted with Rn;

[0682] ring A is selected from the group consisting of: 3-10 membered saturated or partially unsaturated heterocyclyl and 3-10 membered saturated or partially unsaturated carbocyclyl, wherein ring A is substituted with 0 or at least 1 substituent R1a;

[0683] when ring A is 3-10 membered saturated or partially unsaturated carbocyclyl, ring A is substituted with p L2, and L2is not Rn;

[0684] or, when ring A is 3-10 membered saturated or partially unsaturated heterocyclyl, ring A is substituted with p L2;L2is -R2-L3-, and R2is used for direct or indirect linking of a ligand;

[0685] L3is -(C(R3a)(R3b))m-, wherein when L3comprises a methylene unit, 0 or at least 1 methylene unit of L3is independently replaced by -N(R4)C(O)-, -C(O)N(R4)-, -C(O)-, -OC(O)-, -C(O)O-, -NR4-, -O-, -S-, -SO-, -SO2-, -P(R4)-, -P(=O)(R4)-, -N(R4)SO2-, -SO2N(R4)-, -C(=S)-, -C(=NR4)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;

[0686] R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0687] L1is -(C(R5a)(R5b))n-, wherein when L1comprises a methylene unit, 0 or at least 1 methylene unit of L1is independently replaced by -N(R6)C(O)-, -C(O)N(R6)-, -C(O)-, -OC(O)-, -C(O)O-, -NR6-, -O-, -S-, -SO-, -SO2-, -P(R6)-, -P(=O)(R6)-, -N(R6)SO2-, -SO2N(R6)-, -C(=S)-, -C(=NR6)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;

[0688] wherein each R1a, each R2a, each R3a, each R3b, each R4, each R5a, each R5b, each R6and each Rnare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a Ci-6aliphatic group optionally substituted with R;

[0689] wherein each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6 aliphatic group; and m and n are each independently selected from the group consisting of integers ≥ 0, and p is an integer ≥ 1; and

[0690] (b) the anti-PD-1 / PD-L1 antibody or fragment thereof comprises: (i) a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 31 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, preferably wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 21; and / or a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 25; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and (ii) a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 32 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, preferably wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 23; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 24; and / or a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 28;a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 30.

[0691] In more preferred embodiments:

[0692] (a) the anti-HER2 antibody-drug conjugate has a structure shown as formula (III):

[0693]

[0694] (HI) or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0695] wherein:

[0696] q is a connection number, and is an integer from 1 to 16;

[0697] R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;

[0698] R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; and

[0699] wherein each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a Ci-6aliphatic group; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof comprises: (i) a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 35 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, preferably wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 21; and / or a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 25; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and (ii) a light chain comprising or consisting of the amino acid sequence of SEQID NO: 36 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, preferably wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 23; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 24; and / or a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 28; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 30.

[0700] In even more preferred embodiments:

[0701] (a) the anti-HER2 antibody-drug conjugate has a structure shown as formula (IV):

[0702] Trastuzumab

[0703]

[0704] (IV) wherein, q is a connection number and q is selected from the group consisting of integers from 1 to 16, preferably integers from 4 to 12, for example, q is an integer from 6 to 10, for example, n is an integer from 7 to 9, such as 7, 8 or 9, preferably 8; and

[0705] (b) the anti-PD-1 / PD-L1 antibody or fragment thereof comprises two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 35; and two light chains comprising or consisting of the amino acid sequence of SEQ ID NO: 36.

[0706] In even more preferred embodiments: (a) the anti-HER2 antibody-drug conjugate is Compound 1; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof is dostarlimab.

[0707] In other embodiments:

[0708] (a) the antibody-drug conjugate has a structure shown as formula (V)o Trastuzumabb N 0

[0709] W N

[0710] nHII O01

[0711] / 9 I N

[0712] \ o HO O

[0713] —J n

[0714]

[0715] (V) wherein, q is a connection number and q is selected from the group consisting of integers from 1 to 16, preferably integers from 4 to 12, for example, q is an integer from 6 to 10, for example, n is an integer from 7 to 9, such as 7, 8 or 9, preferably 8; and

[0716] (b) the anti-PD-1 / PD-L1 antibody or fragment thereof comprises two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 35; and two light chains comprising or consisting of the amino acid sequence of SEQ ID NO: 36.

[0717] In other embodiments: (a) the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof is dostarlimab.

[0718] Variant polypeptides

[0719] In addition to the specific proteins mentioned herein, the invention also encompasses variants thereof.

[0720] The term "variant" refers to a polypeptide that has an equivalent function to the amino acid sequences described herein, but which includes one or more amino acid substitutions, insertions or deletions. The amino acid sequence may have one or more deletions, insertions or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent molecule.

[0721] Typically, amino acid substitutions may be made, for example from 1, 2 or 3, to 10 or 20 substitutions, provided that the modified sequence retains the required activity or ability. Amino acid substitutions may include the use of non-naturally occurring analogues. Deliberate amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and / or the amphipathic nature of the residues as long as theactivity is retained. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine, valine, glycine, alanine, asparagine, glutamine, serine, threonine, phenylalanine, and tyrosine.

[0722] The effect of deletions, insertions or substitutions may be predicted using any suitable prediction tool e.g. SIFT (Vaser, R., et al., 2016. Nature protocols, 11(1), pp.1-9), PolyPhen-2 (Adzhubei, I., et al., 2013. Current protocols in human genetics, 76(1), pp.7-20), CADD (Rentzsch, P., et al., 2021. Genome medicine, 13(1), pp.1-12), REVEL (loannidis, N. M., et al., 2016. The American Journal of Human Genetics, 99(4), pp.877-885), MetaLR (Dong, C., et al., 2015. Human molecular genetics, 24(8), pp.2125-2137), and / or MutationAssessor (Reva, B., et al., 2011. Nucleic acids research, 39(17), pp.e118-e118). Suitable deletions, insertions or substitutions may be considered tolerated, benign, and / or likely benign.

[0723] In the present context, a variant amino acid sequence is taken to include an amino acid sequence which may be at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85% or at least 90% identical, suitably at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the subject sequence.

[0724] Although a variant can also be considered in terms of similarity (i.e. amino acid residues having similar chemical properties / functions), in the context of the present invention it is preferred to express it in terms of sequence identity.

[0725] The terms “identity” and “% sequence identity” as used herein, may refer to the proportion of nucleotides or amino acids (expressed in percent) of a contiguous nucleotide sequence or contiguous amino acid sequence respectively which across the sequence, are identical to a reference sequence. The identity is calculated by counting the number of aligned nucleobases or amino acids that are identical (a Match) between the sequence of interest and a reference sequence, and dividing that number by the total number of nucleotides or amino acids respectively and multiplying by 100. Therefore, Percentage of Identity = (Matches x 100) / Length of aligned region. Insertions and deletions are not allowed in the calculation of the percentage of identity. Identity comparisons can be conducted by eye, or more usually, with the aid of readily available sequence comparison programs. These commercially available computer programs can calculate % identity between two or more sequences.Percent identity may be calculated over contiguous sequences, i.e. one sequence is aligned with the other sequence and each amino acid or nucleotide in one sequence is directly compared with the corresponding amino acid or nucleotide in the other sequence, one residue at a time. This is called an “ungapped” alignment. Typically, such ungapped alignments are performed only over a relatively short number of residues.

[0726] Although this is a very simple and consistent method, it fails to take into consideration that, for example, in an otherwise identical pair of sequences, one insertion or deletion in the amino acid or nucleotide sequence may cause the following residues or codons to be put out of alignment, thus potentially resulting in a large reduction in percent identity when a global alignment is performed. Consequently, most sequence comparison methods are designed to produce optimal alignments that take into consideration possible insertions and deletions without penalising unduly the overall identity score. This is achieved by inserting “gaps” in the sequence alignment to try to maximise local identity.

[0727] However, these more complex methods assign “gap penalties” to each gap that occurs in the alignment so that, for the same number of identical amino acids or nucleotides, a sequence alignment with as few gaps as possible, reflecting higher relatedness between the two compared sequences, will achieve a higher score than one with many gaps. “Affine gap costs” are typically used that charge a relatively high cost for the existence of a gap and a smaller penalty for each subsequent residue in the gap. This is the most commonly used gap scoring system. High gap penalties will produce optimised alignments with fewer gaps. Most alignment programs allow the gap penalties to be modified. However, it is preferred to use the default values when using such software for sequence comparisons. For example, when using the GCG Wisconsin Bestfit package the default gap penalty for amino acid sequences is -12 for a gap and -4 for each extension.

[0728] Calculation of maximum percent identity therefore firstly requires the production of an optimal alignment, taking into consideration gap penalties. A suitable computer program for carrying out such an alignment is the GCG Wisconsin Bestfit package (University of Wisconsin, U. S. A.; Devereux et al., 1984, Nucleotide sequences Research 12:387). Examples of other software than can perform sequence comparisons include, but are not limited to, the BLAST package (see Ausubel et al., 1999 ibid - Chapter 18), BLAST 2 (see e.g. Tatusova, T. A. and Madden, T. L., 1999. FEMS microbiology letters, 174(2), pp.247-250), FASTA (Atschul et al., 1990, J. Mol. Biol., 403-410), EMBOSS Needle (Madeira, F., et al., 2019. Nucleic acids research, 47(W1), pp. W636-W641) and the GENEWORKS suite of comparison tools. For some applications, it is preferred to use EMBOSS Needle.Once the software has produced an optimal alignment, it is possible to calculate percent sequence identity. The software typically does this as part of the sequence comparison and generates a numerical result. Although the final percent identity can be measured, the alignment process itself is typically not based on an all-or-nothing pair comparison. Instead, a scaled similarity score matrix is generally used that assigns scores to each pairwise comparison based on chemical similarity or evolutionary distance. An example of such a matrix commonly used is the BLOSUM62 matrix.

[0729] Variants may be prepared using standard recombinant DNA techniques such as site-directed mutagenesis. Where insertions are to be made, synthetic DNA encoding the insertion together with 5’ and 3’ flanking regions corresponding to the naturally-occurring sequence either side of the insertion site may be made. The flanking regions will contain convenient restriction sites corresponding to sites in the naturally-occurring sequence so that the sequence may be cut with the appropriate enzyme(s) and the synthetic DNA ligated into the cut. The DNA is then expressed in accordance with the invention to make the encoded protein. These methods are only illustrative of the numerous standard techniques known in the art for manipulation of DNA sequences and other known techniques may also be used.

[0730] Medical Uses and Methods of Treatment

[0731] The combination of the present invention may be used in therapy, for example, for the treatment or prevention of a disease (e.g. cancer).

[0732] In one aspect, the present invention provides the combination of the invention for use in therapy. In another aspect, the present invention provides an anti-HER2 antibody-drug conjugate for use in therapy, wherein the use comprises administering to a subject the combination of the invention. In another aspect, the present invention provides an anti-PD-1 / PD-L1 antibody or fragment thereof for use in therapy, wherein the use comprises administering to a subject the combination of the invention.

[0733] In one aspect, the present invention provides use of the combination of the invention in the manufacture of a medicament. In another aspect, the present invention provides use of an anti-HER2 antibody-drug conjugate in the manufacture of a medicament, wherein the use comprises administering to a subject the combination of the invention. In another aspect, the present invention provides use of an anti-PD-1 / PD-L1 antibody or fragment thereof in the manufacture of a medicament, wherein the use comprises administering to a subject the combination of the invention.In one aspect, the present invention provides use of the combination of the invention in therapy. In another aspect, the present invention provides use of an anti-HER2 antibody-drug conjugate in therapy, wherein the use comprises administering to a subject the combination of the invention. In another aspect, the present invention provides use of an anti-PD-1 / PD-L1 antibody or fragment thereof in therapy, wherein the use comprises administering to a subject the combination of the invention.

[0734] The term "disease" and "disorder" may be used interchangeably herein and may refer to an abnormal condition especially an abnormal medical condition such as an illness or injury, wherein a cell, a tissue, an organ, or an individual is not able to efficiently fulfil its function anymore. Typically, but not necessarily, a disease is associated with specific symptoms or signs indicating the presence of such disease. The presence of such symptoms or signs may thus, be indicative for a cell, a tissue, an organ, or an individual suffering from a disease. An alteration of these symptoms or signs may be indicative for the progression of such a disease.

[0735] A progression of a disease is typically characterised by an increase or decrease of such symptoms or signs which may indicate a "worsening" or "bettering" of the disease. The "worsening" of a disease is characterised by a decreasing ability of a cell, tissue, organ or individual / patient to fulfil its function efficiently, whereas the "bettering" of a disease is typically characterised by an increase in the ability of a cell, tissue, an organ or an individual / patient to fulfil its function efficiently.

[0736] The terms “treat”, “treatment” and “treating” may refer to lessening, reducing or improving at least one symptom associated with an existing disease or condition and / or to slow down, reduce or block the progression of the disease or condition and / or to delay or prevent the onset of symptoms (such as further symptoms) of the disease or condition. The terms “prevent”, “prevention” and “preventing” may refer to preventing the onset of symptoms of a disease or condition, and as such encompasses prophylactic treatment.

[0737] In some embodiments, the combination of the invention may result in a lowered incidence of disease or symptoms, delayed onset of disease or symptoms, and / or reduced severity of disease or symptoms, compared to other therapies that are known in the art.

[0738] The medical uses and methods of treatment described herein may be used in combination with additional treatments and / or medicaments. For example, the medical uses and methods of treatment described herein may be combined with known chemotherapeutic,immunomodulatory and / or radiotherapy treatments in the form of a combination therapy or treatment.

[0739] Treatment of cancer

[0740] The combination of the present invention may be used to treat cancer.

[0741] As used herein, a “cancer disease” or “cancer” includes a disease characterized by aberrantly regulated cellular growth, proliferation, differentiation, adhesion, and / or migration. By “cancer cell” is meant an abnormal cell that grows by a rapid, uncontrolled cellular proliferation and continues to grow after the stimuli that initiated the new growth cease. The term “cancer” also includes cancer metastasis of a primary tumour such as primary prostate cancer. Thus, if reference is made, for example, to prostate cancer, this also includes metastasis of the prostate cancer, for example metastasis to the lung, liver and / or lymph nodes.

[0742] In one aspect, the present invention provides the combination of the invention for use in treating cancer. In another aspect, the present invention provides an anti-HER2 antibody-drug conjugate for use in treating cancer, wherein the use comprises administering to a subject the combination of the invention. In another aspect, the present invention provides an anti-PD-1 / PD-L1 antibody or fragment thereof for use in treating cancer, wherein the use comprises administering to a subject the combination of the invention.

[0743] In one aspect, the present invention provides use of the combination of the invention in the manufacture of a medicament for the treatment of cancer. In another aspect, the present invention provides use of an anti-HER2 antibody-drug conjugate in the manufacture of a medicament for the treatment of cancer, wherein the use comprises administering to a subject the combination of the invention. In another aspect, the present invention provides use of an anti-PD-1 / PD-L1 antibody or fragment thereof in the manufacture of a medicament for the treatment of cancer, wherein the use comprises administering to a subject the combination of the invention.

[0744] In one aspect, the present invention provides use of the combination of the invention in treating cancer. In another aspect, the present invention provides use of an anti-HER2 antibody-drug conjugate in treating cancer, wherein the use comprises administering to a subject the combination of the invention. In another aspect, the present invention provides use of an anti-PD-1 / PD-L1 antibody or fragment thereof in treating cancer, wherein the use comprises administering to a subject the combination of the invention.In one aspect, the present invention provides a method of treating cancer in a subject, comprising administering the combination of the invention to a subject.

[0745] The cancer treated by the present invention may be selected from endometrial cancer, lung cancer, kidney cancer, urinary tract carcinoma, colorectal cancer, prostatic cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, and esophageal cancer. In some embodiments, the cancer is selected from the group consisting of endometrial cancer, breast cancer, colorectal cancer, esophageal carcinoma, ovarian cancer, and vaginal cancer.

[0746] In some embodiments, the cancer is a metastatic cancer. By “metastasis” is meant the spread of cancer cells from its original site to another part of the body. The formation of metastasis is a very complex process and depends on detachment of malignant cells from the primary tumour, invasion of the extracellular matrix, penetration of the endothelial basement membranes to enter the body cavity and vessels, and then, after being transported by the blood, infiltration of target organs. Finally, the growth of a new tumour at the target site depends on angiogenesis. Tumour metastasis often occurs even after the removal of the primary tumour because tumour cells or components may remain and develop metastatic potential. In one embodiment, the term “metastasis” according to the invention relates to “distant metastasis” which relates to a metastasis which is remote from the primary tumour and the regional lymph node system. In one embodiment, the term “metastasis” according to the invention relates to lymph node metastasis.

[0747] In some embodiments, the cancer is an advanced cancer. An advanced cancer is a cancer which has spread (metastasised) or recurred.

[0748] In some embodiments, the cancer is a refractory or unresectable cancer. A refractory cancer is a malignancy for which a particular treatment is ineffective, which is either initially unresponsive to treatment, or which becomes unresponsive over time. An unresectable cancer is that which cannot be removed completely through surgery.

[0749] In some embodiments, the cancer is positive for PD-L1. In some embodiments, PD-L1 is expressed at least on a portion of the cells of the cancer, such as at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In some embodiments, PD-L1 is expressed on the surface of at least a portion of the tumour cells of the solid tumour, such as at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In some embodiments, PD-L1 is expressed on the surface of at least a portion of the tumour cells of the solid tumour and oneor more target expressed on the surface of the tumour cells as described herein is / are expressed (i) a different portion, (ii) a same portion or (iii) an overlapping portion of the tumour cells of the solid tumour.

[0750] HER2-expressing cancers

[0751] In some embodiments, the cancer expresses HER2. HER2 gene amplification and / or protein overexpression has been observed in >30% of all human cancers, including breast cancer, gastric, colon, salivary gland, bladder, and endometrial cancer, including uterine serous carcinoma. HER2 expression in tumours is a predictive marker for response to HER2-targeted therapy in multiple cancers including breast and gastric cancer (see e.g. Yan, M., et al., 2015. Cancer and Metastasis Reviews, 34, pp.157-164; Cocco, E., et al., 2019. Pharmacology & therapeutics, 199, pp.188-196; and Oh, D. Y. and Bang, Y. J., 2020. Nature reviews Clinical oncology, 17(1), pp.33-48).

[0752] HER2 expression may be determined by any suitable method, for example by scoring the degree of HER2 expression or determining positivity or negativity for HER2 expression. The method for scoring the degree of HER2 expression by the IHC method, or the method for determining positivity or negativity for HER2 expression by the ISH method is not particularly limited as long as it is recognized by those skilled in the art. Examples of the method can include a method described in ASCO 2018 for Breast and Endometrial Cancer (see e.g. Wolff, Antonio C., et al. Archives of pathology & laboratory medicine 142, no. 11 (2018): 1364-1382). In particular, algorithms for evaluation of HER2 protein expression by immunohistochemistry (IHC) assay of the invasive component of a specimen, by in situ hybridization (ISH) assay of the invasive component of a specimen using a single-signal (HER2 gene) assay (single-probe ISH), and by in situ hybridization (ISH) assay of the invasive component of a specimen using a dual-signal (HER2 gene) assay (dual-probe ISH), were published by ASCO in 2018.

[0753] Tumours with normal HER2 levels may be referred to as either “HER2-normal” or “HER2-negative” (lacking HER2 overexpression / amplification), while tumours with gene amplification / overexpression may be referred to as “HER2-positive”. HER2 status is most commonly determined using immunohistochemistry (IHC) or in situ hybridization (FISH). Grading of IHC assays is based on a 0, 1+, 2+, and 3+ scoring system, where 0 and 1+ are HER2-negative, 2+ is HER2-equivocal (to be confirmed by ISH), and 3+ is HER2-positive (see e.g. Perez, E. A., et al., 2014. Cancer treatment reviews, 40(2), pp.276-284; and Ahn, S., et al., 2020. Journal of pathology and translational medicine, 54(1), pp.34-44).In some embodiments, the cancer is a HER2-expressing cancer. In some embodiments, the cancer is HER2-normal or HER2-positive. In some embodiments, the cancer is documented as HER2 1+, 2+, or 3+ score by an immunohistochemistry (IHC) test.

[0754] In some embodiments, the cancer is a HER2-overexpressing cancer. In some embodiments, the cancer is HER2-positive. In some embodiments, the cancer is cancer given a score of 3+ for the expression of HER2 in an IHC method or is cancer given a score of 2+ for the expression of HER2 in an IHC method and determined as positive for the expression of HER2 in a ISH method.

[0755] In some embodiments, the cancer is HER2-normal or HER2-positive; and PD-L1 -positive. In some embodiments, the cancer is HER2-positive and PD-L1 -positive.

[0756] Endometrial cancer

[0757] In preferred embodiments, the cancer is endometrial cancer. In some embodiments, the endometrial cancer is HER2-expressing endometrial cancer. In some embodiments, the endometrial cancer is pMMR, HER2-expressing endometrial cancer.

[0758] Endometrial cancer is a disease in which cancer cells form in the tissues of the endometrium. Endometrioid carcinoma of the endometrium is the most common histological subtype of endometrial cancer accounting for 85-90% of cases. The most representative non-endometrioid endometrial carcinoma is uterine serous carcinoma (USC) that accounts for about 10% of all endometrial cancers. Other type non-endometrioid endometrial cancer included carcinosarcoma (2-5%), undifferentiated (5%), clear cell (2-4%), and squamous cell (0.1-0.5%) carcinoma. In some embodiments, the endometrial cancer is an endometrioid endometrial cancer or a non-endometrioid endometrial cancer (see e.g. Bogani, G., et al., 2021. Gynecologic oncology, 162(1), pp.226-234). In some embodiments, the endometrial cancer is an endometrioid endometrial cancer or uterine serous carcinoma (USC).

[0759] The Cancer Genome Atlas categorizes endometrial cancer into four groups according to their molecular profile: ultra-mutated (POLE-mutant), copy number-high (p53-abnormal), copy number-low (no specific molecular profile [NSMP]), and hypermutated (dMMR). Endometrial cancer without defects in MMR genes are called pMMR (see Crosbie, E. J., et al., 2022. The Lancet, 399(10333), pp.1412-1428). In preferred embodiments, the endometrial cancer is pMMR endometrial cancer. In other embodiments, the endometrial cancer is not limited by MMR status.In some embodiments, the cancer is recurrent or primary advanced endometrial cancer. In some embodiments, the cancer is recurrent or primary advanced HER2-expressing endometrial cancer.

[0760] In some embodiments, the cancer is stage III or IV endometrial cancer. In some embodiments, the cancer is HER2-expressing stage III or IV endometrial cancer. For example, the cancer staging may be determined by FIGO staging (see e.g. Berek, J. S., et al., 2023. International Journal of Gynecology & Obstetrics, 162(2), pp.383-394).

[0761] In some embodiments, the cancer is pMMR, recurrent or primary advanced HER2-expressing endometrial cancer. In some embodiments, the cancer is pMMR, stage III or IV HER2-expressing endometrial cancer.

[0762] Subject to be treated

[0763] The combination of the invention may be administered to any subject in need thereof.

[0764] In this specification, the terms “subject” and “patient” are synonymous. As used herein, the term “patient” may refer to a subject for treatment, in particular a diseased subject, including human beings, nonhuman primates or other animals, in particular mammals such as cows, horses, pigs, sheep, goats, dogs, cats or rodents such as mice and rats.

[0765] In a particularly preferred embodiment, the subject is a human. In some embodiments, the subject is aged >18 years. In some embodiments, the subject is an adult human. In some embodiments, the subject is a human female. In some embodiments, the subject is an adult human female.

[0766] In some embodiments, the subject may suffer from and / or have been diagnosed with one or more cancer(s). The subject may suffer from a histologically or cytologically confirmed cancer and / or solid tumour. The subject may suffer from and / or have been diagnosed with a pathologically documented cancer and / or solid tumour. The cancer and / or solid tumour may be any described herein. In preferred embodiments, the subject may suffer from and / or have been diagnosed with one or more HER2-expressing cancers. In some embodiments, the subject may suffer from and / or have been diagnosed with a HER2-normal cancer or a HER2-positive cancer. In some embodiments, the subject may suffer from and / or have been diagnosed with a cancer that is documented as HER2 1+, 2+, or 3+ score by an immunohistochemistry (IHC) test. In some embodiments, the subject may suffer from and / orhave been diagnosed with a cancer which is a HER2 positive cancer. In some embodiments, the subject may suffer from and / or have been diagnosed with a cancer given a score of 3+ for the expression of HER2 in an IHC method or a cancer given a score of 2+ for the expression of HER2 in an IHC method and determined as positive for the expression of HER2 in a ISH method.

[0767] In some embodiments, the subject may suffer from and / or have been diagnosed with a HER2-normal or a HER2-positive; and a PD-L1 -positive cancer. In some embodiments, the subject may suffer from and / or have been diagnosed with a HER2-positive and PD-L1 -positive cancer.

[0768] In some embodiments, the subject has endometrial cancer. In some embodiments, the subject has recurrent or primary advanced endometrial cancer. In some embodiments, the subject has stage lll / IV endometrial cancer or first recurrent endometrial cancer. In some embodiments, the subject has recurrent or primary advanced HER2-expressing endometrial cancer. In preferred embodiments, the endometrial cancer is histologically confirmed. In some embodiments, the subject has histologically confirmed stage lll / IV endometrial cancer, or first recurrent endometrial cancer that is documented as HER2 1+, 2+, or 3+ score by an immunohistochemistry (IHC) test.

[0769] In some embodiments, the subject has proficient mismatch repair (pMMR) endometrial cancer. In some embodiments, the pMMR is histologically confirmed, for example by an immunohistochemistry (IHC) test. In some embodiments, the subject has pMMR, recurrent or primary advanced endometrial cancer. In some embodiments, the subject has pMMR, stage lll / IV endometrial cancer or first recurrent endometrial cancer. In some embodiments, the subject has pMMR, recurrent or primary advanced HER2-expressing endometrial cancer.

[0770] In some embodiments, the subject has been previously treated for the cancer. In some embodiments, the subject has received at least one first-line treatment for cancer. In some embodiments, the subject has received prior chemotherapy. In some embodiments, the subject has received prior immunotherapy. In some embodiments, the subject has received prior targeted therapy. In some embodiments, the subject has completed 2-10, 3-9, or 4-8 cycles of the prior therapy.

[0771] In some embodiments, the subject has received prior treatment with a platinum-based chemotherapy, such as cisplatin, oxaliplatin, and carboplatin. In preferred embodiments, the platinum-based chemotherapy is carboplatin. In some embodiments, the subject has received prior treatment with a taxane, such as paclitaxel, docetaxel or cabazitaxel. In preferredembodiments, the taxane is paclitaxel. In some embodiments, the subject has received prior treatment with an immune checkpoint inhibitor, such as anti-PD-1 / PD-L1 inhibitor. In some embodiments, the anti-PD-1 / PD-L1 inhibitor is selected from any anti-PD-1 / PD-L1 antibody or fragment thereof described herein, for example the anti-PD-1 / PD-L1 antibody or fragment thereof may be identical to that used in the combination therapy. In preferred embodiments, the anti-PD-1 / PD-L1 inhibitor is dostarlimab.

[0772] In some embodiments, the subject has received prior treatment with a platinum-based chemotherapy, a taxane, and an immune checkpoint inhibitor. In some embodiments, the subject has completed 1-8 cycles of the treatment with a platinum-based chemotherapy, a taxane, and an immune checkpoint inhibitor. In some embodiments, the subject has completed 4-8 cycles of the treatment with a platinum-based chemotherapy, a taxane, and an immune checkpoint inhibitor. In some embodiments, the subject has completed at least 6 cycles of the treatment with a platinum-based chemotherapy, a taxane, and an immune checkpoint inhibitor.

[0773] In some embodiments, the subject has received prior treatment with carboplatin, paclitaxel, and a PD-1 / PD-L1 inhibitor (e.g. dostarlimab). In some embodiments, the subject has completed 1-8 cycles of treatment with carboplatin, paclitaxel, and a PD-1 / PD-L1 inhibitor (e.g. dostarlimab). In some embodiments, the subject has completed 4-8 cycles of treatment with carboplatin, paclitaxel, and a PD-1 / PD-L1 inhibitor (e.g. dostarlimab). In some embodiments, the subject has completed at least 6 cycles of treatment with carboplatin, paclitaxel, and a PD-1 / PD-L1 inhibitor (e.g. dostarlimab). In some embodiments, the subject has received prior treatment with (i) carboplatin administered as an IV infusion at AUC 5 mg*mL / min Q3W for 6 cycles, (ii) paclitaxel administered as an IV infusion at 175 mg / m2Q3Wfor 6 cycles, and (iii) dostarlimab administered as an IV infusion at 500 mg Q3W for 6 cycles. Carboplatin dose (mg) may be calculated as: target area under the plasma or serum concentration-time curve (AUC) (mg*min / mL) x (creatinine clearance [CrCI] + 25). For target AUC = 5, the maximum dose is 5 x 150 = 750 mg. Paclitaxel dose may be calculated based on the body surface area, for example Body surface area = square root ([body weight (kg) x height (cm)] / 3600).

[0774] In some embodiments, the subject has achieved complete response (CR), partial response (PR), or stable disease (SD), following the previous treatment. PR, CR, or SD may be according to RECIST version 1.1. PR, CR, or SD may be determined by any suitable method, for example by imaging. In some embodiments, the subject has achieved PR, CR, or SD by imaging according to RECIST version 1.1.In some embodiments, the subject has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2. In some embodiments, the subject has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

[0775] In some embodiments, the subject has not received prior treatment with topoisomerase I inhibitors. In some embodiments, the subject has not received prior treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 inhibitors (other than a combination of a platinum-based chemotherapy, a taxane, and an immune checkpoint inhibitor described above). In some embodiments, the subject has not received prior treatment with topoisomerase I inhibitors or anti-PD-1, anti-PD-L1, or anti-PD-L2 inhibitors (other than a combination of a platinum-based chemotherapy, a taxane, and an immune checkpoint inhibitor described above).

[0776] In some embodiments, the subject: (a) is an adult human female; (b) has recurrent or primary advanced HER2-expressing proficient mismatch repair (pMMR) endometrial cancer; and (c) has received prior treatment with a platinum-based chemotherapy, a taxane, and an immune checkpoint inhibitor.

[0777] In some embodiments, the subject: (a) is an adult human female; (b) has histologically confirmed proficient mismatch repair (pMMR) endometrial cancer; (c) has histologically confirmed stage lll / IV endometrial cancer, or first recurrent endometrial cancer that is documented as HER2 1+, 2+, or 3+ score by an immunohistochemistry (IHC) test; (d) has completed 4-8 cycles of treatment with carboplatin, paclitaxel, and a PD-1 / PD-L1 inhibitor (e.g. dostarlimab) and achieved PR, CR, or SD by imaging according to RECIST version 1.1; and (e) has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2.

[0778] Doses

[0779] The combination of the present invention may be administered to a patient at any appropriate dose. It will be understood that the dose may be selected based on considerations of age, body weight, disease symptoms, disease progression and / or severity, sex, and / or any other factors which may interfere with the therapeutic effects the combination of the present invention.

[0780] In some embodiments, the anti-HER2 antibody-drug conjugate is administered at a dose in the range of from about 1 mg / kg to about 15 mg / kg. In some embodiments, the anti-HER2 antibody-drug conjugate is administered at a dose of at least about 2 mg / kg, at least about 3 mg / kg, at least about 4 mg / kg, at least about 5 mg / kg, at least about 6 mg / kg, at least about 7mg / kg, or at least about 8 mg / kg. In some embodiments, the anti-HER2 antibody-drug conjugate is administered at a dose of about 14 mg / kg or less, about 13 mg / kg or less, about 12 mg / kg or less, about 11 mg / kg or less, about 10 mg / kg or less, about 9 mg / kg or less, or about 8 mg / kg or less. In some embodiments, the anti-HER2 antibody-drug conjugate is administered at a dose in the range of from about 2 mg / kg to about 14 mg / kg, from about 3 mg / kg to about 13 mg / kg, from about 4 mg / kg to about 12 mg / kg, from about 5 mg / kg to about 11 mg / kg, from about 6 mg / kg to about 10 mg / kg, or from about 7 mg / kg to about 9 mg / kg.

[0781] In some embodiments, the anti-HER2 antibody-drug conjugate is administered at a dose in the range of from about 2.2 mg / kg to about 12.0 mg / kg. In some embodiments, the anti-HER2 antibody-drug conjugate is administered at a dose in the range of from about 6.0 mg / kg to about 10.0 mg / kg. In some embodiments, the anti-HER2 antibody-drug conjugate is administered at a dose in the range of from about 7.0 mg / kg to about 9.0 mg / kg. In some embodiments, the anti-HER2 antibody-drug conjugate is administered at a dose of about 8.0 mg / kg.

[0782] In some embodiments, the anti-HER2 antibody-drug conjugate is administered from about every week to about once every four weeks. In some embodiments, the anti-HER2 antibodydrug conjugate is administered from about once every two weeks to about once every four weeks. In some embodiments, the anti-HER2 antibody-drug conjugate is administered about once every three weeks. In some embodiments, the anti-HER2 antibody-drug conjugate is administered about once every 18-24 days. In some embodiments, the anti-HER2 antibodydrug conjugate is administered about once every 21 days.

[0783] In some embodiments, the anti-HER2 antibody-drug conjugate is administered at a dose of about 8.0 mg / kg about once every three weeks.

[0784] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is administered at a dose in the range of from about 100 mg to about 5000 mg. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is administered at a dose of at least about 200 mg, at least about 300 mg, at least about 400 mg, at least about 500 mg, at least about 600 mg, at least about 700 mg, at least about 800 mg, at least about 900 mg, or at least about 1000 mg. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is administered at a dose of about 4500 mg or less, about 4000 mg or less, about 3500 mg or less, about 3000 mg or less, about 2500 mg or less, about 2000 mg or less, about 1900 mg or less, about 1800 mg or less, about 1700 mg or less, about 1600 mg or less, about 1500 mg or less, about 1400mg or less, about 1300 mg or less, about 1200 mg or less, about 1100 mg or less, or about 1000 mg or less.

[0785] In some preferred embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof (e.g., dostarlimab) is administered in a dosage of from about 500 mg to about 2000 mg. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof (e.g., dostarlimab) is administered in a dosage of from about 800 mg to about 1200 mg. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof (e.g., dostarlimab) is administered in a dosage of from about 900 mg to about 1100 mg. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof (e.g., dostarlimab) is administered in a dosage of about 1000 mg.

[0786] In other embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is administered in a dosage of from about 250 mg to about 750 mg. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is administered in a dosage of from about 300 mg to about 700 mg. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof (e.g., dostarlimab) is administered in a dosage of from about 400 mg to about 600 mg. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof (e.g., dostarlimab) is administered in a dosage of about 500 mg.

[0787] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof (e.g., dostarlimab) is administered from about once every week to about once every twelve weeks. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is administered from about once every two weeks to about once every ten weeks. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is administered from about once every three weeks to about once every nine weeks. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is administered from about once every four weeks to about once every eight weeks. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is administered from about once every five weeks to about once every seven weeks. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof (e.g., dostarlimab) is administered about once every six weeks.

[0788] In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof (e.g., dostarlimab) is administered at a dose of about 1000 mg about once every six weeks.

[0789] In some embodiments: (a) the anti-HER2 antibody-drug conjugate is administered at a dose in the range of from about 1 mg / kg to about 15 mg / kg; and (b) the anti-PD-1 / PD-L1 antibodyor fragment thereof (e.g., dostarlimab) is administered at a dose in the range of from about 100 mg to about 5000 mg.

[0790] In some embodiments: (a) the anti-HER2 antibody-drug conjugate is administered at a dose in the range of from about 2.2 mg / kg to about 12.0 mg / kg; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof (e.g., dostarlimab) is administered at a dose in the range of from about 500 mg to about 2000 mg.

[0791] In some embodiments: (a) the anti-HER2 antibody-drug conjugate is administered at a dose in the range of from about 6.0 mg / kg to about 10.0 mg / kg; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof (e.g., dostarlimab) is administered at a dose in the range of from about 800 mg to about 1200 mg.

[0792] In some embodiments: (a) the anti-HER2 antibody-drug conjugate is administered at a dose of about 8.0 mg / kg; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof (e.g., dostarlimab) is administered at a dose of about 1000 mg.

[0793] In some embodiments: (a) the anti-HER2 antibody-drug conjugate is administered at a dose in the range of from about 2.2 mg / kg to about 12.0 mg / kg; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof is administered at a dose in the range of from about 250 mg to about 750 mg. In some embodiments: (a) the anti-HER2 antibody-drug conjugate is administered at a dose in the range of from about 6.0 mg / kg to about 10.0 mg / kg; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof is administered at a dose in the range of from about 400 mg to about 600 mg. In some embodiments: (a) the anti-HER2 antibody-drug conjugate is administered at a dose of about 8.0 mg / kg; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof is administered at a dose of about 500 mg.

[0794] In some embodiments: (a) the anti-HER2 antibody-drug conjugate is administered from about once every week to about once every four weeks; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof is administered from about once every two weeks to about once every ten weeks.

[0795] In some embodiments: (a) the anti-HER2 antibody-drug conjugate is administered from about once every two weeks to about once every four weeks; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof is administered from about once every five weeks to about once every seven weeks.In some embodiments: (a) the anti-HER2 antibody-drug conjugate is administered about once every three weeks; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof is administered about once every six weeks.

[0796] In some embodiments: (a) the anti-HER2 antibody-drug conjugate is administered at a dose in the range of from about 6.0 mg / kg to about 10.0 mg / kg from about once every two weeks to about once every four weeks; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof is administered at a dose in the range of from about 800 mg to about 1200 mg from about once every five weeks to about once every seven weeks.

[0797] In some embodiments: (a) the anti-HER2 antibody-drug conjugate is administered at a dose of about 8.0 mg / kg about once every three weeks; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof is administered at a dose of about 1000 mg about once every six weeks.

[0798] Administration and treatment cycles

[0799] The anti-HER2 antibody-drug conjugate and anti-PD-1 / PD-L1 antibody or fragment thereof may be administered separately by any suitable route and in any suitable form.

[0800] In some embodiments, the anti-HER2 antibody-drug conjugate and anti-PD-1 / PD-L1 antibody or fragment thereof are administered sequentially. In some embodiments, the anti-HER2 antibody-drug conjugate is administered before the anti-PD-1 / PD-L1 antibody or fragment thereof. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is administered before the anti-HER2 antibody-drug conjugate. In some embodiments, the anti-HER2 antibody-drug conjugate and anti-PD-1 / PD-L1 antibody or fragment thereof are administered concomitantly.

[0801] In some embodiments, a dose of the anti-HER2 antibody-drug conjugate and a dose of the anti-PD-1 / PD-L1 antibody or fragment thereof are administered concurrently or consecutively. In some embodiments, a dose of the anti-HER2 antibody-drug conjugate and a dose of the anti-PD-1 / PD-L1 antibody or fragment thereof are administered concurrently. In some embodiments, a dose of the anti-HER2 antibody-drug conjugate and a dose of the anti-PD-1 / PD-L1 antibody or fragment thereof are administered consecutively.

[0802] In some embodiments, the anti-HER2 antibody-drug conjugate and / or the anti-PD-1 / PD-L1 antibody or fragment thereof is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, excipients or diluents. In someembodiments, the anti-HER2 antibody-drug conjugate and the anti-PD-1 / PD-L1 antibody or fragment thereof are each administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, excipients or diluents.

[0803] In some embodiments, the anti-HER2 antibody-drug conjugate and / or the anti-PD-1 / PD-L1 antibody or fragment thereof are administered by oral, parenteral, intraperitoneal, systemic, intravenous (such as intravenous infusion or intravenous drip), intramuscular, subcutaneous, topical, inhalative, rectal, sublingual, transdermal, or vaginal administration.

[0804] In some embodiments, the anti-HER2 antibody-drug conjugate and / or the anti-PD-1 / PD-L1 antibody or fragment thereof is administered intravenously (e.g. by being injected into a subject). In some embodiments, the anti-HER2 antibody-drug conjugate and the anti-PD-1 / PD-L1 antibody or fragment thereof are each administered intravenously (e.g. by being injected into a subject).

[0805] In some embodiments, the anti-HER2 antibody-drug conjugate and / or the anti-PD-1 / PD-L1 antibody or fragment thereof is administered by IV infusion. In some embodiments, the anti-HER2 antibody-drug conjugate and the anti-PD-1 / PD-L1 antibody or fragment thereof are each administered by IV infusion.

[0806] In some embodiments, the combination is administered to a subject once (i.e. as a one-off treatment). For example, the combination may be administered to a subject once over a continuous period of hours or days. In other embodiments, the combination is administered to a subject on multiple, separate occasions (e.g. as part of an on-going treatment). For example, the combination may be administered to a subject on multiple, separate occasions over a total period of hours, days, weeks, months or years (generally described herein as “treatment cycles” or “exposure cycles”).

[0807] The term “treatment cycle” takes its normal meaning in the field of oncology to mean a period of time over which an anti-cancer drug or combination therapy is administered, followed by a rest period during which the drug or combination therapy is not administered. In some embodiments, each treatment cycle is from 1 week to 6 weeks, from 2 weeks to 4 weeks, or about 3 weeks. In each treatment cycle, the period over which the anti-HER2 antibody-drug conjugate and / or the anti-PD-1 / PD-L1 antibody or fragment thereof is administered is preferably 30 minutes to 6 hours, more preferably 40 minutes to 4 hours, more preferably 60 minutes to 3 hours, and the rest period is preferably 7 to 35 days, more preferably 14 to 28 days, even more preferably 18 to 23 days, most preferably about 21 days.In some embodiments, the anti-HER2 antibody-drug conjugate is administered in at least 1 treatment cycle, at least 2 treatment cycles, at least 3 treatment cycles, at least 4 treatment cycles, at least 5 treatment cycles, at least 6 treatment cycles, at least 7 treatment cycles, at least 8 treatment cycles, at least 9 treatment cycles, at least 10 treatment cycles, at least 11 treatment cycles, at least 12 treatment cycles, at least 13 treatment cycles, at least 14 treatment cycles, at least 15 treatment cycles, at least 16 treatment cycles, at least 17 treatment cycles, or at least 18 treatment cycles. In some embodiments, the anti-PD-1 / PD-L1 antibody or fragment thereof is administered in at least 1 treatment cycle, at least 2 treatment cycles, at least 3 treatment cycles, at least 4 treatment cycles, at least 5 treatment cycles, at least 6 treatment cycles, at least 7 treatment cycles, at least 8 treatment cycles, or at least 9 treatment cycles.

[0808] In some embodiments, in a first treatment cycle (and all subsequent odd-numbered treatment cycles) the subject is administered the anti-HER2 antibody-drug conjugate and the anti-PD-1 / PD-L1 antibody or fragment thereof; and in a second treatment cycle (and all subsequent even-numbered treatment cycles) the subject is administered the anti-HER2 antibody-drug conjugate only. In the first treatment cycle, the anti-HER2 antibody-drug conjugate and the anti-PD-1 / PD-L1 antibody or fragment thereof may be administered on the same day, for example over a treatment period of from about 1 hour to about 6 hours. Each treatment cycle may be separated by about 3 weeks.

[0809] In some embodiments, the combination is administered for at least 4 treatment cycles, at least 5 treatment cycles, at least 6 treatment cycles, at least 7 treatment cycles, at least 8 treatment cycles, at least 9 treatment cycles, at least 10 treatment cycles, at least 11 treatment cycles, at least 12 treatment cycles, at least 13 treatment cycles, at least 14 treatment cycles, at least 15 treatment cycles, at least 16 treatment cycles, at least 17 treatment cycles, or at least 18 treatment cycles. In some embodiments, the combination is administered for at least about 3 months, at least about 6 months, at least about 9 months, or at least about 12 months. Typically, there is no upper limit on the number of treatment cycles and treatment is continued until disease progression or unacceptable toxicity occurs, or the patient or oncologist decides to discontinue administration. In some embodiments, the combination is administered for up to about 24 months.

[0810] Pharmaceutical compositions

[0811] The combination of the present invention may be administered in the form of one or more pharmaceutical compositions.In some embodiments, the anti-HER2 antibody-drug conjugate is administered in the form of a pharmaceutical composition; and / or the anti-PD-1 / PD-L1 antibody or fragment thereof is administered in the form of a pharmaceutical composition.

[0812] In some embodiments, the anti-HER2 antibody-drug conjugate is administered in the form of a pharmaceutical composition; and the anti-PD-1 / PD-L1 antibody or fragment thereof is administered in the form of a pharmaceutical composition.

[0813] A pharmaceutical composition may be formulated to be suitable for administration to a patient in order to prevent and / or treat disease. Pharmaceutical compositions can be formulated for administration by different routes, for example, for oral, parenteral, topical, inhalative, intravenous, intramuscular, rectal, sublingual, transdermal, subcutaneous, intratumoural application routes, according to their chemical and physical properties. In some embodiments, the one or more pharmaceutical compositions are in a form suitable for intravenous infusion. In some embodiments, the one or more pharmaceutical compositions are administered intravenously.

[0814] A pharmaceutical composition typically should be sterile and stable under the conditions of manufacture and storage. A pharmaceutical composition may be produced using current good manufacturing practices (CGMP).

[0815] A pharmaceutical composition may comprise solid, semisolid, liquid, transdermal therapeutic systems (TTS). Solid pharmaceutical compositions are selected from the group consisting of tablets, coated tablets, powder, granulate, pellets, capsules, effervescent tablets or transdermal therapeutic systems. Also comprised are liquid pharmaceutical compositions, selected from the group consisting of solutions, syrups, infusions, extracts, solutions for intravenous application, solutions for infusion or solutions of the carrier systems of the present invention. Semisolid pharmaceutical compositions that can be used in the context of the invention comprise emulsion, suspension, creams, lotions, gels, globules, buccal tablets and suppositories.

[0816] In some embodiments, the one or more pharmaceutical compositions further comprises a pharmaceutically acceptable carrier, excipient or diluent. Examples of suitable pharmaceutical carriers, excipient and diluents are described in " Remington's Pharmaceutical Sciences" by E. W. Martin. Such pharmaceutical compositions will contain a therapeutically effective amount of the active agent, preferably in purified form, together with a suitable amount ofcarriers, excipients or diluents so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

[0817] Suitable pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. A sterile saline solution is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. In some embodiments, the one or more pharmaceutical compositions comprise an aqueous diluent or solvent. In some embodiments, the aqueous diluent or solvent may be a phosphate buffered saline solution, such as a sterile phosphate buffered saline solution. In some embodiments, the one or more pharmaceutical compositions comprise a sterile aqueous buffer.

[0818] A pharmaceutical composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These pharmaceutical compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like. The pharmaceutical composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.

[0819] The compounds of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc. In some embodiments, the salt may comprise a metal cation, such as a sodium salt or a potassium salt.

[0820] In some embodiments, the one or more pharmaceutical compositions comprise 0.1 wt.% to 99% wt.% of the active compound (i.e. the anti-HER2 antibody-drug conjugate or the anti-PD-1 / PD-L1 antibody or fragment thereof). In some embodiments, the one or more pharmaceutical compositions contain 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 wt.% of the active compound (i.e. the anti-HER2 antibody-drug conjugate or the anti-PD-1 / PD-L1 antibody or fragment thereof).

[0821] In some embodiments, the one or more pharmaceutical compositions comprise one or more compounds, components and / or active agents, in addition to the anti-HER2 antibody-drug conjugate or anti-PD-1 / PD-L1 antibody or fragment thereof. In some embodiments, the one or more pharmaceutical compositions further comprise one or more selected from this list consisting of: an adjuvant, salt, active polypeptide, compound, component and active agent.

[0822] Example anti-HER2 antibody-drug conjugate formulation

[0823] In some embodiments, the anti-HER2 antibody-drug conjugate is formulated as a composition comprising the anti-HER2 antibody-drug conjugate; histidine or a pharmaceutically acceptable salt thereof; sucrose; and / or polysorbate 80.

[0824] In some embodiments, the composition may comprise 1 to 100 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise 10-50 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise 10-20 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise 20-30 mg / ml histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise 30-50 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise about 10 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise about 20 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise about 25 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise about 30 mM histidine or a pharmaceutically acceptable salt thereof. In these embodiments, the concentration of histidine is expressed as the total concentration of histidine in the composition including the free base and the histidine component of any pharmaceutically acceptable salt thereof present in the composition.

[0825] In some embodiments, the composition also contains sucrose. In some embodiments, the composition may comprise about 20 to about 160 mg / ml sucrose. In some embodiments, the composition may comprise about 40 to about 140 mg / ml sucrose. In some embodiments, the composition may comprise about 60 to about 120 mg / ml sucrose. In some embodiments, thecomposition may comprise about 80 to about 100 mg / ml sucrose. In some embodiments, the composition may comprise about 90 mg / ml sucrose. In some embodiments, the composition may comprise 1 to 20% (w / v) sucrose. In some embodiments, the composition may comprise 5-10 % (w / v) sucrose. In some embodiments, the composition may comprise 8-10 % (w / v) sucrose. In some embodiments, the composition may comprise about 5% (w / v) sucrose. In some embodiments, the composition may comprise about 6% (w / v) sucrose. In some embodiments, the composition may comprise about 7% (w / v) sucrose. In some embodiments, the composition may comprise about 8% (w / v) sucrose. In some embodiments, the composition may comprise about 9% (w / v) sucrose. In some embodiments, the composition may comprise about 10 % (w / v) sucrose.

[0826] In some embodiments, the composition also contains polysorbate 80. In some embodiments, the composition may comprise about 0.1 to about 0.5 mg / ml polysorbate 80. In some embodiments, the composition may comprise about 0.2 to about 0.4 mg / ml polysorbate 80. In some embodiments, the composition may comprise about 0.25 to about 0.35 mg / ml polysorbate 80. In some embodiments, the composition may comprise about 0.3 mg / l polysorbate 80. In some embodiments, the composition may comprise 0.01 to 0.5 % (w / v) polysorbate 80. In some embodiments, the composition may comprise 0.05-0.1% (w / v) polysorbate 80. In some embodiments, the composition may comprise 0.01-0.05% (w / v) polysorbate 80. In some embodiments, the composition may comprise 0.015-0.045% (w / v) polysorbate 80. In some embodiments, the composition may comprise about 0.02% (w / v) polysorbate 80. In some embodiments, the composition may comprise about 0.03% (w / v) polysorbate 80.

[0827] In some embodiments, the pH of the composition may be 5 to 8. In some embodiments, the pH of the composition may be 5 to 7. In some embodiments, the pH of the composition may be 5 to 6. In some embodiments, the pH of the composition may be 5.3 to 5.7. In some embodiments, the pH of the composition may be about 5.5.

[0828] In some embodiments, the anti-HER2 antibody-drug conjugate is formulated as a composition, typically an aqueous composition, comprising:

[0829] about 20mg / ml anti-HER2 antibody-drug conjugate;

[0830] about 25 mM histidine or a pharmaceutically acceptable salt thereof;

[0831] about 9% (w / v) sucrose; and

[0832] about 0.03% (w / v) polysorbate 80,

[0833] and the pH of the composition may be about 5.5. This composition is referred to below as “Formulation 1”.In some embodiments, the anti-HER2 antibody-drug conjugate is formulated as a composition, typically an aqueous composition, comprising:

[0834] about 20mg / ml anti-HER2 antibody-drug conjugate;

[0835] about 0.82 mg / ml L-histidine;

[0836] about 4.14 mg / ml L-histidine hydrochloride monohydrate;

[0837] about 90 mg / ml sucrose; and

[0838] about 0.3 mg / ml polysorbate 80.

[0839] In some embodiments, the anti-HER2 antibody-drug conjugate is formulated as a lyophilized composition, such as a lyophilized powder composition.

[0840] In some embodiments, the lyophilized composition may comprise the anti-HER2 antibodydrug conjugate according in an amount of about 5 to about 500 mg. In some embodiments, the lyophilized composition may comprise the anti-HER2 antibody-drug conjugate n an amount of about 50 to about 250 mg. In some embodiments, the lyophilized composition may comprise the anti-HER2 antibody-drug conjugate in an amount of about 50 to about 150 mg. In some embodiments, the lyophilized composition may comprise the anti-HER2 antibodydrug conjugate in an amount of about 75 to about 125 mg. In some embodiments, the lyophilized composition may comprise the anti-HER2 antibody-drug conjugate in an amount of about 90 to about 110 mg. In some embodiments, the lyophilized composition may comprise the anti-HER2 antibody-drug conjugate in an amount of about 100 mg.

[0841] In some embodiments, the lyophilized composition may comprise histidine. In some embodiments, the lyophilized composition may comprise about 5 to about 40 mg total histidine. In some embodiments, the composition may comprise about 10 to about 30 mg histidine. In some embodiments, the lyophilized composition may comprise about 15 to about 25 mg total histidine. In some embodiments, the lyophilized composition may comprise about 18 to about 22 mg total histidine. In some embodiments, the lyophilized composition may comprise about 19.42 mg total histidine. In these embodiments, the amount of histidine is expressed as the total amount of histidine in the composition including the free base and the histidine component of any pharmaceutically acceptable salt thereof present in the composition.

[0842] In some embodiments, the lyophilized composition may comprise sucrose. In some embodiments, the lyophilized composition may comprise about 100 to about 800 mg sucrose. In some embodiments, the lyophilized composition may comprise about 200 to about 700 mg sucrose. In some embodiments, the lyophilized composition may comprise about 300 to about 600 mg sucrose. In some embodiments, the lyophilized composition may comprise about 400to about 500 mg sucrose. In some embodiments, the composition may comprise about 450 mg sucrose.

[0843] In some embodiments, the lyophilized composition may comprise polysorbate 80. In some embodiments, the lyophilized composition may comprise about 0.5 to about 2.5 mg polysorbate 80. In some embodiments, the lyophilized composition may comprise about 1 to about 2 mg polysorbate 80. In some embodiments, the lyophilized composition may comprise about 1.3 to about 1.7 mg polysorbate 80. In some embodiments, the lyophilized composition may comprise about 1.5 mg polysorbate 80.

[0844] In one embodiment, the anti-HER2 antibody-drug conjugate is formulated as a lyophilized composition, typically a lyophilized powder composition, comprising:

[0845] about 100mg anti-HER2 antibody-drug conjugate;

[0846] about 4.1 mg L-histidine;

[0847] about 20.7 mg L-histidine hydrochloride monohydrate;

[0848] about 450 mg sucrose; and

[0849] about 1.5 mg polysorbate 80.

[0850] In one embodiment, there is provided a lyophilized composition, typically a lyophilized powder composition, comprising: (a) anti-HER2 antibody-drug conjugate, in an amount of about 100 parts by weight; (b) L-histidine, in an amount of about 4.1 parts by weight, relative to 100 parts by weight (a); (c) L-histidine hydrochloride monohydrate; in an amount of about 20.7 parts by weight, relative to 100 parts by weight (a); (d) sucrose, in an amount of about 450 parts by weight, relative to 100 parts by weight (a); and (e) polysorbate 80, in an amount of about 1.5 parts by weight, relative to 100 parts by weight (a).

[0851] Compositions and kits

[0852] The present invention provides a composition or kit comprising the combination of the present invention.

[0853] In one aspect, the present invention provides a composition comprising the combination of the present invention. The composition may be a pharmaceutical composition.

[0854] In another aspect, the present invention provides a composition comprising: (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof. The composition may be a pharmaceutical composition.In another aspect, the present invention provides a kit comprising the combination of the present invention. The combination may be in the form of one or more pharmaceutical compositions. In some embodiments, the kit comprises instructions for use, for example for use as a medicament or for use in treating cancer.

[0855] In another aspect, the present invention provides a kit comprising the composition of the invention. In some embodiments, the kit comprises instructions for use, for example for use as a medicament or for use in treating cancer.

[0856] In another aspect, the present invention provides a kit-of-parts comprising: (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof. In some embodiments, the anti-HER2 antibody-drug conjugate and the anti-PD-1 / PD-L1 antibody or fragment are comprised in separate containers. In some embodiments, the kit-of-parts further comprises instructions for use, for example for use as a medicament or for use in treating cancer.

[0857] EXAMPLES

[0858] The invention will now be further described by way of Examples, which are meant to serve to assist one of ordinary skill in the art in carrying out the invention and are not intended in any way to limit the scope of the invention.

[0859] Example 1: Synthesis of Compound 1 - an anti-hHER2 antibody drug conjugate (ADC) Synthesis of Intermediate 1 - (1S,3R)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxycyclobutane-1-carboxamide

[0860]

[0861] Step 1:

[0862] DIEA (500 mg, 3.87 mmol) was added to a solution of Intermediate 1z (900 mg, 1.69 mmol), HATU (691 mg, 1.88 mmol) and Intermediate 1a (320 mg, 2.00 mmol) in DMF (18 mL) at O °C under nitrogen atmosphere, and the mixture was stirred at 25 °C for 3 h. After the starting material was consumed completely as detected by TLC (EA), the reaction solution was added dropwise to deionized water (320 mL) and filtered to give a grey solid (850 mg, yield: 87%).

[0863] Step 2.

[0864] NaHCO3(42 mg, 0.50 mmol) as a solid was added to a solution of Intermediate 1b (100 mg, 0.174 mmol) in MeOH / DCM (1 / 1, 3 mL), and the mixture was stirred at 25 °C for 3 h. After the reaction was completed as detected by TLC (EA), the reaction solution was filtered, dried by rotary evaporation at low temperature, slurried with aq. HCI (0.5 M, 10 mL), filtered and purified by prep-HPLC (0.1% TFA), and then lyophilized to give a grey solid (15 mg, yield: 16%).

[0865] MS m / z (ESI): 534 [M+1]

[0866] H-NMR (400 MHz, DMSO-D): 8.45(d, 1H), 7.81 (d, 1H), 7.32 (s, 1H), 6.52 (m, 1H), 5.58-5.56 (m, 1 H), 5.44 (s, 2H), 5.14 (dd, 2 H), 3.96 (m, 1H), 3.48 (m, 1H), 3.19 (m, 2H), 2.53-2.28 (m, 3H), 2.48 (s, 3H), 2.20-2.00(m, 4H), 1.95-1.80 (m, 2H), 0.89 (t, 3H)

[0867] Synthesis of Intermediate 2. (1R,3R)-4-(((S)-7-benzyl-19-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12,15-pentaoxo-2,5,8,11,14-pentaazanonadecyl)oxy)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano-[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)cyclobutane-1-carboxamideo o

[0868] I nt 2f

[0869]

[0870] Step 1.

[0871] Benzyl bromide (11.0 g, 64.6 mmol) was added dropwise to a solution of Intermediate 2a (5.00 g, 43.0 mmol) and NaHCO3(10.9 g, 129 mmol) in DMF (50 mL) under nitrogen atmosphere, and the mixture was reacted at 25 °C for 17 h. After the reaction was completed as detected by TLC (PE / EA = 2 / 1), the reaction solution was added to water (500 mL), extracted with EA (250 mL) twice, separated and washed with saturated aqueous sodium chloride solution (500 mL). The organic phase was dried over anhydrous Na2SO4, concentrated and purified by column chromatography (PE: EA = 3:2) to give a colourless liquid (5.1 g, yield: 57.1%).

[0872] Step 2.A solution of Intermediate 2b (4.50 g, 21.8 mmol) in THF (10 mL) was added dropwise to a solution of Intermediate 2z (4.00 g, 10.9 mmol) and TsOH (800 mg, 4.65 mmol) in THF (30 mL) at 0 °C under nitrogen atmosphere, and the mixture was reacted at 25 °C for 2 h. After the reaction was completed as detected by TLC (PE / EA = 1 / 2), the reaction solution was added to water (200 mL), extracted with EA (200 mL) twice and separated. The organic phase was dried over anhydrous Na2SO4, concentrated and purified by column chromatography (PE / EA = 3 / 2) to give a white solid (1.56g, yield: 26%).

[0873] Step 3.

[0874] Pd / C (80 mg) was added to a mixed solution of Intermediate 2c (800 mg, 1.55 mmol) in EtOH (8 mL) and EA (8 mL) at 0 °C under hydrogen atmosphere, and the mixture was stirred at 0 °C for 2.5 h. After the reaction was completed as detected by LCMS, the reaction solution was filtered through Celite®, and the filter cake was washed with EA (200 mL). The filtrate was concentrated, dissolved with THF (20 mL) and dried by rotary evaporation to give a white solid (600 mg, yield: 91%).

[0875] Step 4.

[0876] DIEA (152 mg, 1.18 mmol) was added to a solution of Intermediate 2d (220 mg, 0.515 mmol), Intermediate 1z (250 mg, 0.47 mmol) and HATU (214 mg, 0.56 mmol) in DMF (6 mL) at 0 °C under nitrogen atmosphere, and the mixture was reacted at 0 °C for 2 h. After the reaction was completed as detected by LCMS, the reaction solution was added to an aqueous citric acid solution (pH = 4) (150 mL), and filtered. The filter cake was washed with water (175 mL), dried under filtration, and dried with an oil pump to give a brown solid (260 mg, yield: 66%).

[0877] Step 5.

[0878] Diethylamine (8 mL) was added dropwise to a solution of Intermediate 2e (260 mg, 0.309 mmol) in DCM (30 mL) at 0 °C under nitrogen atmosphere, and the mixture was reacted at 0 °C for 3 h. After the reaction was completed as detected by LCMS, the reaction solution was added to a petroleum ether solution (600 mL) at 0 °C, and a solid was precipitated. The resulting mixture was left to stand until the solid was adsorbed on the bottom of the flask, and the solution was poured out and dried with an oil pump to give a brown solid (90 mg, yield: 47.1%).

[0879] Step 6.

[0880] HATU (74 mg, 0.19 mmol) was added to a solution of Intermediate 2f (90 mg, 0.13 mmol), Intermediate 2y (92 mg, 0.19 mmol) and DIEA (50 mg, 0.39 mmol) in DMF (2.5 mL) at 0 °C under nitrogen atmosphere, and the mixture was reacted at 0 °C for 2 h. After the reactionwas completed as detected by LCMS, the reaction mixture was added to an aqueous citric acid solution (30 mL) at pH 4 at 0 °C, and a flocculent solid was precipitated. The resulting mixture was filtered, and purified by PTLC (DCM / MeOH = 10 / 1) to give a pale yellow solid (9.2 mg, yield: 6%).

[0881] MS m / z (ESI): 1074 [M+1]

[0882] H-NMR (400 MHz, MeOD): 7.65 (d, 1H), 7.62 (s, 1H), 7.30-7.21 (m, 5H), 6.79 (s, 2H), 5.69-5.65 (m, 1 H), 5.57 (d, 1H), 5.43-5.10 (m, 3H), 4.70 (d, 2H), 4.48-4.39 (m, 2H), 4.10-4.05 (m, 1H), 4.01-3.75 (m, 5H),3.46 (t, 2H), 3.22-3.15 (m, 2H), 3.07-3.00 (m, 1H), 2.75 (m, 1H), 2.62 (m, 1H), 2.45 (s, 3H), 2.37-2.20 (m, 6H), 2.10-2.02 (m, 2H), 2.00-1.92 (m, 2H) 1.68-1.57 (m, 6H), 1.01 (t, 3H)

[0883] Synthesis of Compound 1:

[0884] The antibody trastuzumab is thawed at room temperature. EDTA solution (20 mM) and a reduction buffer (20 mM PB, 150 mM NaCI, pH 6.9 ± 0.1) are added to the antibody solution. Then 0.5 M Na2HPO4or 0.3 M NaH2PO4buffer is used to adjust the pH to 7.0. Tris (2-carboxyethyl) phosphine (TECP) hydrochloride powder is weighed and dissolved in water for injection (WFI) to prepare a TCEP solution. Then the solution is added to the antibody solution (TCEP to antibody molar ratio is 8-10). The reduction reaction lasts 2.0 - 4.0 hours at room temperature. The linker-payload Intermediate 2 powder is weighed and dissolved in dimethylsulfoxide (DMSO). Then the linker-payload DMSO solution is added to the mixing bag reactor. After addition of Intermediate 2 DMSO solution, the organic phase concentration is 10% (v / v) and Intermediate 2 / mAb molar ratio is 13. The conjugation reaction is allowed to proceed for 2.0 -6.0 hours at room temperature. After conjugation, the ADC solution is purified by LIF / DF, with the dialysis buffer of 25 mM Histidine buffer, pH 5.5. The ADC concentration is 20.2 mg / mL and the drug to antibody ratio (DAR) value is determined as 7.8 by RP-HPLC method.

[0885] The resulting Compound 1 is shown below. The drug to antibody ratio (DAR) distribution of the composition, shown as Nain Compound 1, is detected by reducing ADC molecules to separated heavy chain and light chain, then further separating and quantifying each LC and HC species of different linker payload numbers with reversed phase high performance liquid chromatography (RP-HPLC). The DAR ratio is determined to be about 7.7.Trastuzumab

[0886]

[0887] Example 2: Phase 1 / 2a study of Compound 1 an anti-hHER2 ADC in endometrial cancer

[0888] A Phase 1 / 2a, multicenter, open-label, first in human study is ongoing to assess the safety, tolerability, pharmacokinetics, and preliminary antitumour activity of Compound 1 in subjects with advanced / metastatic solid tumours.

[0889] The study consists of two parts: Part 1 (Phase 1, dose-escalation) adopts an accelerated titration at first dose followed by classic “3+3” design to identify the maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) with seven doses ranging from 2.2 to 12 mg / kg; Part 2 (Phase 2a, dose-expansion) is initiated to assess safety / tolerability and efficacy in subjects with selected HER2-expressing or HER2-mutant malignant solid tumours. The study includes subjects with HER2-expressing (immunohistochemistry [IHC] 1 / 2 / 3+ or in situ hybridization [ISH] +) advanced / unresectable, recurrent, or metastatic endometrial cancer who are refractory to or intolerable to standard treatment, or for which no standard treatment is available. Compound 1, formulated as Formulation 1, is administered intravenously once every 3 weeks until disease progression, withdrawal of consent, or unacceptable toxicity. Adverse events (AEs) are coded using Medical Dictionary for Regulatory Activities (MedDRA) and graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0). Tumour responses are assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1).

[0890] As of May 8, 2023, 32 subjects with endometrial cancer had received 7 or 8 mg / kg doses of Compound 1. The most common histological sub-type was uterine serous papillary carcinoma (LISPC, 34.4%), adenocarcinoma (25.0%), and uterine carcinosarcoma (UCS, 18.8%). The median treatment duration was 2.6 (range, 0.7-10.4) months with 29 subjects (90.6%) remaining on treatment. Median number of prior regimens for metastatic disease was 2 (range, 1-10). Nineteen subjects (59.4%) had prior immunotherapy therapy. A total of 17 subjects were evaluable for response. Ten subjects (58.8%) had objective partial tumour response (4confirmed, and 6 requiring further confirmation) per RECIST 1.1: 7 LISPC (87.5%, 7 / 8), 1 UCS (50.0%, 1 / 2), 1 mixed adenocarcinoma (50.0%, 1 / 2), and 1 adenocarcinoma (33.3%, 1 / 3). The objective response rates (ORRs) for subjects at 7 and 8 mg / kg dose were 50.0% (2 / 4) and 61.5% (8 / 13), respectively. The overall disease control rate (DCR) was 94.1%. Treatment-emergent adverse events (TEAEs) of any grade occurred in 30 subjects (93.8%), and the most common (>20%) were nausea (50.0%), fatigue (31.2%), and vomiting (28.1%); of >grade 3 occurred in 10 subjects (31.2%), and the most common (>5%) were hypokalaemia (12.5%), anaemia (6.2%), and syncope (6.2%). No TEAEs led to drug discontinuation or death. No interstitial lung disease occurred.

[0891] Compound 1 demonstrates a manageable safety profile and promising anti-tumour activity, with high disease control in subjects with advanced / metastatic endometrial cancer.

[0892] Example 3: Study design to assess the therapeutic activity of an anti-hHER2-ADC (Compound 1) in combination with an anti-hPD1 antibody (dostarlimab) in a human xenograft PBMC mouse model

[0893] To investigate the combination of an anti-hHER2-ADC (Compound 1) and an anti-PD1 antibody (dostarlimab), a xenograft mouse model engrafted with human PBMCs is established as follows.

[0894] B-NDG B2M KO plus (vendor Biocytogen) mice are subcutaneously inoculated with 5x106HCC1954 (human breast cancer) cells. When the mean tumour volume reaches 80-120 mm3mice are randomized and injected with 10*106human PBMCs intraperitoneally (i.p.). When the tumour size is approximately 150-200 mm3, a second randomization is performed if needed followed by treatments with the ADC / antibody indicated below are started. 20 mg / kg of anti-hPD-1 antibody and 5-10 mg / kg of anti-hHER2-ADC are administered up to two times, once a week (qw). Monotherapy control groups G2 and G3 are treated only either with the anti-hPD1 antibody or the anti-hHER2-ADC. The vehicle control group G1 is treated with PBS only. Tumour volume and body weight are monitored. The study design is summarized in Table 2.

[0895] The combination of the anti-hHER2-ADC and the anti-hPD1 antibody (dostarlimab) is expected to result in tumour regression and / or long-term tumour control, whereas monotherapy treatments are expected to result in shorter-term tumour control and / or outgrowth of tumours.Table 2: Xenograft model study design anti-hHER2-ADC + anti-hPD1 antibody

[0896] Dosing Groups Treatment Dose

[0897] Schedule G1 Vehicle - G2 Anti-hPD1 20 mg / kg qw

[0898] G3 anti-hHER2-ADC 5-10 mg / kg qw

[0899]

[0900] G4 Anti-hPD1 + anti-hHER2-ADC 20 mg / kg and 5-10 mg / kg qw

[0901] The combination of the anti-hHER2-ADC and other anti-hPD-1 / hPD-L1 antibodies are also tested using the same assay, and are also expected to result in tumour regression and / or long-term tumour control, whereas monotherapy treatments are expected to result in shorter-term tumour control and / or outgrowth of tumours.

[0902] Example 4: A Phase III, randomized, double-blind trial of Compound 1 plus dostarlimab versus placebo plus dostarlimab in participants with pMMR, recurrent or primary advanced HER2-expressing endometrial cancer

[0903] Based on preliminary data from the ongoing first in human Phase l / lla trial, Compound 1 has shown promising anti-tumour activity in participants with advanced / unresectable, or metastatic HER2-overexpressing and HER2-low (IHC 3+ or IHC 2+ or IHC 1+ or ISH+) endometrial cancer who have progressed on or after standard treatment.

[0904] ADCs such as Compound 1 may induce immunomodulatory effects and therefore may combine favourably with PD-1 / PD-L1 inhibitors. There are a number of pre-clinical and early-stage clinical trials that have demonstrated anti-tumour effects (see e.g. Wei, Q., et al., 2024. Journal of Hematology & Oncology, 17(1), p.1). Moreover, ADCs in combination with PD-1 / PD-L1 inhibitors have been approved for the treatment of cancer, e.g., enfortumab vedotin in combination with pembrolizumab is approved by the FDA for participants with cisplatin-ineligible urothelial cancer.

[0905] This is a randomized, double-blind, multi-site, Phase III trial designed to compare the efficacy and safety of Compound 1 + dostarlimab with that of placebo + dostarlimab following pretreatment of chemotherapy plus dostarlimab in participants with pMMR, recurrent or primary advanced (Stage III or IV), HER2-expressing endometrial cancer. Participants will be enrolled after pre-treatment with 6 cycles of carboplatin + paclitaxel + dostarlimab for primary advanced or recurrent endometrial cancer. A summary of the trial is shown in Figure 1.The potential benefit to a participant on this trial is prolonged progression-free survival (PFS) and overall survival (OS), reduction of tumour lesions (ORR), and improvement of quality of life in endometrial cancer. Enrolling participants based on HER2-expression tumour status is expected to maximize the likelihood of clinical benefit from the trial treatment based on the mode of action of HER2 targeted therapies and clinical experience to date using targeted therapies in the breast oncology setting.

[0906] The primary objectives of this trial are:

[0907] (1) to compare the efficacy of Compound 1 + dostarlimab with placebo + dostarlimab following pre-treatment of chemotherapy plus dostarlimab in terms of a hazard ratio (HR) for progression-free survival (PFS) as assessed by the investigator in participants with pMMR, HER2-expressing endometrial cancer; and

[0908] (2) to compare the efficacy of Compound 1 + dostarlimab followed by any subsequent therapy with placebo + dostarlimab followed by any subsequent therapy in terms of a HR for overall survival (OS) in participants with pMMR, HER2-expressing endometrial cancer pre-treated with chemotherapy plus dostarlimab.

[0909] Secondary efficacy objectives will include PFS as assessed by Blinded Independent Central Review (BICR), objective response rate (ORR) and duration of response (DoR) as assessed by the investigator and BICR, and safety and tolerability profile.

[0910] The trial consists of a screening / pre-treatment period, a screening period (Day -28 to Day -1 of the pre-treatment period), a pre-treatment period, a pre-randomization visit (Day -21 to Day -1 of main treatment period), a main treatment period, an End of Treatment (EoT) Visit, a safety follow-up period, an efficacy follow-up period, and a long-term survival follow-up. The expected treatment duration of the pre-treatment period per participant is ~4.2 months. The expected duration of the main treatment period per participant is up to ~24 months, followed by an anticipated long-term / survival follow-up period of up to ~91 months (i.e., expected final analysis timing is 91 months after first participant randomized). The expected overall duration of the trial as a whole is up to ~96 months (assuming ~5 months of pre-treatment and screening).

[0911] Participants are eligible to be enrolled in the pre-treatment period if they meet all of the eligibility criteria:

[0912] • Are adults (defined as ≥18 years of age or acceptable age according to local regulations at the time of giving informed consent for pre-treatment).• Have histologically confirmed primary measurable Stage III or Stage IV (with or without measurable disease) endometrial cancer, or first recurrent endometrial cancer (including carcinosarcoma).

[0913] o Measurable disease will be defined by RECIST 1.1 as assessed by the investigator.

[0914] o For Stage III disease, measurable disease must be present at the start of treatment with carboplatin + paclitaxel + dostarlimab.

[0915] • Have documented HER2-expressing status defined as an IHC score of 1+, 2+, or 3+ as determined by central laboratory testing for HER2 protein expression during screening for the pre-treatment period.

[0916] • Have confirmed pMMR status as determined by central laboratory testing using IHC during screening for the pre-treatment period.

[0917] • Have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

[0918] Participants are eligible to be enrolled in the main treatment period if they meet all of the following eligibility criteria:

[0919] • Have completed up to 6 cycles but no less than 4 cycles of carboplatin + paclitaxel + dostarlimab during the pre-treatment period without permanently discontinuing dostarlimab.

[0920] • Have achieved partial response (PR) or complete response (CR) or stable disease (SD) by imaging, based on RECIST version 1.1, as assessed by the investigator, at the completion of the pre-treatment period.

[0921] • Have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2, as assessed within 7 days prior to the start of the main treatment period.

[0922] A total of -648 HER2 expressing endometrial cancer pMMR participants will be randomized 1:1 to receive either Compound 1 + dostarlimab or placebo + dostarlimab.

[0923] All participants will receive carboplatin + paclitaxel + dostarlimab during the pre-treatment period:

[0924] • Dostarlimab will be administered as an IV infusion at 500 mg Q3W for 6 cycles.

[0925] • Paclitaxel will be administered as an IV infusion at 175 mg / m2Q3W for 6 cycles. • Carboplatin will be administered as an IV infusion at AUC 5 mg*mL / min Q3W for 6 cycles.Participants who achieve a CR, PR or SD after ~6 cycles of pre-treatment and meet the eligibility criteria for the main treatment will be randomly assigned to either Compound 1 + dostarlimab or placebo + dostarlimab. The trial treatments are as follows:

[0926] • Compound 1 or placebo will be administered as an intravenous (IV) infusion every 21 days (i.e., Q3W) at 8 mg / kg for up to 24 months, or until PD, unacceptable toxicity, or withdrawal of the participant’s consent, whichever occurs first.

[0927] • Dostarlimab will be administered as an IV infusion 1,000 mg Q6W for up to 24 months, or until PD, unacceptable toxicity, or withdrawal of the participant’s consent, whichever occurs first.

[0928] The primary endpoints (PFS as assessed by the investigator and OS) will be compared between treatment groups using the log-rank test, stratified by the randomization strata at randomization. The HR and its two-sided 95% confidence limits will be estimated using Cox’s proportional hazards model stratified by the randomization strata and with treatment as covariate. Additionally, Kaplan-Meier curves (product limit estimates) will be presented by treatment groups together with a summary of associated statistics (e.g., median survival time and survival rates including the corresponding two-sided 95% confidence intervals).

[0929] Based on the totality of evidence generated from all participants treated across all indications within the ongoing trial for Compound 1 (NCT05150691), including efficacy and safety data, PK, and exposure-response analyses of safety and efficacy, 8 mg / kg Q3W of Compound 1 has been determined to be the optimal dose. The recommended dostarlimab dose is 500 mg Q3W for 6 cycles with carboplatin and paclitaxel, followed by 1,000 mg of dostarlimab as a single-agent Q6W. As participants of this trial will be enrolled after completing 6 cycles of dostarlimab in combination with carboplatin and paclitaxel, the dose of 1,000 mg / kg Q6W is selected for this trial.

[0930] Based on findings from the double-blind RUBY trial (NCT03981796), the Kaplan-Meier probability of survival at 24 months in the dostarlimab arm was lower in the pMMR population as compared to that observed for the dMMR population, indicating the benefit with dostarlimab alone in the pMMR population is smaller and limited (Powell MA, et al. Ann Oncol.

[0931] 2024;35(8):728-738). Several studies that have investigated HER2 positivity and MMR status have demonstrated that HER2 positivity is more common in pMMR (Plotkin A, et al., Cancers (Basel). 2024;16(11):2100). As the response rates in patients with pMMR tumours to PD-1 inhibitors were much lower than response rates in patients with dMMR tumours, there is a high unmet medical need in pMMR endometrial cancer, and the novel combination of an anti-HER2 antibody-drug conjugate (e.g., Compound 1) with an anti-PD-1 / PD-L1 antibody or fragment thereof (e.g., dostarlimab) may provide benefit in this patient population.

[0932] All publications mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described methods and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in molecular biology or related fields are intended to be within the scope of the following claims

Claims

CLAIMS1. A combination of:(a) an anti-HER2 antibody-drug conjugate; and(b) an anti-PD-1 / PD-L1 antibody or fragment thereof, wherein:(a) the anti-HER2 antibody-drug conjugate has a structure shown as formula (I):(l)or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:q is a connection number and is an integer from 1 to 16;L is -La-Lb-Lc-;La- is- Lb- is:-Lc- is -CH2-;U is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;V is selected from the group consisting of: (C1-6) alkylene, (C3-10) cycloalkylene, or (C1-6) alkylene-(C3-10) cycloalkylene;R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; andeach R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

2. A combination of:(a) an anti-HER2 antibody-drug conjugate; and(b) an anti-PD-1 / PD-L1 antibody or fragment thereof, for use in treating cancer in a subject, wherein:(a) the anti-HER2 antibody-drug conjugate has a structure shown as formula (I):(I)or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:q is a connection number and is an integer from 1 to 16;L is -La-Lb-Lc-;La- is- Lb- is:-Lc- is -CH2-;U is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;V is selected from the group consisting of: (C1-6) alkylene, (C3-10) cycloalkylene, or (C1-6) alkylene-(C3-10) cycloalkylene;R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; andeach R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

3. An anti-HER2 antibody-drug conjugate for use in treating cancer in a subject, wherein the use comprises administering to the subject:(a) the anti-HER2 antibody-drug conjugate; and(b) an anti-PD-1 / PD-L1 antibody or fragment thereof, wherein:(a) the anti-HER2 antibody-drug conjugate has a structure shown as formula (I):Trastuzumabb(I)or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:q is a connection number and is an integer from 1 to 16;L is -La-Lb-Lc-;La- is- Lb- is:-Lc- is -CH2-;U is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;V is selected from the group consisting of: (C1-6) alkylene, (C3-10) cycloalkylene, or (C1-6) alkylene-(C3-10) cycloalkylene;R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; andeach R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

4. An anti-PD-1 / PD-L1 antibody or fragment thereof for use in treating cancer in a subject, wherein the use comprises administering to the subject:(a) an anti-HER2 antibody-drug conjugate; and(b) the anti-PD-1 / PD-L1 antibody or fragment thereof, wherein:(a) the anti-HER2 antibody-drug conjugate has a structure shown as formula (I):or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:q is a connection number and is an integer from 1 to 16;L is -La-Lb-Lc-;La- iso- Lb- is:-Lc- is -CH2-;U is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;V is selected from the group consisting of: (C1-6) alkylene, (C3-10) cycloalkylene, or (C1-6) alkylene-(C3-10) cycloalkylene;R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; andeach R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

5. The combination according to claim 1, combination for use according to claim 2, anti-HER2 antibody-drug conjugate for use according to claim 3, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to claim 4, wherein the anti-HER2 antibody-drug conjugate has aor a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:the connection number q is an integer from 1 to 16;I— iS -La-Lb-Lc”,La- is-Lc- is -CH2-;X1is saturated C, and X1is substituted with Rn;ring A is selected from the group consisting of: 3-10 membered saturated or partially unsaturated heterocyclyl and 3-10 membered saturated or partially unsaturated carbocyclyl, wherein ring A is substituted with 0 or at least 1 substituent R1a;when ring A is 3-10 membered saturated or partially unsaturated carbocyclyl, ring A is substituted with p L2, and L2is not Rn;or, when ring A is 3-10 membered saturated or partially unsaturated heterocyclyl, ring A is substituted with p L2;L2is -R2-L3-, and R2is used for direct or indirect linking of a ligand;L3is -(C(R3a)(R3b))m-, wherein when L3comprises a methylene unit, 0 or at least 1 methylene unit of L3is independently replaced by -N(R4)C(O)-, -C(O)N(R4)-, -C(O)-, -OC(O)-, -C(O)O-, -NR4-, -O-, -S-, -SO-, -SO2-, -P(R4)-, -P(=O)(R4)-, -N(R4)SO2-, -SO2N(R4)-, -C(=S)-, -C(=NR4)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;L1is -(C(R5a)(R5b))n-, wherein when L1comprises a methylene unit, 0 or at least 1 methylene unit of L1is independently replaced by -N(R6)C(O)-, -C(O)N(R6)-, -C(O)-, -OC(O)-, -C(O)O-, -NR6-, -O-, -S-, -SO-, -SO2-, -P(R6)-, -P(=O)(R6)-, -N(R6)SO2-, -SO2N(R6)-, -C(=S)-, -C(=NR6)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;wherein each R1a, each R2a, each R3a, each R3b, each R4, each R5a, each R5b, each R6and each Rnare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a Ci-6aliphatic group optionally substituted with R;wherein each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6 aliphatic group; and m and n are each independently selected from the group consisting of integers > 0, and p is an integer ≥ 1.

6. The combination according to claim 5, combination for use according to claim 5, anti-HER2 antibody-drug conjugate for use according to claim 5, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to claim 5, wherein ring A is a 4 membered saturated carbocyclyl.

7. The combination according to claim 5 or 6, combination for use according to claim 5 or 6, anti-HER2 antibody-drug conjugate for use according to claim 5 or 6, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to claim 5 or 6, wherein ring A is substituted with 1 L2.

8. The combination according to any one of claims 5-7, combination for use according to any of one claims 5-7, anti-HER2 antibody-drug conjugate for use according to any one of claims 5-7, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 5-7, wherein m is 0, and L3is a covalent bond.

9. The combination according to any one of claims 5-8, combination for use according to any one of claims 5-8, anti-HER2 antibody-drug conjugate for use according to any one of claims 5-8, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 5-8, wherein n is 1, and L1is -C(R5a)(R5b)- wherein 1 methylene unit of L1is replaced by -C(O)-.

10. The combination according to any one of claims 5-9, combination for use according to any one of claims 5-9, anti-HER2 antibody-drug conjugate for use according to any one of claims 5-9, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 5-9, wherein the anti-HER2 antibody-drug conjugate has the structure represented by formula (HI):Trastuzumabwherein the connection number q is an integer from 1 to 16;wherein R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; andwherein each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

11. The combination according to claim 10, combination for use according to claim 10, anti-HER2 antibody-drug conjugate for use according to claim 10, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to claim 10, wherein R2is -O- or -S-.

12. The combination according to any one of claims 5-11, combination for use according to any one of claims 5-11, anti-HER2 antibody-drug conjugate for use according to any one of claims 5-11, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 5-11, wherein the anti-HER2 antibody-drug conjugate has the structure represented by formula (IV):Trastuzumab(IV) wherein the connection number q is an integer from 1 to 16.

13. The combination according to any one of claims 1 or 5-12, combination for use according to any one of claims 2 or 5-12, anti-HER2 antibody-drug conjugate for use according to any one of claims 3 or 5-12, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-12, wherein q is an integer from 4 to 12, preferably wherein q is an integer from 6 to 10, more preferably wherein q is an integer from 7 to 9.

14. The combination according to any of claims 1 one or 5-13, combination for use according to any one of claims 2 or 5-13, anti-HER2 antibody-drug conjugate for use according to any one of claims 3 or 5-13, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-13, wherein q is 8.

15. The combination according to claim 1, combination for use according to claim 2, anti-HER2 antibody-drug conjugate for use according to claim 3, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to claim 4, wherein the anti-HER2 antibody-drug conjugate is in the form of a composition comprising one or more anti-HER2 antibody-drug conjugates having(l')or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:q’ is an average connection number and is an integer or decimal from 1 to 16;L is -La-Lb-Lc-;La- iso- Lb- is:-Lc- is -CH2-;U is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;V is selected from the group consisting of: (C1-6) alkylene, (C3-10) cycloalkylene, or (C1-6) alkylene-(C3-10) cycloalkylene;R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; andeach R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

16. The combination according to claim 15, combination for use according to claim 15, anti-HER2 antibody-drug conjugate for use according to claim 15, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to claim 15, wherein the composition comprises one or more anti-HER2 antibody-drug conjugates having the structure shown as formula (II’):or a tautomer, mesomer, enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:q’ is an average connection number and is an integer or decimal from 1 to 16;L is -La-Lb-Lc-;La- is-Lc- is -CH2-;X1is saturated C, and X1is substituted with Rn;ring A is selected from the group consisting of: 3-10 membered saturated or partially unsaturated heterocyclyl and 3-10 membered saturated or partially unsaturated carbocyclyl, wherein ring A is substituted with 0 or at least 1 substituent R1a;when ring A is 3-10 membered saturated or partially unsaturated carbocyclyl, ring A is substituted with p L2, and L2is not Rn;or, when ring A is 3-10 membered saturated or partially unsaturated heterocyclyl, ring A is substituted with p L2;L2is -R2-L3-, and R2is used for direct or indirect linking of a ligand;L3is -(C(R3a)(R3b))m-, wherein when L3comprises a methylene unit, 0 or at least 1 methylene unit of L3is independently replaced by -N(R4)C(O)-, -C(O)N(R4)-, -C(O)-, -OC(O)-, -C(O)O-, -NR4-, -O-, -S-, -SO-, -SO2-, -P(R4)-, -P(=O)(R4)-, -N(R4)SO2-, -SO2N(R4)-, -C(=S)-, -C(=NR4)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;L1is -(C(R5a)(R5b))n-, wherein when L1comprises a methylene unit, 0 or at least 1 methylene unit of L1is independently replaced by -N(R6)C(O)-, -C(O)N(R6)-, -C(O)-, -OC(O)-, -C(O)O-, -NR6-, -O-, -S-, -SO-, -SO2-, -P(R6)-, -P(=O)(R6)-, -N(R6)SO2-, -SO2N(R6)-, -C(=S)-, -C(=NR6)-, -N=N-, -C=N-, -N=C- or-C(=N2)-;wherein each R1a, each R2a, each R3a, each R3b, each R4, each R5a, each R5b, each R6and each Rnare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a Ci-6aliphatic group optionally substituted with R;wherein each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6 aliphatic group; and m and n are each independently selected from the group consisting of integers > 0, and p is an integer ≥ 1.

17. The combination according to claim 15 or 16, combination for use according to claim 15 or 16, anti-HER2 antibody-drug conjugate for use according to claim 15 or 16, or anti-PD- 1 / PD-L1 antibody or fragment thereof for use according to claim 15 or 16, wherein the composition comprises one or more anti-HER2 antibody-drug conjugates having the structurewherein the average connection number q’ is an integer or decimal from 1 to 16; wherein R2is selected from the group consisting of: -O-, -(R2a)N-, -S- and -P(=O)(R2a)-;R2ais hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra)(Rb), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra)(Rb), -SO2N(Ra)(Rb), -OC(O)R, -N(R)SO2R, or a C1-6aliphatic group optionally substituted with R; andwherein each R, each Raand each Rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or a C1-6aliphatic group.

18. The combination according to any one of claims 15-17, combination for use according to any one of claims 15-17, anti-HER2 antibody-drug conjugate for use according to any one of claims 15-17, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 15-17, wherein the composition comprises one or more anti-HER2 antibody-drug conjugates having the structure shown as formula (IV’):Trastuzumab(IV) wherein the average connection number q’ is an integer or decimal from 1 to 16.

19. The combination according to any one of claims 15-18, combination for use according to any one of claims 15-18, anti-HER2 antibody-drug conjugate for use according to any one of claims 15-18, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 15-18, wherein the average connection number q’ is an integer or decimal from 2 to 14, preferably wherein the average connection number q’ is an integer or decimal from 6 to 10, more preferably wherein the average connection number q’ is an integer or decimal from 7 to 9.

20. The combination according to any one of claims 1 or 5-19, combination for use according to any one of claims 2 or 5-19, anti-HER2 antibody-drug conjugate for use according to any of claims one 3 or 5-19, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-19, wherein the anti-PD-1 / PD-L1 antibody or fragment thereof is not a bispecific antibody comprising an antibody or fragment thereof that specifically binds to VEGF.

21. The combination according to any one of claims 1 or 5-20, combination for use according to any one of claims 2 or 5-20, anti-HER2 antibody-drug conjugate for use according to any one of claims 3 or 5-20, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-20, wherein the anti-PD-1 / PD-L1 antibody or fragment thereof binds to human PD-1 or human PD-L1 with a dissociation constant (KD) of less than or equal to 1 nanomolar.

22. The combination according to any one of claims 1 or 5-21, combination for use according to any one of claims 2 or 5-21, anti-HER2 antibody-drug conjugate for use according to any one of claims 3 or 5-21, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according toany one of claims 4 or 5-21, wherein the anti-PD-1 / PD-L1 antibody or fragment is selected from: dostarlimab or a fragment thereof, pembrolizumab or a fragment thereof, nivolumab or a fragment thereof, cemiplimab or a fragment thereof, atezolizumab or a fragment thereof, durvalumab or a fragment thereof, or avelumab or a fragment thereof.

23. The combination according to any one of claims 1 or 5-21, combination for use according to any one of claims 2 or 5-21, anti-HER2 antibody-drug conjugate for use according to any one of claims 3 or 5-21, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-21, wherein the anti-PD-1 / PD-L1 antibody or fragment is an anti-PD-1 antibody or fragment thereof.

24. The combination according to any one of claims 1 or 5-23, combination for use according to any one of claims 2 or 5-23, anti-HER2 antibody-drug conjugate for use according to any one of claims 3 or 5-23, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-23, wherein the anti-PD-1 / PD-L1 antibody or fragment thereof comprises:(i) a heavy chain variable region comprising: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 21; and a light chain variable region comprising: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 23; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, wherein the CDRs are defined according to the Kabat numbering system; and / or(ii) a heavy chain variable region comprising: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 25; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and a light chain variable region comprising: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 28; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 30, wherein the CDRs are defined according to the IMGT numbering system.

25. The combination according to any one of claims 1 or 5-24, combination for use according to any one of claims 2 or 5-24, anti-HER2 antibody-drug conjugate for use according to anyone of claims 3 or 5-24, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-24, wherein the anti-PD-1 / PD-L1 antibody or fragment thereof comprises:(i) a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 31 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and(ii) a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 32 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

26. The combination according to any one of claims 1 or 5-25, combination for use according to any one of claims 2 or 5-25, anti-HER2 antibody-drug conjugate for use according to any one of claims 3 or 5-25, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-25, wherein the anti-PD-1 / PD-L1 antibody or fragment thereof comprises:(i) a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 35 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and(ii) a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

27. The combination according to any one of claims 1 or 5-26, combination for use according to any one of claims 2 or 5-26, anti-HER2 antibody-drug conjugate for use according to any one of claims 3 or 5-26, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-26, wherein the anti-PD-1 / PD-L1 antibody or fragment thereof comprises two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 35; and two light chains comprising or consisting of the amino acid sequence of SEQ ID NO: 36.

28. The combination according to any one of claims 1 or 5-27, combination for use according to any one of claims 2 or 5-27, anti-HER2 antibody-drug conjugate for use according to any one of claims 3 or 5-27, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-27, wherein the anti-PD-1 / PD-L1 antibody or fragment thereof is a monoclonal antibody.

29. The combination according to any one of claims 1 or 5-28, combination for use according to any one of claims 2 or 5-28, anti-HER2 antibody-drug conjugate for use according to any one of claims 3 or 5-28, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-28, wherein the anti-PD-1 / PD-L1 antibody or fragment thereof is dostarlimab.

30. The combination for use according to any one of claims 2 or 5-29, anti-HER2 antibodydrug conjugate for use according to any one of claims 3 or 5-29, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-29, wherein the subject is a human subject, preferably wherein the subject is an adult human.

31. The combination for use according to any one of claims 2 or 5-30, anti-HER2 antibodydrug conjugate for use according to any one of claims 3 or 5-30, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-30, wherein the cancer is a HER2-expressing cancer.

32. The combination for use according to any one of claims 2 or 5-31, anti-HER2 antibodydrug conjugate for use according to any one of claims 3 or 5-31, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-31, wherein the cancer is selected from endometrial cancer, lung cancer, kidney cancer, urinary tract carcinoma, colorectal cancer, prostatic cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, and esophageal cancer.

33. The combination for use according to any one of claims 2 or 5-32, anti-HER2 antibodydrug conjugate for use according to any one of claims 3 or 5-32, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-32, wherein the cancer is endometrial cancer, such as uterine serous carcinoma (USC).

34. The combination for use according to claim 33, anti-HER2 antibody-drug conjugate for use according to claim 33, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to claim 33, wherein the subject has proficient mismatch repair (pMMR) endometrial cancer.

35. The combination for use according to claim 33 or 34, anti-HER2 antibody-drug conjugate for use according to claim 33 or 34, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to claim 33 or 34, wherein the subject has recurrent or primary advanced endometrial cancer.

36. The combination for use according to any one of claims 33-35, anti-HER2 antibody-drug conjugate for use according to any one of claims 33-35, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 33-35, wherein the subject is a subject with pMMR, recurrent or primary advanced HER2-expressing endometrial cancer.

37. The combination for use according to any one of claims 2 or 5-36, anti-HER2 antibodydrug conjugate for use according to any one of claims 3 or 5-36, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-36, wherein the subject has been previously treated for the cancer.

38. The combination for use according to any one of claims 2 or 5-37, anti-HER2 antibodydrug conjugate for use according to any one of claims 3 or 5-37, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-37, wherein the subject has been previously treated for the cancer with carboplatin, paclitaxel, and a PD-1 / PD-L1 inhibitor.

39. The combination for use according to claim 38, anti-HER2 antibody-drug conjugate for use according to claim 38, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to claim 38, wherein following treatment with carboplatin, paclitaxel, and a PD-1 / PD-L1 inhibitor the subject achieved complete response (CR), partial response (PR), or stable disease (SD), for example determined by imaging, according to RECIST version 1.1.

40. The combination for use according to any one of claims 2 or 5-39, anti-HER2 antibodydrug conjugate for use according to any one of claims 3 or 5-39, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-39, wherein the anti-HER2 antibody-drug conjugate and anti-PD-1 / PD-L1 antibody or fragment thereof are administered separately.

41. The combination for use according to any one of claims 2 or 5-40, anti-HER2 antibodydrug conjugate for use according to any one of claims 3 or 5-40, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-40, wherein the anti-HER2 antibody-drug conjugate and anti-PD-1 / PD-L1 antibody or fragment thereof are each administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, excipients or diluents.

42. The combination for use according to any one of claims 2 or 5-41, anti-HER2 antibodydrug conjugate for use according to any one of claims 3 or 5-41, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-41, wherein the anti-HER2antibody-drug conjugate is administered intravenously, preferably wherein the anti-HER2 antibody-drug conjugate is administered by IV infusion.

43. The combination for use according to any one of claims 2 or 5-42, anti-HER2 antibodydrug conjugate for use according to any one of claims 3 or 5-42, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-42, wherein the anti-HER2 antibody-drug conjugate is administered every 3 weeks.

44. The combination for use according to any one of claims 2 or 5-43, anti-HER2 antibodydrug conjugate for use according to any one of claims 3 or 5-43, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-43, wherein the anti-HER2 antibody-drug conjugate is administered in a dosage of from 2.2 mg / kg to 12.0 mg / kg, preferably from 6.0 mg / kg to 10.0 mg / kg, or about 8.0 mg / kg.

45. The combination for use according to any one of claims 2 or 5-44, anti-HER2 antibodydrug conjugate for use according to any one of claims 3 or 5-44, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-44, wherein the anti-PD-1 / PD-L1 antibody or fragment thereof is administered intravenously, preferably wherein the anti-PD-1 / PD-L1 antibody or fragment thereof is administered by IV infusion.

46. The combination for use according to any one of claims 2 or 5-45, anti-HER2 antibodydrug conjugate for use according to any one of claims 3 or 5-45, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-45, wherein the anti-PD-1 / PD-L1 antibody or fragment thereof is administered every 6 weeks.

47. The combination for use according to any one of claims 2 or 5-46, anti-HER2 antibodydrug conjugate for use according to any one of claims 3 or 5-46, or anti-PD-1 / PD-L1 antibody or fragment thereof for use according to any one of claims 4 or 5-46, wherein the anti-PD-1 / PD-L1 antibody or fragment thereof is administered in a dosage of from 500 mg to 2000 mg, preferably from 800 mg to 1200 mg, or about 1000 mg.

48. A composition comprising: (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

49. A kit-of-parts comprising: (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

50. A method of treating cancer in a subject, the method comprising administering to the subject: (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

51. Use of a combination of (a) an anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof, in the manufacture of a medicament for treating cancer.

52. Use of an anti-HER2 antibody-drug conjugate in the manufacture of a medicament for treating cancer in a subject, the use comprising administering to the subject: (a) the anti-HER2 antibody-drug conjugate; and (b) an anti-PD-1 / PD-L1 antibody or fragment thereof.

53. Use of an anti-PD-1 / PD-L1 antibody or fragment thereof in the manufacture of a medicament for treating cancer in a subject, the use comprising administering to the subject: (a) an anti-HER2 antibody-drug conjugate; and (b) the anti-PD-1 / PD-L1 antibody or fragment thereof.

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