Combination therapy for cancer treatment

Abstract

A combination of a. a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and b. an antibody-drug conjugate having the formula (I), as defined herein, for use in treating cancer in a subject, is disclosed. Dosage regimes for the combination and use of the combination in treating specific cancers are also disclosed.

Description

[0001] COMBINATION THERAPY FOR CANCER TREATMENT

[0002] Field of the Invention

[0003] The present application relates to the field of biomedicine, and in particular to a binding agent and an antibody-drug conjugate and uses thereof. The invention relates to a combination of a binding agent that comprises (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and an antibody-drug conjugate, as defined herein, comprising an antibody or fragment thereof that specifically binds to a target expressed on the surface of a tumour cell, typically when administered at the dosages defined herein. Methods for using the binding agent and the antibody-drug conjugate of the present invention are also provided.

[0004] Background of the Invention

[0005] Antibody-drug conjugates (ADCs) and immunotherapy have each prompted a revolution in the treatment of cancer.

[0006] ADCs, comprising monoclonal antibodies conjugated to cytotoxic agents (payloads) via a linker, have emerged as novel therapeutic options. Upon binding with the cell surface antigen targeted by the specific antibody, the ADC is internalized by the tumour cell and processed by the endo-lysosomal system. Within the tumour cognate antigen-positive cells are bound by the antibody, the payload is released through the cleavable linker technology and results in cytotoxic activity.

[0007] ADCs can induce tumour cell death through the so-called bystander effect, which occurs when the cytotoxic warhead diffuses across the cell membrane to neighbouring cells, thus inducing their apoptosis. ADCs interact with cancer and immune cells by eliciting mechanisms such as immunogenic cell death, antibody-dependent cell-mediated cytotoxicity and dendritic cell activation, ultimately providing potential synergism with immunotherapy. ADCs induce tumour-specific adaptive immunity,increasing the infiltration of T cells into the tumour microenvironment, whereas immune-checkpoint inhibitors reinvigorate exhausted T cells, enhancing anti-tumour immune responses.

[0008] The approval of immunotherapy, such as immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) has dramatically changed the treatment landscape for cancer subjects, and, combination therapy targeting multiple immune checkpoints has recently been explored to provide greater clinical benefits and broader indications.

[0009] Despite these promising improvements, response to immunotherapy treatment is not guaranteed in all cancer subjects and only a limited fraction of patients obtained a long-term benefit of ADCs and immunotherapy.

[0010] There is therefore an unmet need for improved methods for cancer treatment. The effect of combining any given ADC and any given binding agent in a combination therapy cannot always be predicted.

[0011] Summary of the Invention

[0012] In one aspect of the invention, there is provided a combination of

[0013] a. a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and

[0014] b. an antibody-drug conjugate having the formula (I):

[0015]

[0016] or a tautomer, mesomer, enantiomer thereof, or a pharmaceutically acceptable salt thereof wherein:

[0017] Ab is sacituzumab;

[0018] L IS -La-Lb-Lc-^

[0019] La- is

[0020] o

[0021] - Lb- is:

[0022]

[0023] -Lc- is -CH2-;

[0024] R1is selected from the group consisting of: -O-, -(R2)N-, -P(=O)(R2)- and -S-; X is -LJ-CH2-C(O)-;

[0025] L1is -(C(R3a)(R3b))m-, wherein 0 or at least 1 methylene unit of L1is independently replaced b

[0026]

[0027] y -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-;

[0028] wherein each R2, each R3a, each R3band each R4bare 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,

[0029] or a C1-6 aliphatic 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)S02H or a C1-6 aliphatic group;

[0030] m is selected from the group consisting of integers > 0,

[0031] when R1is -O- or -HN-, at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-, or each R3aand each R3bare not both hydrogen; and

[0032] n is a connection number and is an integer from 1 to 10;

[0033] for use in treating cancer in a subject.

[0034] In one aspect of the invention, there is provided a combination of:

[0035] a. a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and

[0036] b. an antibody-drug conjugate having the formula (I):

[0037]

[0038] or a tautomer, mesomer, enantiomer thereof, or a pharmaceutically acceptable salt thereof wherein:

[0039] Ab is sacituzumab;

[0040] L is -La-Lb-Lc-;La- is

[0041] o

[0042] - Lb- is:

[0043]

[0044] -Lc- is -CH2-;

[0045] R1is selected from the group consisting of: -O-, -(R2)N-, -P(=O)(R2)- and -S-;

[0046] X is -LJ-CH2-C(0)-;

[0047] L1is -(C(R3a)(R3b))m-, wherein 0 or at least 1 methylene unit of L1is independently replaced b

[0048]

[0049] y -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-;

[0050] wherein each R2, each R3a, each R3band each R4bare 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,

[0051] or a C1-6 aliphatic group optionally substituted with R;

[0052] 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)S02H or a C1-6 aliphatic group;

[0053] m is selected from the group consisting of integers > 0,

[0054] when R1is -O- or -HN-, at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-, or each R3aand each R3bare not both hydrogen; and

[0055] n is a connection number and is an integer from 1 to 10;

[0056] for use in treating cancer in a subject,

[0057] wherein the use comprises administering the antibody-drug conjugate of formula (I) at a dose of from about 2 mg / kg to about 5 mg / kg.

[0058] In one aspect of the invention, there is provided:a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction,

[0059] for use in treating cancer in a subject, the use comprising administering to the subject: a. the binding agent; and

[0060] b. an antibody-drug conjugate having the formula (I):

[0061]

[0062] or a tautomer, mesomer, enantiomer thereof, or a pharmaceutically acceptable salt thereof wherein:

[0063] Ab is sacituzumab;

[0064] L is -La-Lb-Lc-;

[0065] La- is

[0066] o

[0067] - Lb- is:

[0068]

[0069] -Lc- is -CH2-;

[0070] R1is selected from the group consisting of: -O-, -(R2)N-, -P(=O)(R2)- and -S-;

[0071] X is -LJ-CH2-C(0)-;L1is -(C(R3a)(R3b))m-, wherein 0 or at least 1 methylene unit of L1is independently replaced b

[0072]

[0073] y -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-;

[0074] wherein each R2, each R3a, each R3band each R4bare 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,

[0075] or a C1-6 aliphatic group optionally substituted with R;

[0076] 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;

[0077] m is selected from the group consisting of integers > 0,

[0078] when R1is -O- or -HN-, at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-, or each R3aand each R3bare not both hydrogen;

[0079] n is a connection number and is an integer from 1 to 10; wherein the use comprises administering the antibody-drug conjugate of formula (I) at a dose of from about 2 mg / kg to about 5 mg / kg.

[0080] In one aspect of the invention, there is provided:

[0081] an antibody-drug conjugate having the formula (I):

[0082]

[0083] or a tautomer, mesomer, enantiomer thereof, or a pharmaceutically acceptable salt thereof wherein:Ab is sacituzumab;

[0084] L is -La-Lb-Lc-;

[0085] La- is

[0086] O

[0087] - Lb- is:

[0088]

[0089] -Lc- is -CH2-;

[0090] R1is selected from the group consisting of: -O-, -(R2)N-, -P(=O)(R2)- and -S-;

[0091] X is -LJ-CH2-C(0)-;

[0092] L1is -(C(R3a)(R3b))m-, wherein 0 or at least 1 methylene unit of L1is independently replaced b

[0093]

[0094] y -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-;

[0095] wherein each R2, each R3a, each R3band each R4bare 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,

[0096] or a C1-6 aliphatic group optionally substituted with R;

[0097] 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)S02H or a C1-6 aliphatic group;

[0098] m is selected from the group consisting of integers > 0,

[0099] when R1is -O- or -HN-, at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-, or each R3aand each R3bare not both hydrogen;

[0100] n is a connection number and is an integer from 1 to 10,

[0101] for use in treating cancer in a subject, the use comprising administering to the subject: a. a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second bindingregion which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction; and

[0102] b. the antibody-drug conjugate;

[0103] wherein the use comprises administering the antibody-drug conjugate of formula (I) at a dose of from about 2 mg / kg to about 5 mg / kg.

[0104] In one aspect of the invention, there is provided:

[0105] an antibody-drug conjugate having the formula (I):

[0106]

[0107] or a tautomer, mesomer, enantiomer thereof, or a pharmaceutically acceptable salt thereof wherein:

[0108] Ab is sacituzumab;

[0109] L IS -La-Lb-Lc-;

[0110] La- is

[0111] o

[0112] - Lb- is:

[0113]

[0114] -Lc- is -CH2-;

[0115] R1is selected from the group consisting of: -O-, -(R2)N-, -P(=O)(R2)- and -S-;

[0116] X is -LJ-CH2-C(0)-;L1is -(C(R3a)(R3b))m-, wherein 0 or at least 1 methylene unit of L1is independently replaced b

[0117]

[0118] y -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-;

[0119] wherein each R2, each R3a, each R3band each R4bare 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,

[0120] or a C1-6 aliphatic group optionally substituted with R;

[0121] 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;

[0122] m is selected from the group consisting of integers > 0,

[0123] when R1is -O- or -HN-, at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-, or each R3aand each R3bare not both hydrogen; and

[0124] n is a connection number and is an integer from 1 to 10;

[0125] and a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction,

[0126] for use in treating cancer in a subject, the use comprising administering to the subject: a. the binding agent; and

[0127] b. the antibody-drug conjugate at a dose of from about 2 mg / kg to about 5 mg / kg.

[0128] In one aspect of the invention, there is provided a method of treating cancer in a subject, comprising administering to the subject:

[0129] a. a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and

[0130] b. an antibody-drug conjugate having the formula (I):

[0131]

[0132] or a tautomer, mesomer, enantiomer thereof, or a pharmaceutically acceptable salt thereof wherein:

[0133] Ab is sacituzumab;

[0134] L IS -La-Lb-Lc-^

[0135] La- is

[0136] o

[0137] - Lb- is:

[0138]

[0139] -Lc- is -CH2-;

[0140] R1is selected from the group consisting of: -O-, -(R2)N-, -P(=O)(R2)- and -S-; X is -LJ-CH2-C(O)-;

[0141] L1is -(C(R3a)(R3b))m-, wherein 0 or at least 1 methylene unit of L1is independently replaced b

[0142]

[0143] y -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-;

[0144] wherein each R2, each R3a, each R3band each R4bare 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,

[0145] or a C1-6 aliphatic 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)S02H or a C1-6 aliphatic group;

[0146] m is selected from the group consisting of integers > 0,

[0147] when R1is -O- or -HN-, at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-, or each R3aand each R3bare not both hydrogen; and

[0148] n is a connection number and is an integer from 1 to 10;

[0149] wherein the antibody-drug conjugate is administered at a dose of from about 2 mg / kg to about 5 mg / kg.

[0150] In one aspect of the invention, there is provided use of a combination of:

[0151] a. a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and

[0152] b. an antibody-drug conjugate having the formula (I):

[0153]

[0154] or a tautomer, mesomer, enantiomer thereof, or a pharmaceutically acceptable salt thereof wherein:

[0155] Ab is sacituzumab;

[0156] L is -La-Lb-Lc-;

[0157] La- isO

[0158] - Lb- is:

[0159]

[0160] -Lc- is -CH2-;

[0161] R1is selected from the group consisting of: -O-, -(R2)N-, -P(=O)(R2)- and -S-;

[0162] X is -L1-CH2-C(O)-;

[0163] L1is -(C(R3a)(R3b))m-, wherein 0 or at least 1 methylene unit of L1is independently replaced b

[0164]

[0165] y -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-;

[0166] wherein each R2, each R3a, each R3band each R4bare 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,

[0167] or a C1-6 aliphatic group optionally substituted with R;

[0168] 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)S02H or a C1-6 aliphatic group;

[0169] m is selected from the group consisting of integers > 0,

[0170] when R1is -O- or -HN-, at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-, or each R3aand each R3bare not both hydrogen; and

[0171] n is a connection number and is an integer from 1 to 10;

[0172] in the manufacture of a medicament for use in treating cancer in a subject, wherein the use comprises administering the antibody-drug conjugate of formula (I) at a dose of from about 2 mg / kg to about 5 mg / kg.

[0173] In another aspect, there is provided a combination of:

[0174] a. a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second bindingregion which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and

[0175] b. an antibody-drug conjugate having the formula (I):

[0176]

[0177] or a tautomer, mesomer, enantiomer thereof, or a pharmaceutically acceptable salt thereof wherein:

[0178] Ab is sacituzumab;

[0179] L IS -La-Lb-Lc-^

[0180] La- is

[0181] o

[0182] - Lb- is:

[0183]

[0184] -Lc- is -CH2-;

[0185] R1is selected from the group consisting of: -O-, -(R2)N-, -P(=O)(R2)- and -S-; X is -LJ-CH2-C(0)-;

[0186] L1is -(C(R3a)(R3b))m-, wherein 0 or at least 1 methylene unit of L1is independently replaced b

[0187]

[0188] y -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-;

[0189] wherein each R2, each R3a, each R3band each R4bare 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,

[0190] or a Ci-6 aliphatic group optionally substituted with R;

[0191] 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-6 aliphatic group;

[0192] m is selected from the group consisting of integers > 0,

[0193] when R1is -O- or -HN-, at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-, or each R3aand each R3bare not both hydrogen; and

[0194] n is a connection number and is an integer from 1 to 10;

[0195] for use in treating non-squamous non-small-cell lung cancer with or without actionable genomic alterations (AGA) in a subject.

[0196] Advantages

[0197] The combination therapy of the invention exhibits a number of advantages compared with the individual components when used alone. Without wishing to be bound by theory, the following advantages are expected to be conferred by the novel combination therapy compared with the individual components.

[0198] Firstly, the binding agent component of the combination of the invention can specifically act as an immune amplifier. The PD-L1 -targeting arm of the binding agent is capable of block the PD1-PDL1 interaction.

[0199] Moreover, the combination therapy of the invention may also benefit from the anti-angiogenic anti-VEGF-A arm of the binding agent. Combining ADCs with such anti-angiogenic therapy, such as the binding agent component may facilitate better tumour penetration and exposure to the ADC, resulting in more effective eradication of tumour cells.

[0200] The present inventors have surprisingly found that the effectiveness of an ADC can be increased, e.g. synergistically, by co-administration of a binding agent (e.g. bispecificantibody) which antagonizes the PD-1 / PD-L1 interaction and the VEGF / VEGFR interaction. Combining such binding agents with ADCs may lead to better patient outcomes as it is suggested that ADCs could stimulate tumour immunity and increase the sensitivity of tumours to PD-L1 inhibition, including ‘cold tumours’ not generally responsive to immunotherapy. Additionally, increased sensitivity of tumours to ADCs could occur via targeting VEGF-A.

[0201] Thus, the present disclosure generally embraces the immunotherapeutic treatment of cancer in a subject comprising (1) the administration of an antibody-drug conjugate, as defined herein, combined with (2) the administration of a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, thereby blocking the PD-1 / PD-L1 inhibitory axis and inhibiting the VEGF / VEGFR pathway in cancer cells.

[0202] The two components of the combination therapy of the invention, namely the ADC as defined herein and the binding agent as defined herein, are therefore considered to mutually amplify each other’s effects, preferably synergistically. The ADC component can pave the way for the immunomodulatory effects of the binding agent, and the binding agent can increase the efficacy of the ADCs in solid tumours.

[0203]

[0204] of the

[0205] Figure 1: Anti-tumour efficacy study in a syngeneic hTROP2-MC38 tumour model. The combination of anti-hTROP2-ADC with anti -mPDLlxm VEGF resulted in complete tumour growth regression and long-term tumour control while in corresponding monotherapy groups tumour growth was only reduced.

[0206] Figure 2: Anti -turn our efficacy study in a syngeneic hTROP2-MC38 tumour model. The combination of anti-hTROP2-ADC with anti -mPDLlxm VEGF resulted in lower tumour weights at the termination of the study (day 28 after treatment start) compared to the corresponding monotherapies. Statistical analysis via One-way ANOVAfollowed Dunnett’s test on mean tumour weight of the treatment group versus 0.9% sodium chloride injection group on study endpoint, *p <0.05, ***p <0.001, ****p <0.0001.

[0207] Figure 3: Anti -turn our efficacy study in an A375 xenograft PBMC-co-injected tumour model. The combination of anti-hTROP2-ADC with anti-hPDLlxhVEGF resulted in tumour regression and long-term tumour control while in corresponding monotherapy groups tumour growth was only reduced.

[0208] Figure 4: Anti -turn our efficacy study in an A375 xenograft PBMC-co-injected tumour model. The combination of anti-hTROP2-ADC with anti-hPDLlxhVEGF resulted in lower tumour weights at the termination of the study (day 29 post inoculation) compared with the corresponding monotherapies.

[0209] Figure 5: Monotherapy safety of Compound 1 and Compound 2. Data labels are shown in % for any grade Treatment Related Adverse Event (TRAE). Compound 1 : data from Phase 1 / 2 clinical trial, data cut-off December 15, 2024 for 256 patients with advanced solid tumours who received Compound 1 monotherapy (2 mg / kg to 6 mg / kg Q3W). Compound 2: data from Phase 1 / 2 clinical trial, data cut-off October 18, 2024 for 384 patients with advanced solid tumours who received Compound 2 monotherapy (1 mg / kg to 45 mg / kg Q2W or 20 mg / kg to 45 mg / kg Q3W).

[0210] Figure 6: Graphical Overview of the Phase l / 2a clinical trial as described in example 4. The classic "3+3" design will be applied in Part 1 (dose escalation) to find an appropriate dose for expansion and overview of the cohorts of Part 2 (dose expansion) of the clinical trial. DLT: dose-limiting toxicity; AGA: actionable genomic alterations; NSCLC: non-small cell lung cancer; L: line; PROC: platinum-resistant ovarian cancer; TNBC: triple-negative breast cancer; ORR: overall response rate; ECOG PS: Eastern Cooperative Oncology Group Performance Status; RECIST: Response Evaluation Criteria in Solid Tumours.

[0211] Figure 7: Safety profile of 67 patients that received Compound 1 + Compound 2 Q3W in the Phase l / 2a clinical trial as described in example 4.Figure 8: Overview of Treatment Related Adverse Events (TRAEs) of patients that received Compound 1 + Compound 2 Q3W in the Phase l / 2a clinical trial as described in example 4. AST: Aspartate aminotransferase; UTE Urinary Tract Infection; WBC: white blood cell.

[0212] Figure 9: Waterfall plot of best change from baseline in sum of target lesion diameters (%) showing early efficacy in Cohort PM4 (2L-4L PROC), amongst 13 evaluable patients. Data from the Phase l / 2a clinical trial as described in example 4.

[0213] Figure 10: Waterfall plot of best change from baseline in sum of target lesion (%) showing early efficacy in Cohort 5 IL TNBC amongst 29 / 30 evaluable patients. Data from the Phase l / 2a clinical trial as described in example 4.

[0214] Figure 11 : Precision-cut tumor tissue slices from seven ovarian cancer patients were treated with control media, Compound 1 (500 ng / mL), Compound 2 (35 pg / mL), or a combination of Compound 1 and Compound 2 as described in example 5.

[0215] Definitions

[0216] The terms indicated for explanation of the invention and the disclosure have the following meaning, unless otherwise indicated in the description or the claims.

[0217] Additional definitions are set forth throughout the detailed description.

[0218] The terms used herein may be defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", H.G.W. Leuenberger, B.

[0219] Nagel, and H. Kolbl, Eds., Helvetica Chimica Acta, CH-4010 Basel, Switzerland, (1995).

[0220] The practice of the present disclosure may employ, unless otherwise indicated, conventional chemistry, biochemistry, cell biology, immunology, and recombinant DNA techniques which are explained in the literature in the field (c , e.g., Organikum, Deutscher Verlag der Wissenschaften, Berlin 1990;

[0221] Streitwieser / Heathcook, "Organische Chemie", VCH, 1990; Bey er / W alter, "Lehrbuch der Organischen Chemie", S. Hirzel Verlag Stuttgart, 1988; Carey / Sundberg,"Organische Chemie", VCH, 1995; March, "Advanced Organic Chemistry", John Wiley & Sons, 1985; Rompp Chemie Lexikon, Falbe / Regitz (Hrsg.), Georg Thieme Verlag Stuttgart, New York, 1989; Molecular Cloning: A Laboratory Manual, 2nd Edition, J. Sambrook etal. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989.

[0222] Terms “a” and “an” and “the” and similar reference used in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0223] The terms “about” or “approximately” as used herein denotes a range of ±10% of a reference value. For examples, “about 10” defines a range of 9 to 11. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about” or “approximately” in that context.

[0224] It will be understood that the terms “binding to”, “binds”, “targeting” and “targets” are interchangeable.

[0225] The term "binding agent" in the context of the present disclosure refers to any agent capable of binding to desired antigens. In certain embodiments, the binding agent is an antibody, antibody fragment, or construct thereof. The binding agent may also comprise synthetic, modified or non-naturally occurring moieties, in particular nonpeptide moieties. Such moieties may, for example, link desired antigen-binding functionalities or regions such as antibodies or antibody fragments. In one embodiment, the binding agent is a synthetic construct comprising antigen-binding CDRs or variable regions.

[0226] A binding region as defined herein (such as an antibody or a fragment thereof as defined herein) which "antagonizes the PD-1 / PD-L1 interaction" means that the binding region is antagonistic towards the PD-1 / PD-L1 signalling pathway. In particular, such binding region which antagonizes the PD-1 / PD-L1 interaction totally or partially inhibits, reduces, interferes with or negatively modulates the PD-1 / PD-L1signalling pathway by binding to PD-1, PD-L1, or both. Preferably, the binding region which antagonizes the PD-1 / PD-L1 interaction mediates its antagonistic activity in a manner that totally inhibits (z.e., blocks) or partially reduces the binding of PD-L1 to PD-1.

[0227] A binding region as defined herein (such as an antibody or a fragment thereof as defined herein) which "antagonizes the VEGF / VEGFR interaction" means that the binding region is antagonistic towards the VEGF / VEGFR signalling pathway. In particular, such binding region which antagonizes the VEGF / VEGFR interaction totally or partially inhibits, reduces, interferes with or negatively modulates the VEGF / VEGFR signalling pathway by binding to VEGF, VEGFR, or both. Preferably, the binding region which antagonizes the VEGF / VEGFR interaction mediates its antagonistic activity in a manner that totally inhibits (i.e., blocks) or partially reduces the binding of VEGF to VEGFR.

[0228] “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. Antibodies may comprise several “regions” or “domains” and the terms may be used interchangeably herein. An antibody may recognise an antigen via the fragment antigen-binding (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 (CHI, CH2, and CH3) and a light chain comprises a variable domain (VL) and one constant domain (CL). Examples antibodies include a human antibody, a mouse antibody, a camelid antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, a monoclonal antibody, and a polyclonal antibody.

[0229] 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 isinvolved 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 antibody, such as a single chain variable fragment (scFv), a single-domain antibody (sdAb), a nanobody, and a VHH. 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 “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.

[0230] The term “bispecific antibody” may refer to a molecule which binds to two different target molecules and which comprises or consists of one or more antibodies and / or antibody fragments. The one or more antibodies and / or antibody fragments may include any described herein, including a human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, a monoclonal antibody, a polyclonal antibody, 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 singledomain antibody (sdAb), a nanobody, a VHH, and a camelid antibody. A bispecific antibody may comprise a single chain or two or more chains.

[0231] “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 (Kabat et al., 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 et al. (1989) Nature 342:878-883) or the IMGT numbering system (Lefranc et al., Dev. Comparat. Immunol.27:55-77, 2003; Ehrenmann F, Kaas Q, Lefranc M P. IMGT / 3Dstructure-DB and IMGT / DomainGap Align: a database and a tool for immunoglobulins or antibodies, T cell receptors, MHC, IgSF and MhcSFfJ], Nucleic acids research, 2009;38(suppl_l):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 (for example, see Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003).

[0232] “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.

[0233] Unless expressly specified otherwise, the term “comprising” is used in the context of the present disclosure to indicate that further members may optionally be present in addition to the members of the list introduced by “comprising”. It is, however, contemplated as specific embodiments of the present invention that each time the term “comprising” is used, this shall also encompass the possibility of no further members being present, i.e., for the purpose of this embodiment “comprising” can be understood as having the meaning of “consisting of’.

[0234] “Combination therapy” refers to the binding agent (e.g. bispecific antibody) disclosed herein that specifically binds to PD-L1 and VEGF in combination with an antibodydrug conjugate disclosed herein for use in a method of treating a subject with cancer. Each component of the combination therapy, i.e., the binding agent (e.g. bispecific antibody) and the antibody-drug conjugate may be administered separately. For example, the combination can be administered sequentially in this order, in reverse order, concomitantly, or combinations thereof.The term “diluent” relates to a diluting and / or thinning agent. Moreover, the term “diluent” includes any one or more of fluid, liquid or solid suspension and / or mixing media. Examples of suitable diluents include ethanol, glycerol, and water.

[0235] As used herein, the term “effective amount” refers to an amount of a given substance that is sufficient in quantity to produce a desired effect, including an improvement or remediation of the disease, disorder, or symptoms of the disease or condition. A therapeutically effective amount of a therapeutic agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the therapeutic agent to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the therapeutic agent are outweighed by the therapeutically beneficial effects. In the case that a reaction in a patient is insufficient with an initial dose, higher doses (or effectively higher doses achieved by a different, more localized route of administration) may be used. In case that unwanted side effects occur in a patient with a dose, lower doses (or effectively lower doses achieved by a different, more localized route of administration) may be used. The combination therapy described herein is to be administered to a patient in need therefore in an effective amount.

[0236] The term “excipient” as used herein refers to a substance which may be present in a pharmaceutical composition of the present disclosure but is not an active ingredient. Examples of excipients, include without limitation, carriers, binders, diluents, lubricants, thickeners, surface active agents, preservatives, stabilizers, emulsifiers, buffers, flavouring agents, or colorants.

[0237] “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. The term “human antibody” may be used interchangeably with the terms "fully humanized antibody", "fully human antibody" or "completely human antibody", which may also be known as "fully humanized monoclonal antibody".“Humanized antibody” refers to forms of antibodies that contain sequences from nonhuman (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.

[0238] The "Programmed Death- 1 (PD-1)" receptor refers to an immuno-inhibitory receptor belonging to the CD28 family. PD-1 (also known as CD279) is expressed predominantly on previously activated T cells in vivo, and binds to two ligands, PD-L1 (also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273). The term "PD-1" as used herein includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1. "Programmed Death Ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that downregulates T cell activation and cytokine secretion upon binding to PD-1. The term "PD-L1" as used herein includes human PD-L1 (hPD-Ll), variants, isoforms, and species homologs of hPD-Ll, such as macaque (cynomolgus monkey), African elephant, wild boar and mouse PD-L1 (cf, e.g., Genbank accession no. NP_054862.1, XP_005581836, XP_003413533, XP_005665023 and NP_068693, respectively), and analogues having at least one common epitope with hPD-Ll. The term "PD-L2" as used herein includes human PD-L2 (hPD-L2), variants, isoforms, and species homologs of hPD-L2, and analogues having at least one common epitope with hPD-L2. The ligands of PD-1 (PD-L1 and PD-L2) are expressed on the surface of antigen-presenting cells, such as dendritic cells or macrophages, and other immune cells. Binding of PD-1 to PD-L1 or PD-L2 results in downregulation of T cell activation. Cancer cells expressing PD-L1 and / or PD-L2 are able to switch off T cells expressing PD-1 what results in suppression of the anticancer immune response. The interaction between PD-1 and its ligands results in a decrease in tumour infiltrating lymphocytes, a decrease in T cell receptor mediated proliferation, and immune evasion by the cancerous cells. Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well.The term "VEGF" as used herein refers to vascular endothelial growth factor (VEGF) which is a member of the platelet-derived growth factor family of cystine-knot growth factors, z.e., a group of signal proteins involved in vasculogenesis and angiogenesis. Upon binding to tyrosine kinase receptors (VEGF receptors (VEGFRs)), the VEGFR dimerizes and becomes activated through transphosphorylation. Overexpression of VEGF can cause vascular diseases. Drugs which target VEGF (e.g., aflibercept, bevacizumab, ranibizumab, and pegaptanib) can inhibit VEGF and, thus, slow such diseases. In one embodiment, VEGF is human VEGF. In some embodiments, VEGF is human VEGF-A.

[0239] The term "VEGFR" as used herein refers to a VEGF receptor, which is tyrosine kinase receptor. Upon binding of a VEGF to the VEGFR, the VEGFR dimerizes and becomes activated through transphosphorylation.

[0240] "Isolated" means altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not "isolated", but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is "isolated". An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell. In a preferred embodiment, the combination partner used in the present disclosure is in substantially purified form.

[0241] 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.

[0242] 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 Fcdomain, 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).

[0243] Examples of multispecific antibodies include bispecific and trispecific antibodies.

[0244] The term “pharmaceutical composition” relates to a composition comprising a therapeutically effective agent, preferably together with pharmaceutically acceptable carriers, diluents and / or excipients. Said pharmaceutical composition is useful for treating, preventing, or reducing the severity of a disease by administration of said pharmaceutical composition to a subject.

[0245] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means solvents, dispersion media, coatings, antibacterial agents and antifungal agents, isotonic agents, and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. In certain embodiments, the pharmaceutically acceptable carrier or excipient is not naturally occurring.

[0246] The term “plurality” refers to the state of being plural.

[0247] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to polymers of amino acids.

[0248] A “single domain antibody” (sdAb) is an antibody composed of a single variable domain (e.g., heavy chain variable region) composed of antibody fragments.

[0249] 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. Compared with antibodiescomposed of heavy chain and light chain, single domain antibodies have high solubility, high stability to heat, pH, protease and other deforming agents, and only need single-chain expression to facilitate large-scale production. As used herein, the term “framework region” or “FR” residues refers to those amino acid residues in an antibody variable region other than the CDR residues as defined above.

[0250] An antibody that “specifically binds to” a specified target protein is 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 binding fragments thereof, useful in the present invention will 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 is said to bind specifically to a polypeptide comprising a given amino acid sequence, e.g., the amino acid sequence of a mature human PD-L1 molecule, if it binds to polypeptides comprising that sequence but does not bind to proteins lacking that sequence.

[0251] “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.

[0252] In the present application, the term "aliphatic group" generally refers to a linear hydrocarbon, branched hydrocarbon or cyclic hydrocarbon having 1 to 12 carbonatoms, 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. For example, aliphatic groups have 1 to 12, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms.

[0253] 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.

[0254] 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 or 1 to 4 carbon atoms. Exemplary alkylene groups include methylene, ethylene (i.e., 1,1-ethylene, 1,2-ethylene), propylene (i.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 (cis or trans or a mixture thereof), 1,4-butylene, 1 , 1 -isobutylene, 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-l,2-diyl). A "substituted alkylene" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkylene group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkylene group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituent may be the same or different). In one embodiment, the alkylene is substituted with one or more, such as 1, 2 or 3, such as 1 or 2, such as 1 substituents selected from List A.

[0255] 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 carbon-carbon 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), i.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) carboncarbon double bonds, such as comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 carboncarbon double bonds, such as 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon doublebonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carboncarbon double bond(s) may be in cis (Z) or trans (E) configuration. Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl (i.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. A "substituted alkenyl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkenyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkenyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). In one embodiment, the alkenyl is substituted with one or more, such as 1, 2 or 3, such as 1 or 2, such as 1 substituents selected from List A.

[0256] 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.

[0257] Alkynyl groups can optionally have one or more carbon-carbon triple bonds.

[0258] Generally, the maximal number of carbon-carbon 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. A "substituted alkynyl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkynyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10,such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkynyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). In one embodiment, the alkynyl is substituted with one or more, such as 1, 2 or 3, such as 1 or 2, such as 1 substituents selected from List A.

[0259] The terms "cycloalkyl" and “cycloalkenyl” represents cyclic non-aromatic versions of "alkyl" and "alkenyl" 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. Exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl. The cycloalkyl or cycloalkenyl group may consist of one ring (monocyclic), two rings (bicyclic), or more than two rings (polycyclic). A "substituted cycloalkyl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to a cycloalkyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the cycloalkyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). In one embodiment, the cycloalkyl or cycloalkenyl is substituted with one or more, such as 1, 2 or 3, such as 1 or 2, such as 1 substituents selected from List A.

[0260] List A substituents can be selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, haloalkyl, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, -NH2, -C(O)H, -CO2H, -C(O)alkyl, -C(O)2alkyl, SChalkyl, NH(CO)alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -SO2NH2 or -NHSChalkyl. In some embodiments, the list A substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, halogen (such as F, Cl, or Br), -CF3 -CHF2, and -CH2F.The term "halogen" generally refers to fluorine, chlorine, bromine or iodine, and it may be, for example, fluorine or chlorine.

[0261] In the present application, the term "optional" or "optionally" generally means that the event or circumstance subsequently described may, but not necessarily, occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "heterocyclyl group optionally substituted with alkyl" means that alkyl may be, but not necessarily, present, and that the description may include instances where the heterocyclyl group is or is not substituted with alkyl.

[0262] In the present application, the term "substituted" generally means that one or more hydrogen atoms in the group, for example, up to 5 (e.g., 1 to 3) hydrogen atoms, are each independently substituted with a corresponding number of substituents. A substituent is only in its possible chemical position, and those skilled in the art will be able to determine (by experiments or theories) possible or impossible substitution without undue efforts. For example, it may be unstable when amino or hydroxy having a free hydrogen is bound to a carbon atom having an unsaturated (such as olefin) bond.

[0263] In the present application, the term "0 or more (e.g., 0 or at least 1, 0 or 1, or 0) methylene units are replaced "generally means that when the structure comprises one or more methylene units, the one or more methylene units may be unsubstituted or replaced by one or more groups that are not methylene (e.g., -NHC(O)-, -C(O)NH-, -C(O)-, -OC(O)-, -C(O)O-, -NH-, -O-, -S-, -SO-, -SO2-, -PH-, -P(=O)H-, -NHSO2-, -SO2NH-, -C(=S)-, -C(=NH)-, -N=N-, -C=N-, -N=C- or -C(=N2)-).

[0264] The term "amino acid" and "amino acid residue" may herein be used interchangeably, and are not to be understood limiting. Amino acids are organic compounds containing amine (-NH2) and carboxyl (-COOH) functional groups, along with a side chain (R group) specific to each amino acid. In the context of the present disclosure, amino acids may be classified based on structure and chemical characteristics. Thus, classes of amino acids may be reflected in one or both of the following tables:Table 1: Main classification based on structure and general chemical characterization ofR group

[0265] Class Amino acid

[0266] Acidic Residues D and E

[0267] Basic Residues K, R, and H

[0268] Hydrophilic Uncharged Residues S, T, N, and Q

[0269] Aliphatic Uncharged Residues G, A, V, L, and I

[0270] Non-polar Uncharged Residues C, M, and P

[0271] Aromatic Residues F, Y, and W

[0272]

[0273] Table 2: Alternative Physical and Functional Classifications of Amino Acid Residues Class Amino acid

[0274] Hydroxyl group containing residues S and T

[0275] Aliphatic residues I, L, V, and M

[0276] Cycloalkenyl-associated residues F, H, W, and Y

[0277] Hydrophobic residues A, C, F, G, H, I, L, M, R, T, V, W, and Y

[0278] Negatively charged residues D and E

[0279] Polar residues C, D, E, H, K, N, Q, R, S, and T Positively charged residues H, K, and R

[0280] Small residues A, C, D, G, N, P, S, T, and V

[0281] Very small residues A, G, and S

[0282] Residues involved in turn formation A, C, D, E, G, H, K, N, Q, R, S, P, and T

[0283] Flexible residues Q, T, K, S, G, P, D, E, and R

[0284]

[0285] Unless indicated to the contrary, an "amino acid" or "amino acid residue" as used herein preferably refers to one of the 22 natural amino acids, 20 of which are listed in Table 1 (and are encoded by the universal genetic code) and the remaining 2 of which are selenocysteine and pyrrolysine (these 2 amino acids are incorporated into proteins by unique synthesis mechanisms). These 22 amino acids are also called "proteinogenic amino acids" or "natural amino acids". The term "unnatural aminoacid" as used herein refers to any amino acid which is not a natural amino acid e.g., citrulline and homocysteine are examples of unnatural amino acids).

[0286] The percent identity between two sequences is a function of the number of identical positions shared by the sequences (ie., % homology = # of identical positions / total # of positions x 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The percent identity between two nucleotide or amino acid sequences may e.g., be determined using the algorithm of E. Meyers and W. Miller, Comput. Appl. Biosci 4, 11-17 (1988) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences may be determined using the Needleman and Wunsch, J. Mol. Biol. 48, 444-453 (1970) algorithm.

[0287] The degree of similarity or identity is given preferably for an amino acid region which is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or about 100% of the entire length of the reference amino acid sequence. For example, if the reference amino acid sequence consists of 200 amino acids, the degree of similarity or identity is given preferably for at least about 20, at least about 40, at least about 60, at least about 80, at least about 100, at least about 120, at least about 140, at least about 160, at least about 180, or about 200 amino acids, in some embodiments continuous amino acids. In some embodiments, the degree of similarity or identity is given for the entire length of the reference amino acid sequence. The alignment for determining sequence similarity, preferably sequence identity can be done with art known tools, preferably using the best sequence alignment, for example, using Align, using standard settings, preferably EMBOSS rneedle, Matrix: Blosum62, Gap Open 10.0, Gap Extend 0.5.

[0288] The disclosure describes nucleic acid sequences and amino acid sequences having a certain degree of similarity or identity to a given nucleic acid sequence or amino acid sequence, respectively (a reference sequence). "Sequence similarity" indicates thepercentage of amino acids that either are identical or that represent conservative amino acid substitutions. "Sequence identity" between two amino acid sequences indicates the percentage of amino acids that are identical between the sequences. "Sequence identity" between two nucleic acid sequences indicates the percentage of nucleotides that are identical between the sequences.

[0289] The terms "% identical" and "% identity" or similar terms are intended to refer, in particular, to the percentage of nucleotides or amino acids which are identical in an optimal alignment between the sequences to be compared. Said percentage is purely statistical, and the differences between the two sequences may be but are not necessarily randomly distributed over the entire length of the sequences to be compared. Comparisons of two sequences are usually carried out by comparing the sequences, after optimal alignment, with respect to a segment or "window of comparison", in order to identify local regions of corresponding sequences. The optimal alignment for a comparison may be carried out manually or with the aid of the local homology algorithm by Smith and Waterman, 1981, Ads App. Math. 2, 482, with the aid of the local homology algorithm by Neddleman and Wunsch, 1970, J. Mol. Biol. 48, 443, with the aid of the similarity search algorithm by Pearson and Lipman, 1988, Proc. Natl Acad. Sci. USA 88, 2444, or with the aid of computer programs using said algorithms (GAP, BESTFIT, FASTA, BLAST P, BLAST N and TFASTA in Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Drive, Madison, Wis.). In some embodiments, percent identity of two sequences is determined using the BLASTN or BLASTP algorithm, as available on the United States National Centre for Biotechnology Information (NCBI) website (e.g., atblast.ncbi.nlm.nih.gov / Blast.cgi). In some embodiments, the algorithm parameters used for BLASTN algorithm on the NCBI website include: (i) Expect Threshold set to 10; (ii) Word Size set to 28; (iii) Max matches in a query range set to 0; (iv) Match / Mismatch Scores set to 1, -2; (v) Gap Costs set to Linear; and (vi) the filter for low complexity regions being used. In some embodiments, the algorithm parameters used for BLASTP algorithm on the NCBI website include: (i) Expect Threshold set to 10; (ii) Word Size set to 3; (iii) Max matches in a query range set to 0; (iv) Matrix set to BLOSUM62; (v) Gap Costs set to Existence: 11 Extension: 1; and (vi) conditional compositional score matrix adjustment. Percentage identity maybe obtained by determining the number of identical positions at which the sequences to be compared correspond, dividing this number by the number of positions compared (e.g., the number of positions in the reference sequence) and multiplying this result by 100.

[0290] In some embodiments, the degree of similarity or identity is given for a region which is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or about 100% of the entire length of the reference sequence. For example, if the reference amino acid sequence consists of 200 amino acid residues, the degree of identity is given for at least about 100, at least about 120, at least about 140, at least about 160, at least about 180, or about 200 amino acid residues, in some embodiments continuous amino acid residues. In some embodiments, the degree of similarity or identity is given for the entire length of the reference sequence.

[0291] Nucleic acid sequences or amino acid sequences having a particular degree of similarity or identity to a given nucleic acid sequence or amino acid sequence, respectively, may have at least one functional property of said given sequence, e.g., and in some instances, are functionally equivalent to said given sequence. One important property includes an immunogenic property, in particular when administered to a subject. In some embodiments, a nucleic acid sequence or amino acid sequence having a particular degree of similarity or identity to a given nucleic acid sequence or amino acid sequence is functionally equivalent to the given sequence.

[0292] Homologous amino acid sequences exhibit according to the present disclosure at least 40%, in particular at least 50%, at least 60%, at least 70%, at least 80%, at least 90% and preferably at least 95%, at least 98 or at least 99% identity of the amino acid residues.

[0293] Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range.

[0294] Unless otherwise indicated herein, each individual value is incorporated into the specification as if it was individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwiseclearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), provided herein is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any nonclaimed element essential to the practice of the invention.

[0295] All patents, patent applications, and other publications cited in this application are incorporated by reference in the entirety for all purposes. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0296] The combination therapy of the invention

[0297] The present invention provides a combination of

[0298] a. a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction; and

[0299] b. an antibody-drug conjugate of formula (I), as defined herein.

[0300] This combination will be referred to generally herein as “the combination therapy of the invention”. In this regard, both the binding agent and the antibody-drug conjugate may be as defined in its broadest aspect or any of the preferred aspects as described herein.

[0301]

[0302] The combination therapy of the present invention comprises an antibody-drug conjugate comprising an antibody or fragment thereof, as defined herein, that specifically binds to a target expressed on the surface of a tumour cell. It will be understood by the skilled person that the term “antibody-drug conjugate” encompasses both specific antibody-drug conjugates having a DAR (as defined below) which is integral, and compositions (as defined below) containing a mixture ofantibody-drug conjugates having different DARs, resulting in an average DAR (as defined below) which can be non-integral.

[0303] Targets which are expressed on the surface of a tumour cell may be identified by means of various molecular biological and immunological methods known in the art (see e.g. Carter, P., et al., 2004. Endocrine-related cancer, 11(4), pp.659-687). An ideal expression profile is abundant and homogeneous antigen expression on the external surface of all tumour cells for multiple tumour types with the majority of patients for each tumour type, and absent from normal tissue. In some embodiments, the target is expressed on the surface of solid tumour cells.

[0304] In some embodiments, the target is expressed with higher expression on the surface of tumour cells as compared to healthy cells. In some embodiments, the target is expressed at a level sufficient to distinguish a tumour cell from healthy cells.

[0305] Evaluation of antigen expression on the surface may be determined by any suitable method, for example by immunohistochemistry e.g. tissue microarray immunohistochemistry (see e.g. Hoos, A. and Cordon-Cardo, C., 2001. Laboratory investigation, 81(10), pp.1331-1338).

[0306] 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). The cytotoxic or chemotherapeutic drug refers to a drug that reduces or eliminates the viability of a cell. Suitable cytotoxic or chemotherapeutic drugs are known in the art.

[0307] The antibody-drug conjugate for use in the combination therapy of the present invention is an antibody-drug conjugate of formula (I):

[0308]

[0309] or a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0310] wherein:

[0311] Ab is sacituzumab;

[0312] n is a connection number, and is an integer from 1 to 10;

[0313] L is -La-Lb-Lc-;

[0314] La- is

[0315] o

[0316] - Lb- is:

[0317]

[0318] -Lc- is -CH2-;

[0319] R1is selected from the group consisting of: -O-, -(R2)N-, -P(=O)(R2)- and -S-;

[0320] X is -LJ-CH2-C(O)-;

[0321] L1is -(C(R3a)(R3b))m-, wherein 0 or at least 1 methylene unit of L1is independently replaced b

[0322]

[0323] y -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-;

[0324] wherein each R2, each R3a, each R3band each R4bare 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-6 aliphatic group optionally substituted with R;

[0325] 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;

[0326] m is selected from the group consisting of integers > 0;

[0327] when R1is -O- or -HN-, at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-, or each R3aand each R3bare not both hydrogen.

[0328] In some embodiments, the antibody-drug conjugate for use in the combination therapy of the present invention is an antibody-drug conjugate of formula (II):

[0329] Sacituzumab H l\L A H

[0330] N

[0331] Ho

[0332] ,NH

[0333] O

[0334] N— %

[0335] HO'

[0336]

[0337] " (II) or a pharmaceutically acceptable salt thereof,

[0338] wherein:

[0339] n is an connection number, and is an integer from 1 to 10.

[0340] The compounds of formula (I) and general and specific methods for their synthesis are disclosed as compounds of formula (III-D) in WO2022 / 068878 and published national applications derived therefrom. In particular, the compound of formula (II) where n is 4, also referred to herein as “Compound 1”, is disclosed as compound ADC-III-28 in WO2022 / 068878 and published national applications derived therefrom.In one embodiment of the antibody-drug conjugate for use according to the present invention, the antibody component, the drug component, and / or if present, the linker component, may take the structures shown herein. In another embodiment, the antibody component, the drug component, and / or if present, the linker component of the antibody-drug conjugate for use in the present invention may take the form of a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer of any of the structures shown, or a mixture thereof.

[0341] It will be understood that the term “connection number” when referring to a specific antibody-drug conjugate refers to the number of drug molecules connected (e.g. conjugated) to the antibody in any single antibody-drug conjugate. In this specification the terms “connection number”, “drug-antibody ratio” and “DAR” are synonymous.

[0342] Thus, the “connection number n” can be considered as the specific number of linked payload (e.g. cytotoxic drugs) conjugated to the antibody in a given antibody-drug conjugate. It will also be understood that the connection number n can affect the safety and therapeutic effectiveness of the 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. In particular, a reverse phase HPLC (RP-HPLC) method, can be used to calculate the DAR of the antibodydrug conjugates used in the present invention, including but not limited to the compound of formula (II) as defined herein.

[0343] As used herein, the connection number n is an integer from 1 to 10.

[0344] In some embodiments, the connection number n may be an integer selected from the list of ranges selected from: 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2.In some embodiments, the connection number n may be an integer selected from the list of ranges selected from: 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, or 9 to 10.

[0345] In some embodiments, the connection number n may be an integer selected from the list of ranges selected from: 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, or 9 to 10.

[0346] In some embodiments, the connection number n may be selected from the group of integers of: 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0347] In some embodiments, the connection number n may be 1 to 8. In some embodiments, the connection number n may be 2 to 7. In some embodiments, the connection number n may be 3 to 6. In some embodiments, the connection number n may be 3 to 4. In some embodiments, the connection number n may be 3. In some embodiments, the connection number n may be 4. In some embodiments, the connection number n may be 5. In some embodiments, the connection number n may be 6.

[0348] In some embodiments, the antibody-drug conjugate may be a compound of formula (II) having the structure below:

[0349] Sacituzumab H l\L A H

[0350] N YHO

[0351] ,NH

[0352] O T N— N* \\ / - HO'

[0353]

[0354] " (II)

[0355] In a preferred embodiment, the antibody-drug conjugate is Compound 1, which is a compound of formula (II) wherein n is 4. Compound 1 is disclosed as compound ADC-III-28 and general and specific methods for its synthesis are disclosed in WO2022 / 068878 and published national applications derived therefrom.

[0356] The antibody component and the drug component of the antibody-drug conjugate of the invention are linked (i.e. conjugated) to each other via the linker as defined in the claims. 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 may be covalently linked to a linker. Suitably, one region of the linker may bind to the antibody and another region of the linker may bind to the drug.

[0357] In some embodiments, the linker is conjugated to a cysteine residue in the antibody, through a connecting sulfur atom.

[0358] In some embodiments, the linker may be a cleavable linker. In some embodiments, the linker may be a maleimide tetrapeptide-based cleavable linker.

[0359] Compositions containing ADCs

[0360] In some embodiments, the combination therapy of the present invention uses compositions containing antibody-drug conjugates (ADCs) as defined herein, and mixtures thereof, for uses as defined herein.

[0361] 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. Thus, the average connection number n’ can be considered as the number of linked payload (e.g. cytotoxic drugs) per antibody when expressed as an average across the whole of the composition. It will also be understood that the average connection number n’ 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, ELISAassays and HPLC, in particular reverse phase HPLC (RP-HPLC), as exemplified in Example 1 below.

[0362] 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” may refer 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.

[0363] As used herein, the average connection number n’ is an integer or a decimal from 1 to 10.

[0364] In some embodiments, the average connection number n’ may be an integer or a decimal selected from the list of ranges selected from: 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2.

[0365] In some embodiments, the average connection number n’ may be an integer or a decimal selected from the list of ranges selected from: 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, or 9 to 10.

[0366] In some embodiments, the average connection number n’ may be an integer or a decimal selected from the list of ranges selected from: 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, or 9 to 10.

[0367] In some embodiments, the average connection number n’ may be selected from the group of integers of: 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.In some embodiments, the average connection number n’ may be selected from the group of integers or decimals of: 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.

[0368] In some embodiments, the average connection number n’ may be an integer or a decimal from 1 to 8. In some embodiments, the average connection number n’ may be an integer or a decimal from 2 to 7. In some embodiments, the average connection number n’ is an integer or a decimal from 3 to 6. In some embodiments, the average connection number n’ is an integer or a decimal from 4 to 7. In some embodiments, the average connection number n’ is an integer or a decimal from 4 to 6. In some embodiments, the average connection number n’ is an integer or a decimal from 3.5 to 4.5. In some embodiments, the average connection number n’ is an integer or a decimal from 4 to 5. In some embodiments, the average connection number n’ is an integer or a decimal from 5 to 6. In some embodiments, the average connection number n’ is about 3. In some embodiments, the average connection number n’ is about 3.1. In some embodiments, the average connection number n’ is about 3.2. In some embodiments, the average connection number n’ is about 3.3. In some embodiments, the average connection number n’ is about 3.4. In some embodiments, the average connection number n’ is about 3.5. In some embodiments, the average connection number n’ is about 3.6. In some embodiments, the average connection number n’ is about 3.7. In some embodiments, the average connection number n’ is about 3.8. In some embodiments, the average connection number n’ is about 3.9. In some embodiments, the average connection number n’ is about 4. In some embodiments, the average connection number n’ is about 4.1. In some embodiments, the average connection number n’ is about 4.2. In some embodiments, the average connection number n’ is about 4.3. In some embodiments, the average connection number n’ is about 4.4. In some embodiments, the average connection number n’ is about 4.5. In some embodiments, the average connection number n’ is about 4.6. In some embodiments, the average connection number n’ is about 4.7. In someembodiments, the average connection number n’ is about 4.8. In some embodiments, the average connection number n’ is about 4.9. In some embodiments, the average connection number n’ is about 5.

[0369] In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is a compound of formula (II’) or a pharmaceutically acceptable salt thereof, and the average connection number n’ may be an integer or a decimal selected from the range of about 4 to about 6. In some embodiments, the antibodydrug conjugate or a pharmaceutically acceptable salt thereof is a compound of formula (IF) or a pharmaceutically acceptable salt thereof, and the average connection number n’ may be an integer or a decimal selected from the range of about 4 to about 5. In some embodiments, the antibody-drug conjugate is a compound of formula (II’) or a pharmaceutically acceptable salt thereof, and the average connection number n’ may be selected from the group of integers or decimals of: 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 and 5.0.

[0370] Antibody component

[0371] According to the invention, the antibody of the antibody-drug conjugate is an anti-TROP2 antibody or fragment thereof.

[0372] TROP2 may refer to a transmembrane glycoprotein encoded by the Tacstd2 gene and may also be known as TACSTD2, epithelial glycoprotein- 1 antigen (EGP-1), EGP1, GA733-1, GA7331, GP50, M1S1 or tumour-associated calcium signal transducer 2.

[0373] An example amino acid sequence for TROP2 is shown in SEQ ID NO: 74:

[0374] MARGPGLAPPPLRLPLLLLVLAAVTGHTAAQDNCTCPTNKMTVCSPDGPGGR CQCRALGSGMAVDCSTLTSKCLLLKARMSAPKNARTLVRPSEHALVDNDGL YDPDCDPEGRFKARQCNQTSVCWCVNSVGVRRTDKGDLSLRCDELVRTHHI LIDLRHRPTAGAFNHSDLDAELRRLFRERYRLHPKFVAAVHYEQPTIQIELRQ NTSQKAAGDVDIGDAAYYFERDIKGESLFQGRGGLDLRVRGEPLQVERTLIY YLDEIPPKFSMKRLTAGLIAVIVVVVVALVAGMAVLVITNRRKSGKYKKVEI KELGELRKEPSL (SEQ ID NO: 74)In preferred embodiments, the anti-TROP2 antibody or fragment thereof is sacituzumab. Sacituzumab may refer to an anti-TROP2 antibody having the CDRs, variable region sequences, and heavy and light chain sequences provided below.

[0375] Kabat HCDR1 NYGMN (SEQ ID NO: 58)

[0376] Kabat HCDR2 WINTYTGEPTYTDDFKG (SEQ ID NO: 59)

[0377] Kabat HCDR3 GGFGSSYWYFDV (SEQ ID NO: 60)

[0378] Kabat LCDR1 KASQDVSIAVA (SEQ ID NO: 61)

[0379] Kabat LCDR2 SASYRYT (SEQ ID NO: 62)

[0380] Kabat LCDR3 QQHYITPLT (SEQ ID NO: 63)

[0381] IMGT HCDR1 GYTFTNYG (SEQ ID NO: 64)

[0382] IMGT HCDR2 INTYTGEP (SEQ ID NO: 65)

[0383] IMGT HCDR3 ARGGFGSSYWYFDV (SEQ ID NO: 66)

[0384] IMGT LCDR1 QDVSIA (SEQ ID NO: 67)

[0385] IMGT LCDR2 SAS (SEQ ID NO: 68)

[0386] IMGT LCDR3 QQHYITPLT (SEQ ID NO: 69)

[0387] VH QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAP GQGLKWMGWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQI SSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVSS (SEQ ID NO: 70)

[0388] VL DIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKA PKLLIYSASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYY CQQHYITPLTFGAGTKVEIK (SEQ ID NO: 71) Heavy chain QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAP GQGLKWMGWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQI S SLKADDTAVYFCARGGFGS S YWYFD VWGQGSL VTVS S AST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CI<VSNI<ALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

[0389]

[0390] IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 72) Light chain DIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKA PKLLIYSASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYY CQQHYITPLTFGAGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0391] (SEQ ID NO: 73)

[0392]

[0393] In some embodiments, the antibody-drug conjugate comprises an anti-TROP2 antibody or fragment thereof which is derived from sacituzumab.

[0394] In some embodiments, a heavy chain variable region of the anti-TROP2 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 58; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 59; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 60; and a light chain variable region of the anti-TROP2 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 61; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 62; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 63, wherein the CDRs are defined according to the Kabat numbering system.

[0395] In some embodiments, a heavy chain variable region of the anti-TROP2 antibody or fragment thereof comprises: (i) a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 64; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 65; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 66; and a light chain variable region of the anti-TROP2 antibody or fragment thereof comprises: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 67; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 68; and (iii) a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 69, wherein the CDRs are defined according to the IMGT numbering system.In some embodiments, a heavy chain variable region of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 70, or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and a light chain variable region of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 71 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

[0396] In some embodiments, a heavy chain variable region of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 70, or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 58; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 59; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 60; and a light chain variable region of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 71 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 61; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 62; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 63.

[0397] In some embodiments, a heavy chain variable region of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 70, or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 64; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 65; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 66; and a light chain variable region of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 71 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, whereinthe light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 67; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 68; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 69.

[0398] In some embodiments, a heavy chain variable region of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 70; and a light chain variable region of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 71. In some embodiments, a heavy chain variable region of the anti-TROP2 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 70; and a light chain variable region of the anti-TROP2 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 71.

[0399] In some embodiments, a heavy chain of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of the amino acid sequence of SEQ ID NO: 72, or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and a light chain of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

[0400] In some embodiments, a heavy chain of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 72, or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 58; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 59; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 60; and a light chain of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 61; aLCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 62; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 63.

[0401] In some embodiments, a heavy chain of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 72, or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, wherein the heavy chain variable region comprises: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 64; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 65; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 66; and a light chain of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity thereto, wherein the light chain variable region comprises: a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 67; a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 68; and a LCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 69.

[0402] In some embodiments, a heavy chain of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 72; and a light chain of the anti-TROP2 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 73. In some embodiments, a heavy chain of the anti-TROP2 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 72; and a light chain of the anti-TROP2 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 73.

[0403] In some embodiments, the anti-TROP2 antibody or fragment thereof comprises or consists of two heavy chains comprising or consisting of the amino acid sequence of SEQ ID NO: 72; and two light chains comprising or consisting of the amino acid sequence of SEQ ID NO: 73. In some embodiments, the anti-TROP2 antibody or fragment thereof comprises or consists of two heavy chains consisting of the amino acid sequence of SEQ ID NO: 72; and two light chains consisting of the amino acid sequence of SEQ ID NO: 73.Linker

[0404] The moiety of the antibody-drug conjugate of formula (I) above comprises a linker L, which is a chemical structural fragment, which is linked to the antibody sacituzumab 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 directly linked to the ligand via a covalent bond, and may also be linked to the ligand via a linker structure.

[0405] In some embodiments, the linker L is conjugated to a cysteine residue in the antibody, through a connecting sulfur atom.

[0406] The linker structure is a structure shown as -La-Lb-Lc- as defined herein.

[0407]

[0408] / Payload

[0409] The moiety of the antibody-drug conjugate of formula (I) above contains a drug linked to the antibody sacituzumab Ab via linker L. The remaining moieties of the antibody-drug conjugate, i.e. all those structures including R1and all structures to the right of it in formula (I), are termed “the drug moiety” or “the payload moiety”. In use, the bond between L and R1is cleaved, and R1and all structures to the right of it are released in vivo.

[0410] In the compounds used in the invention, X is -L1-CH2-C(O)-.

[0411] In the compounds used in the invention, L1is -(C(R3a)(R3b))m-.

[0412] In one embodiment, m is not 0. In one embodiment, m is 1.

[0413] In one embodiment, each R3aand each R3bare not both hydrogen.

[0414] In one embodiment, R3ais a Ci-6 aliphatic group. In one embodiment, R3ais a Ci-6 alkyl group. In one embodiment, R3ais a Ci-4 alkyl group. In one embodiment, R3aisa Ci-3 alkyl group. In one embodiment, R3ais methyl or ethyl. In one embodiment, R3ais methyl.

[0415] In one embodiment, R3bis hydrogen.

[0416] In one embodiment, X is -L1-CH2-C(O)-, L1is -(C(R3a)(R3b))m-, m is not 0, and each R3aand each R3bare not both hydrogen.

[0417] In one embodiment, m is 1, and L1is -C(R3a)(R3b)-.

[0418] In one embodiment, R3ais a Ci-6 aliphatic group, and R3bis hydrogen.

[0419] In one embodiment, R3ais methyl, and R3bis hydrogen.

[0420] In one embodiment, R1is -O-.

[0421] In one embodiment, the antibody-drug conjugate comprises the following structure:

[0422]

[0423] In one embodiment, the payload compound released is a compound of formula (III):

[0424]

[0425] The compound of formula (III) is disclosed as compound P-III-30 and general and specific methods for its synthesis are disclosed in WO2022 / 068878 and published national applications derived therefrom.

[0426] The Binding Agent

[0427] Without wishing to be bound by theory, the combination of the ADC disclosed herein and the binding agent (e.g. an anti PD-L1 anti-VEGF bispecific antibody) beneficially, e.g. synergistically, increases the treatment efficacy in a variety of solid tumour types, without inducing relevant overlapping toxicity.

[0428] The binding agent component of the combination of the invention is a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGFR, or both and which antagonizes the VEGF / VEGFR interaction (this binding agent is also referred to herein as "anti-PD-1 / PD-LlxVEGF / VEGFR binding agent").

[0429] Upon administration, the anti-PD-1 / PD-LlxVEGF / VEGFR binding agent binds to both (i) PD-1 / PD-L1 and (ii) VEGF / VEGFR and therefore blocks or partially reduces the PD-l / PD-Lland VEGF / VEGFR signalling pathways. This results in a decreased immunosuppression in the tumour microenvironment and reduced neo-angiogenesis. Thus, the co-administration of an anti-PD-1 / PD-LlxVEGF / VEGFR binding agent as described herein can also reduce immunosuppression in the tumour microenvironment and / or reduce neo-angiogenesis and, thus, can enhance the tumour-antigen specific immune response of the ADC, thereby resulting in an increased effectiveness of the treatment of tumours.

[0430] The second binding region of the binding agent (e.g. the anti angiogenic part of a bispecific antibody) is contemplated to facilitate ADC penetration and exposure of tumour cells, allowing for ADC dose reduction and resulting in a lower ADC toxicity. For the immunotherapy component, it is suggested that the ADCs can increase the efficacy of immunotherapeutic agents. The implicated mode of action of this combination strategy includes induction of immunogenic cell death, dendritic cellmaturation, increase of T-cell infiltration, as well as potentiation of immunological memory and expression of immune-regulatory proteins such as PD-L1 and MHC.

[0431] The binding agent may be formulated for administration to a subject. The binding agent may be formulated as a liquid, a solid, or a combination thereof. In some embodiments, the binding agent is formulated as a liquid. The binding agent may be formulated for injection or infusion. In some embodiments, the binding agent is formulated for intravenous administration.

[0432] First binding region which binds to PD-L PD-LL or both and which antagonizes the PD-1 / PD-L1 interaction

[0433] One component of the anti-PD-1 / PD-LlxVEGF / VEGFR binding agent is a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD- 1 / PD-L1 interaction. Thus, this first binding region comprises an antagonist of the PD-1 / PD-L1 interaction, such as an anti-PD-1 antibody, a PD-1 binding fragment thereof, an anti-PD-Ll antibody, or a PD-L1 binding fragment thereof.

[0434] Al. Anti-PD-Ll antibodies or PD-L1 binding fragments thereof

[0435] In some embodiments, the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises an anti-PD-Ll antibody or a PD-L1 binding fragment thereof.

[0436] In some embodiments, PD-L1 is human PD-L1, in particular human PD-L1 comprising the sequence set forth in SEQ ID NO: 52, 53, 54, or 55.

[0437] In some embodiments, the anti-PD-Ll antibody or a PD-L1 binding fragment thereof (anti-PD-Ll antibody or fragment thereof) specifically binds to PD-L1.

[0438] In some embodiments, the anti-PD-Ll antibody or fragment thereof is a VHH of an anti-PD-Ll antibody.

[0439] In some embodiments, the CDRs are defined according to the Kabat numbering system. Thus, in some embodiments, the anti-PD-Ll antibody or fragment thereofcomprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 1; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, wherein the CDRs are defined according to the Kabat numbering system.

[0440] In some embodiments, the CDRs are defined according to the IMGT numbering system. Thus, in some embodiments, the anti-PD-Ll antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 5; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 6, wherein the CDRs are defined according to the IMGT numbering system.

[0441] In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises or consists of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises or consists of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 7, wherein the amino acid sequence comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 1, 2, and 3, respectively, or (ii) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 4, 5, and 6, respectively. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 7.

[0442] A2. Anti-PD-1 antibodies or PD-1 binding fragments thereof

[0443] In some embodiments, the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises an anti -PD-1 antibody or a PD-1 binding fragment thereof.In some embodiments, PD-1 is human PD-1, in particular human PD-1 comprising the sequence set forth in SEQ ID NO: 49, 50, or 51.

[0444] In some embodiments, the anti -PD-1 antibody or a PD-1 binding fragment thereof (anti-PD-1 antibody or fragment thereof) specifically binds to PD-1.

[0445] In some embodiments, the anti-PD-1 antibody or fragment thereof is an scFv of an anti-PD-1 antibody.

[0446] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL).

[0447] In some embodiments, the CDRs are defined according to the IMGT numbering system. Thus, in some embodiments, (I) a VH of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 30; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 31, and / or (II) a VL of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 32; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 33; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 34, wherein the CDRs are defined according to the IMGT numbering system.

[0448] In some embodiments, the CDRs are defined according to the Kabat numbering system. Thus, in some embodiments, (I) a VH of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 35; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 36; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 37, and / or (II) a VL of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 38; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 39; and (iii) a CDR3 comprising or consisting of the amino acidsequence of SEQ ID NO: 40, wherein the CDRs are defined according to the Kabat numbering system.

[0449] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises VH having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 41, and a VL having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 42. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VH having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 41, and a VL having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 42, wherein either (i) the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 29, 30, and 31, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 32, 33, and 34, respectively, or (ii) the VH chain variable region comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 35, 36, and 37, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 38, 39, and 40, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 41, and (II) comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 42.

[0450] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 43. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 43, wherein the amino acid sequence comprises (i) the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 29, 30, 31, 32, 33, and 34, respectively,or (ii) the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 35, 36, 37, 38, 39, and 40, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 43.

[0451] Second binding region which binds to VEGF, VEGFR, or both and which antagonizes the VEGF / VEGFR interaction

[0452] Another component of the anti-PD-1 / PD-LlxVEGF / VEGFR binding agent is a second binding region which binds to VEGF, VEGFR, or both and which antagonizes the VEGF / VEGFR interaction. Thus, this second binding region comprises an antagonist of the VEGF / VEGFR interaction, such as an anti- VEGF antibody, a VEGF binding fragment thereof, a protein comprising a VEGFR domain, an anti-VEGFR antibody, or a VEGF binding fragment thereof.

[0453] Bl. Anti-VEGF antibodies or VEGF binding fragments thereof

[0454] In some embodiments, the second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction comprises an anti-VEGF antibody or a VEGF binding fragment thereof, preferably an anti-VEGF-A antibody or a VEGF -A binding fragment thereof.

[0455] In some embodiments, VEGF is human VEGF, in particular human VEGF comprising the sequence set forth in SEQ ID NO: 56 or human VEGF-A comprising the sequence set forth in SEQ ID NO: 57.

[0456] In some embodiments, the anti-VEGF antibody or a VEGF binding fragment thereof (anti-VEGF antibody or fragment thereof) specifically binds to VEGF, in particular to VEGF-A.

[0457] In some embodiments, the anti-VEGF antibody or fragment thereof is a full-length anti-VEGF antibody.

[0458] In some embodiments, the anti-VEGF antibody or fragment thereof may comprise avariable region that specifically binds to VEGF, in particular VEGF-A. In some embodiments, the anti-VEGF antibody or fragment thereof comprises a heavy chain variable region and a light chain variable domain. In some embodiments, the anti-VEGF antibody or fragment thereof comprises a heavy chain and a light chain. In some embodiments, the anti-VEGF antibody or fragment thereof comprises two heavy chains and two light chains.

[0459] In some embodiments, the anti-VEGF antibody or fragment thereof comprises a constant region, preferably derived from a human antibody, preferably the constant region is selected from the constant region of human IgGl, IgG2, IgG3 or IgG4.

[0460] In some embodiments, the anti-VEGF antibody or fragment thereof comprises (a) a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 20, and / or a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 21.

[0461] In some embodiments, the CDRs are defined according to the Kabat numbering system. Thus, in some embodiments, (I) a VH of the anti-VEGF antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 8; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 10, and (II) a VL of the anti-VEGF antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 11; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 12; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 13, wherein the CDRs are defined according to the Kabat numbering system.

[0462] In some embodiments, the CDRs are defined according to the IMGT numbering system. Thus, in some embodiments, (I) a VH of the anti-VEGF antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 14; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 15; and (iii) a CDR3 comprising or consisting of the amino acidsequence of SEQ ID NO: 16, and (II) a VL of the anti-VEGF antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 17; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 18; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 19, wherein the CDRs are defined according to the IMGT numbering system.

[0463] In some embodiments, the anti-VEGF antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 20, and (II) a VL comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 21. In some embodiments, the anti-VEGF antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 20, and (II) a VL comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 21, wherein either (i) the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 8, 9, and 10, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 11, 12, and 13, respectively, or (ii) the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 14, 15, and 16, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 17, 18, and 19, respectively. In some embodiments, the anti-VEGF antibody or fragment thereof comprises (I) a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 20, and (II) comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 21.

[0464] In some embodiments, the anti-VEGF antibody or fragment thereof comprises a CHI domain, preferably comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to the amino acid sequence of SEQ ID NO: 22.

[0465] In some embodiments, the anti-VEGF antibody or fragment thereof comprises a Fc domain comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 23.

[0466] In some embodiments, the anti-VEGF antibody or fragment thereof comprises a CL domain, preferably comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 24.

[0467] In some embodiments, the anti-VEGF antibody or fragment thereof comprises (I) an HC comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 25, and (II) an LC comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 26. In some embodiments, the anti-VEGF antibody or fragment thereof comprises (I) an HC comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 25, and (II) an LC comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 26, wherein either (i) the HC comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 8, 9, and 10, respectively, and the LC comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 11, 12, and 13, respectively, or (ii) the HC comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 14, 15, and 16, respectively, and the LC comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 17, 18, and 19, respectively. In some embodiments, the anti-VEGF antibody or fragment thereof comprises (I) an HC comprising or consisting of the amino acid sequence of SEQ ID NO: 25, and (II) an LC comprising or consistingof the amino acid sequence of SEQ ID NO: 26.

[0468] In some embodiments, the anti-VEGF antibody comprises or consists of two HCs each comprising the amino acid sequence of SEQ ID NO: 25; and two LCs each comprising the amino acid sequence of SEQ ID NO: 26.

[0469] Specific embodiments of the anti-PD-1 / PD-LlxVEGF / VEGFR binding agent

[0470] In some embodiments, the anti-PD-1 / PD-LlxVEGF / VEGFR binding agent comprises a multispecific antibody, preferably a bispecific antibody.

[0471] The anti-PD-1 / PD-LlxVEGF / VEGFR binding agent can comprise any of the first and second binding regions as outlined above, in any combination.

[0472] In a particularly preferred embodiment, the anti-PD-1 / PD-LlxVEGF / VEGFR binding agent comprises (i) the PD-L1 binding sequences, such as the VHH sequences and the anti-PD-Ll HCDRs thereof as disclosed above; and (ii) a VEGF binding antibody or VEGFR-binding fragment thereof as disclosed above, such as bevacizumab.

[0473] In some embodiments, the multispecific (preferably bispecific) anti-PD-l / PD-LlxVEGF / VEGFR binding agent comprises an anti-VEGF antibody (e.g., anti-VEGF-A antibody) and / or an anti-PD-Ll single domain antibody. In some embodiments, the anti-PD-1 / PD-LlxVEGF / VEGFR binding agent comprises an anti-VEGF antibody (e.g., anti-VEGF-A antibody) and / or an anti-PD-1 single-chain variable fragment.

[0474] Cl. Anti-PD-LlxVEGF antibodies

[0475] In some preferred embodiments, the anti-PD-1 / PD-LlxVEGF / VEGFR binding agent is a bispecific anti-PD-LlxVEGF antibody, z.e., a bispecific antibody, wherein the first binding region of the bispecific antibody binds to PD-L1 and the second binding region binds to VEGF, preferably to VEGF-A.In some embodiments, the anti-PD-LlxVEGF antibody is a bispecific antibody that comprises (a) an antibody or fragment thereof that specifically binds to PD-L1 as described herein and (b) an antibody or fragment thereof that specifically binds to VEGF as described herein.

[0476] In some embodiments, the anti-PD-LlxVEGF antibody comprises an anti -VEGF antibody as described herein and at least one anti-PD-Ll single domain antibody as described herein, preferably an anti-VEGF antibody as described herein and two anti-PD-Ll single domain antibodies as described herein, more preferably an anti-VEGF antibody as described herein and two anti-PD-Ll VHHs as described herein.

[0477] In some embodiments of the anti-PD-LlxVEGF antibody, the at least one anti-PD-Ll single domain antibody may be fused to the anti-VEGF antibody. In some embodiments, each anti-PD-Ll single domain antibody is terminally fused to the anti-VEGF antibody. In some preferred embodiments, each anti-PD-Ll single domain antibody is fused to: (i) the C-terminus of a heavy chain; (ii) the N-terminus of a heavy chain; (iii) the C-terminus of a light chain; or (iv) the N-terminus of a light chain. In particularly preferred embodiments, each anti-PD-Ll single domain antibody is fused to the C-terminus of an anti-VEGF antibody, preferably the C-terminus of a heavy chain. The anti -PD-L lx VEGF antibody more preferably comprises an anti-VEGF antibody and two anti-PD-Ll VHHs, wherein each heavy chain of the anti-VEGF antibody is fused to an anti-PD-Ll VHH, more preferably at the C-terminus of the heavy chain of the anti-VEGF antibody. The anti-PD-Ll single domain antibody (in particular, VHH) can be fused to the anti-VEGF antibody by a linker, e.g., a peptide linker, for example a glycine and serine-rich linker (GS-linker) or any suitable linker known in the art, such as linker a comprising or consisting of the amino acid sequence of SEQ ID NO: 46.

[0478] In particularly preferred embodiments, the anti-PD-LlxVEGF antibody comprises (i) an anti-VEGF antibody comprising two heavy chains as described herein; and (ii) two anti-PD-Ll VHHs, wherein each heavy chain of the anti-VEGF antibody is fused to an anti-PD-Ll VHH through a linker comprising the amino acid sequence of SEQ ID NO: 46 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, 99%,or 100% identity to the amino acid sequence of SEQ ID NO: 46.

[0479] In particularly preferred embodiments, the anti-PD-LlxVEGF antibody comprises two anti-PD-Ll VHHs as described herein, wherein each VHH is fused to the C-terminus of an anti-VEGF-A antibody as described herein, preferably the C-terminus of each heavy chain of the anti-VEGF-A antibody. The anti-PD-LlxVEGF antibody can therefore comprise an anti-VEGF-A antibody as described herein and two anti-PD-Ll VHHs as described herein, wherein each heavy chain of the anti-VEGF-A antibody is fused to an anti-PD-Ll VHH through a linker, such as a linker comprising the amino acid sequence shown in SEQ ID NO: 46 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 46.

[0480] In some embodiments, the anti-PD-LlxVEGF antibody comprises (A) a heavy chain (HC) comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 27, and (B) a light chain (LC) comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 28, wherein the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 8, 9 and 10, respectively, and (ii) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 1, 2, and 3, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 11, 12, and 13, respectively. In some alternative embodiments, the anti-PD-LlxVEGF antibody comprises (A1) a heavy chain (HC) comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 27, and (B1) a light chain (LC) comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 28, wherein the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 14, 15, and 16, respectively, and (ii) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 4, 5, and 6, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences setforth in: SEQ ID NO: 17, 18, and 19, respectively.

[0481] In some particularly preferred embodiments, the anti-PD-LlxVEGF antibody comprises (i) a heavy chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 27 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 27; and (ii) a light chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 28 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 28.

[0482] In some particularly preferred embodiments, the anti-PD-LlxVEGF antibody comprises (i) a heavy chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and (ii) a light chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 28. In some particularly preferred embodiments, the anti-PD-LlxVEGF antibody comprises (i) two heavy chains each comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and (ii) two light chains each comprising or consisting of the amino acid sequence of SEQ ID NO: 28.

[0483] Such an anti-PD-LlxVEGF antibody comprising two heavy chain- VHH fusions having the amino acid sequence of SEQ ID NO: 27 and two light chains having the amino acid sequence of SEQ ID NO: 28 is referred to herein as “Compound 2” and disclosed as compound "Ava-2GS-NSD" in WO 2022 / 042719. Compound 2 is also known as BNT327, BMS986545, and pumitamig.

[0484] C2. Anti-PD-lxVEGF antibodies

[0485] In some embodiments, the anti-PD-1 / PD-LlxVEGF / VEGFR binding agent is a bispecific anti-PD-lxVEGF antibody, z.e., a bispecific antibody, wherein the first binding region of the bispecific antibody binds to PD-1 and the second binding region binds to VEGF, preferably to VEGF-A.In some embodiments, the anti-PD-lxVEGF antibody is abispecific antibody that comprises (a) an antibody or fragment thereof that specifically binds to PD-1 as described herein and (b) an antibody or fragment thereof that specifically binds to VEGF as described herein.

[0486] In some embodiments, the anti-PD-lxVEGF antibody comprises an anti-VEGF antibody as described herein and at least one anti -PD-1 scFv as described herein, preferably an anti-VEGF antibody as described herein and at least two anti -PD-1 scFvs as described herein, more preferably an anti-VEGF antibody as described herein and two anti -PD-1 scFvs as described herein.

[0487] In some embodiments of the anti-PD-lxVEGF antibody, the at least one anti -PD-1 scFv may be fused to the anti-VEGF antibody. In some embodiments, each anti -PD-1 scFv is terminally fused to the anti-VEGF antibody. In some preferred embodiments, each anti -PD-1 scFv is fused to: (i) the C-terminus of a heavy chain; (ii) the N-terminus of a heavy chain; (iii) the C-terminus of a light chain; or (iv) the N-terminus of a light chain. In particularly preferred embodiments, each anti-PD-1 scFv is fused to the C-terminus of an anti-VEGF antibody, preferably the C-terminus of a heavy chain. The anti-PD-lxVEGF antibody more preferably comprises an anti-VEGF antibody and two anti-PD-1 scFvs, wherein each heavy chain of the anti-VEGF antibody is fused to an anti-PD-1 scFv, more preferably at the C-terminus of the heavy chain of the anti-VEGF antibody. The anti-PD-1 scFv can be fused to the anti-VEGF antibody by a linker, e.g., a peptide linker, for example a glycine and serine-rich linker (GS-linker) or any suitable linker known in the art, such as linker a comprising or consisting of the amino acid sequence of SEQ ID NO: 47.

[0488] In particularly preferred embodiments, the anti-PD-lxVEGF antibody comprises (i) an anti-VEGF antibody comprising two heavy chains as described herein; and (ii) two anti-PD-1 scFvs, wherein each heavy chain of the anti-VEGF antibody is fused to an anti-PD-1 scFv through a linker, wherein the linker preferably comprises or consists of the amino acid sequence of SEQ ID NO: 47 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 47.In particularly preferred embodiments, the anti-PD-lxVEGF antibody comprises two anti-PD-1 scFvs as described herein, wherein each anti-PD-1 scFv is fused to the C-terminus of an anti-VEGF-A antibody as described herein, preferably the C-terminus of each heavy chain of the anti-VEGF-A antibody. The anti-PD-lxVEGF antibody can therefore comprise an anti-VEGF-A antibody as described herein and two anti-PD-1 scFvs as described herein, wherein each heavy chain of the anti-VEGF-A antibody is fused to an anti-PD-1 scFv through a linker, such as a linker comprising or consisting of the amino acid sequence shown in SEQ ID NO: 47 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 47.

[0489] In some embodiments, the anti-PD-lxVEGF antibody comprises (A) a heavy chain (HC) comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 44, and (B) a light chain (LC) comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 45, wherein the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 8, 9, and 10, respectively, and (ii) the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 35, 36, 37, 38, 39, and 40, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 11, 12, and 13, respectively. In some alternative embodiments, the anti-PD-LlxVEGF antibody comprises (A1) a heavy chain (HC) comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 44, and (B1) a light chain (LC) comprising or consisting of an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 45, wherein the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 14, 15, and 16, respectively, and (ii) the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 29, 30, 31, 32, 33, and 34, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences setforth in: SEQ ID NO: 17, 18, and 19, respectively.

[0490] In some particularly preferred embodiments, the anti-PD-lxVEGF antibody comprises or consists of (i) a heavy chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 44; and (ii) a light chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 45 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 45.

[0491] In some particularly preferred embodiments, the anti-PD-lxVEGF antibody comprises (i) a heavy chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 44; and (ii) a light chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 45. In some particularly preferred embodiments, the anti-PD-lxVEGF antibody comprises or consists of (i) two heavy chains each comprising or consisting of the amino acid sequence of SEQ ID NO: 44; and (ii) two light chains each comprising or consisting of the amino acid sequence of SEQ ID NO: 45.

[0492] Such an anti-PD-lxVEGF antibody comprising two heavy chains each having the amino acid sequence of SEQ ID NO: 44 and two light chains each having the amino acid sequence of SEQ ID NO: 45 is referred to herein as “Compound 3” and is also known as ivonescimab.

[0493] Example binding agent sequences

[0494] Table 3 below provides a listing of certain sequences referenced herein:

[0495] Description Sequence (and SEQ ID NO)

[0496] Anti-PD-Ll antibody or fragment thereof

[0497] HCDR1 (Kabat) SYWMY (SEQ ID NO: 1)

[0498] HCDR2 (Kabat) SINSDSSSTYYRDSVKG (SEQ ID NO: 2)

[0499] HCDR3 (Kabat) DPGGYA (SEQ ID NO: 3)

[0500]

[0501] HCDR1 (IMGT) GFTFSSYW (SEQ ID NO: 4)

[0502] HCDR2 (IMGT) INSDSSST (SEQ ID NO: 5)

[0503] HCDR3 (IMGT) AKDPGGYA (SEQ ID NO: 6)

[0504] EVQLQESGGGL VQPGGSLRLSC AASGFTF S SYWMYWLR QAPGKGLEWVSSINSDSSSTYYRDSVKGRFTISRDNAKNT VHH LYLQMNSLKSEDTAVYYCAKDPGGYAKGQGTQVTVSS

[0505] (SEQ ID NO: 7)

[0506] Anti-VEGF antibody or fragment thereof

[0507] HCDR1 (Kabat) NYGMN (SEQ ID NO: 8)

[0508] HCDR2 (Kabat) WINTYTGEPTYAADFKR (SEQ ID NO: 9)

[0509] HCDR3 (Kabat) YPHYYGSSHWYFDV (SEQ ID NO: 10)

[0510] LCDR1 (Kabat) SASQDISNYLN (SEQ ID NO: 11)

[0511] LCDR2 (Kabat) FTSSLHS (SEQ ID NO: 12)

[0512] LCDR3 (Kabat) QQYSTVPWT (SEQ ID NO: 13)

[0513] HCDR1 (IMGT) GYTFTNYG (SEQ ID NO: 14)

[0514] HCDR2 (IMGT) INTYTGEP (SEQ ID NO: 15)

[0515] HCDR3 (IMGT) AKYPHYYGSSHWYFDV (SEQ ID NO: 16)

[0516] LCDR1 (IMGT) QDISNY (SEQ IDNO: 17)

[0517] LCDR2 (IMGT) FTS (SEQ ID NO: 18)

[0518] LCDR3 (IMGT) QQYSTVPWT (SEQ ID NO: 19)

[0519] EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVR QAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKS VH T AYLQMNSLRAEDT AV YYC AKYPHYYGS SHWYFD VWG QGTLVTVSS (SEQ ID NO: 20) DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKP VL GKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPED FATYYCQQYSTVPWTFGQGTKVEIK (SEQ ID NO: 21) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS CHI WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 22) DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC

[0520] Fc

[0521] VVVDVSHEDPEVI<FNWYVDGVEVHNAI<TI<PREEQYNST

[0522]

[0523] YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 23) RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ CL WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 24) EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVR QAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKS T AYLQMNSLRAEDT AV YYC AK YPHYYGS SHWYFD VWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV PS S SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP

[0524] Heavy chain

[0525] CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVI<FNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 25) DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKP GKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPED FATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSD

[0526] Light chain

[0527] EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC (SEQ ID NO: 26)

[0528] Bispecific antibody PD-L1 x VEGF EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVR QAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKS T AYLQMNSLRAEDT AV YYC AK YPHYYGS SHWYFD VWG HC VHH fusion QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV PS S SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP

[0529]

[0530] CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVI<FNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGEVQLQ ESGGGLVQPGGSLRLSC AASGFTF S S YWMYWLRQAPGK GLEWVSSINSDSSSTYYRDSVKGRFTISRDNAKNTLYLQM NSLKSEDTAVYYCAKDPGGYAKGQGTQVTVSS (SEQ ID NO: 27) DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKP GKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPED FATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSD LC EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC (SEQ ID NO: 28)

[0531] Anti-PD-1 antiboc y or fragment thereof

[0532] HCDR1 (IMGT) GFAFSSYD (SEQ ID NO: 29)

[0533] HCDR2 (IMGT) ISGGGRYT (SEQ ID NO: 30)

[0534] HCDR3 (IMGT) ANRYGEAWFAY (SEQ ID NO: 31)

[0535] LCDR1 (IMGT) QDINTY (SEQ ID NO: 32)

[0536] LCDR2 (IMGT) RAN (SEQ ID NO: 33)

[0537] LCDR3 (IMGT) LQYDEFPLT (SEQ ID NO: 34)

[0538] HCDR1 (Kabat) SYDMS (SEQ ID NO: 35)

[0539] HCDR2 (Kabat) TISGGGRYTYYPDSVKG (SEQ ID NO: 36)

[0540] HCDR3 (Kabat) RYGEAWFAY (SEQ ID NO: 37)

[0541] LCDR1 (Kabat) RASQDINTYLS (SEQ ID NO: 38)

[0542] LCDR2 (Kabat) RANRLVS (SEQ ID NO: 39)

[0543] LCDR3 (Kabat) LQYDEFPLT (SEQ ID NO: 40)

[0544] EVQLVESGGGL VQPGGSLRLSC AASGF AF S S YDMSWVRQ APGKGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNN VH LYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVT

[0545] V (SEQ ID NO: 41)

[0546]

[0547] DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKP VL GKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPE DMATYYCLQYDEFPLTFGAGTKLELKR (SEQ ID NO: 42) EVQLVESGGGL VQPGGSLRLSC AASGF AF S S YDMSWVRQ APGKGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNN LYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVT

[0548] scFv fusion VSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSMSASVG DRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVS GVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPL TFGAGTKLELKR (SEQ ID NO: 43)

[0549] Bispecific antibody PD-1 x VEGF

[0550] EVQLVESGGGL VQPGGSLRLSC AASGYTFTNYGMNWVR QAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKS T AYLQMNSLRAEDT AV YYC AKYPHYYGS SHWYFD VWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV PS S SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVI<FNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE HC scFv fusion PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGS GGGGSEVQLVESGGGL VQPGGSLRLSC AASGF AF S SYDM SWVRQAPGKGLDWVATISGGGRYTYYPDSVKGRFTISRD NSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQ GTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSM SASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRA NRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQY DEFPLTFGAGTKLELKR (SEQ ID NO: 44) DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKP LC GKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPED FATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSD

[0551]

[0552] EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC (SEQ ID NO: 45)

[0553] Linker for bispeci: ic antibodies

[0554] Linker a GGGGSGGGGSG (SEQ ID NO: 46)

[0555] Linker b GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 47) Linker c GGSGGSGGSGGSGGS (SEQ ID NO: 48)

[0556] PD-1, PD-L1, VEGF, VEGFR MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFS PALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTD KLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRN DSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPS PD-1

[0557] PSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAA RGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPE PPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPL RPEDGHCSWPL (SEQ ID NO: 49) MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFF PALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTD KLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRN DSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPS PD-1 isoform 1

[0558] PSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAA RGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPE PPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPL RPEDGHCSWPL (SEQ ID NO: 50) MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFS PALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTD KLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRN DSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPS PD-1 isoform 2

[0559] PSPRSAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAA RGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPE PPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPL RPEDGHCSWPL (SEQ ID NO: 51)

[0560]

[0561] MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIE CKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQH SSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMIS YGGADYI<RITVI<VNAPYNI<INQRILVVDPVTSEHELTCQ PD-L1

[0562] AEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTST LRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNER THLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTN SKKQSDTHLEET (SEQ ID NO: 52) MRIFAVFIFMTYWHLLNAPYNKINQRILVVDPVTSEHELT CQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNV PD-L1 isoform 1 TSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPP NERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQ DTNSKKQSDTHLEET (SEQ ID NO: 53) MRIFAVFIFMTYWHLLNAPYNKINQRILVVDPVTSEHELT CQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNV PD-L1 isoform 2 TSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPP NERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQ DTNSKKQSDTHLEET (SEQ ID NO: 54) MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIE CKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQH PD-L1 isoform 3 SSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMIS YGGADYI<RITVI<VNAPYNI<INQRILVVDPVTSEHELTCQ AEGYPKAEVIWTSSDHQVLSGD (SEQ ID NO: 55) VEGF MNFLLSWVHWSLALLLYLHHAK (SEQ ID NO: 56)

[0563] MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPG GGVEGVGARGVALKLFVQLLGCSRFGGAVVRAGEAEPS GAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKP GSWTGEAAVCADSAPAARAPQALARASGRGGRVARRGA VEGF-A EESGPPHSPSRRGSASRAGPGRASETMNFLLSWVHWSLA LLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRS YCHPIETLVDIFQEYPDEIEYIFKPSCVPLMRCGGCCNDEG LECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNKCECR PKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVPCGP

[0564]

[0565] CSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTC RCDKPRR (SEQ ID NO: 57)

[0566]

[0567] Table 3

[0568] Preferred combinations

[0569] In preferred embodiments, the antibody-drug conjugate has the structural formula (II), as defined above, and the binding agent is Compound 2, as defined herein.

[0570] In other preferred embodiments, the antibody-drug conjugate is Compound 1, as defined herein, and the binding agent is Compound 2, as defined herein.

[0571] In one embodiment, the antibody-drug conjugate has the structural formula (II), as defined above, and the binding agent is Compound 3, as defined herein.

[0572] In one embodiment, the antibody-drug conjugate is Compound 1, as defined herein, and the binding agent is Compound 3, as defined herein.

[0573] Dose

[0574] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at any dose suitable to enable it to exhibit a therapeutic effect.

[0575] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 2 mg / kg to about 5 mg / kg.

[0576] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 2.5 mg / kg to about 4.5 mg / kg.

[0577] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered a dose of from about 3 mg / kg to about 4 mg / kg.In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 3 mg / kg to about 3.5 mg / kg.

[0578] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 2.5 mg / kg to about 3.5 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 2.8 mg / kg to about 3.2 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 2.9 mg / kg to about 3.1 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 3 mg / kg.

[0579] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 3.0 mg / kg to about 4.0 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 3.3 mg / kg to about 3.7 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 3.4 mg / kg to about 3.6 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 3.5 mg / kg.

[0580] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 3.5 mg / kg to about 4.5 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 3.8 mg / kg to about 4.2 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 3.9 mg / kg to about 4.1 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 4.0 mg / kg.

[0581] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered once every 2 weeks.In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered once every 3 weeks.

[0582] In each of the above embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is preferably Compound 1.

[0583] In one embodiment, the binding agent may be administered at any dose suitable to enable it to exhibit a therapeutic effect.

[0584] In one embodiment, the binding agent may be administered at a dose of from about 15 mg / kg to about 35 mg / kg.

[0585] In one embodiment, the binding agent may be administered at a dose of from about 15 mg / kg to about 25 mg / kg.

[0586] In one embodiment, the binding agent may be administered at a dose of from about 25 mg / kg to about 35 mg / kg.

[0587] In one embodiment, the binding agent may be administered at a dose of from about 28 mg / kg to about 32 mg / kg. In one embodiment, the binding agent may be administered at a dose of from about 29 mg / kg to about 31 mg / kg. In one embodiment, the binding agent may be administered at a dose of about 30 mg / kg.

[0588] In one embodiment, the binding agent may be administered at a dose of from about 18 mg / kg to about 25 mg / kg. In one embodiment, the binding agent may be administered at a dose of from about 19 mg / kg to about 21 mg / kg. In one embodiment, the binding agent may be administered at a dose of about 20 mg / kg.

[0589] In one embodiment, the binding agent may be administered once every 2 weeks.

[0590] In one embodiment, the binding agent may be administered once every 3 weeks.In each of the above embodiments, the binding agent is preferably a bispecific antibody that comprises (a) an antibody or fragment thereof that specifically binds to PD-L1 and (b) an antibody or fragment thereof that specifically binds to VEGF, as defined and exemplified herein. In each of the above embodiments, the bispecific antibody is preferably “Compound 2” as defined herein.

[0591] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 2.5 mg / kg to about 4.5 mg / kg, and the binding agent may be administered at a dose of from about 15 mg / kg to about 35 mg / kg.

[0592] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered a dose of from about 3 mg / kg to about 4 mg / kg, and the binding agent may be administered at a dose of from about 15 mg / kg to about 25 mg / kg.

[0593] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered a dose of from about 3 mg / kg to about 4 mg / kg, and the binding agent may be administered at a dose of from about 25 mg / kg to about 35 mg / kg.

[0594] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 2.8 mg / kg to about 3.2 mg / kg, and the binding agent may be administered at a dose of from about 28 mg / kg to about 32 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 2.9 mg / kg to about 3.1 mg / kg, and the binding agent may be administered at a dose of from about 29 mg / kg to about 31 mg / kg.

[0595] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 3.3 mg / kg to about 3.7 mg / kg, and the binding agent may be administered at a dose of from about 28 mg / kg to about 32 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceuticallyacceptable salt thereof may be administered at a dose of from about 3.4 mg / kg to about 3.6 mg / kg, and the binding agent may be administered at a dose of from about 29 mg / kg to about 31 mg / kg.

[0596] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 3.8 mg / kg to about 4.2 mg / kg, and the binding agent may be administered at a dose of from about 28 mg / kg to about 32 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 3.9 mg / kg to about 4.1 mg / kg, and the binding agent may be administered at a dose of from about 29 mg / kg to about 31 mg / kg.

[0597] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 2.8 mg / kg to about 3.2 mg / kg, and the binding agent may be administered at a dose of from about 18 mg / kg to about 22 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 2.9 mg / kg to about 3.1 mg / kg, and the binding agent may be administered at a dose of from about 19 mg / kg to about 21 mg / kg.

[0598] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 3.3 mg / kg to about 3.7 mg / kg, and the binding agent may be administered at a dose of from about 18 mg / kg to about 22 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 3.4 mg / kg to about 3.6 mg / kg, and the binding agent may be administered at a dose of from about 19 mg / kg to about 21 mg / kg.

[0599] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 3.8 mg / kg to about 4.2 mg / kg, and the binding agent may be administered at a dose of from about 18 mg / kg to about 22 mg / kg. In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of from about 3.9 mg / kg toabout 4.1 mg / kg, and the binding agent may be administered at a dose of from about 19 mg / kg to about 21 mg / kg.

[0600] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 3 mg / kg, and the binding agent may be administered at a dose of about 30 mg / kg.

[0601] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 3 mg / kg, and the binding agent may be administered at a dose of about 20 mg / kg.

[0602] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 3.5 mg / kg, and the binding agent may be administered at a dose of about 30 mg / kg.

[0603] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 3.5 mg / kg, and the binding agent may be administered at a dose of about 20 mg / kg.

[0604] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 4.0 mg / kg, and the binding agent may be administered at a dose of about 30 mg / kg.

[0605] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of about 4.0 mg / kg, and the binding agent may be administered at a dose of about 20 mg / kg.

[0606] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered at a dose of about 3 mg / kg, and the binding agent is administered at a dose of about 30 mg / kg for use in the treatment of ovarian cancer, more preferably platinum resistant ovarian cancer (PROC).In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered at a dose of about 3.5 mg / kg, and the binding agent is administered at a dose of about 30 mg / kg for use in the treatment of a solid tumour, more preferably an advanced or metastatic solid tumour.

[0607] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered at a dose of about 3.5 mg / kg, and the binding agent is administered at a dose of about 30 mg / kg for use in the treatment of breast cancer, more preferably triple negative breast cancer.

[0608] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered at a dose of about 3.5 mg / kg, and the binding agent is administered at a dose of about 30 mg / kg for use in the treatment of NSCLC.

[0609] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered at a dose of about 3.5 mg / kg, and the binding agent is administered at a dose of about 30 mg / kg for use in the treatment of cervical cancer.

[0610] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered at a dose of about 3 mg / kg once every 3 weeks (Q3W), and the binding agent is administered at a dose of about 30 mg / kg once every 3 weeks (Q3W) for use in the treatment of ovarian cancer.

[0611] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered at a dose of about 3.5 mg / kg once every 3 weeks (Q3W), and the binding agent is administered at a dose of about 30 mg / kg once every 3 weeks (Q3W) for use in the treatment of a solid tumour, more preferably an advanced or metastatic solid tumour.

[0612] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered at a dose of about 3 mg / kg once every 3 weeks (Q3W), and the binding agent is administered at a dose of about 30 mg / kg once every 3 weeks (Q3W) for use in the treatment of platinum resistant ovarian cancer (PROC).In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered at a dose of about 3.5 mg / kg once every 3 weeks (Q3W), and the binding agent is administered at a dose of about 30 mg / kg once every 3 weeks (Q3W) for use in the treatment of breast cancer, more preferably triple negative breast cancer.

[0613] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered at a dose of about 3.5 mg / kg once every 3 weeks (Q3W), and the binding agent is administered at a dose of about 30 mg / kg once every 3 weeks (Q3W) for use in the treatment of NSCLC.

[0614] In one embodiment, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered at a dose of about 3.5 mg / kg once every 3 weeks (Q3W), and the binding agent is administered at a dose of about 30 mg / kg once every 3 weeks (Q3W) for use in the treatment of cervical cancer.

[0615] In each of the above embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is preferably Compound 1, and the binding agent is preferably Compound 2.

[0616] Medical Uses and Methods of Treatment

[0617] The combination therapy of the invention is used for the treatment of cancer.

[0618] Cancer is a well-known term that refer to a disease or group of diseases involving abnormal cell growth. The term “cancer” may be used interchangeably with “tumour” or “cancerous disease”.

[0619] “Tumour” as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumours and secondary neoplasms. A solid tumour is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumours are named for the type of cells that form them. Examples ofsolid tumours are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumours (National Cancer Institute, Dictionary of Cancer Terms).

[0620] The term "disease" and "disorder" may be used interchangeably herein, referring 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. 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.

[0621] The terms “treat”, “treatment” and “treating” refers 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.

[0622] The terms “prevent”, “prevention” and “preventing” refers to preventing the onset of symptoms of a disease or condition, and as such encompasses prophylactic treatment.

[0623] In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to 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.In some embodiments, the cancer is selected from esophageal cancer (e.g., esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumour, lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) with or without actionable oncogenic alterations (AGA) (e.g., small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, triple-negative breast cancer (TNBC), head and neck cancer, cervical cancer, endometrial cancer, gastro-intestinal cancer, colorectal cancer, liver cancer, kidney cancer, urothelial cancer, solid tumour, non-Hodgkin lymphoma, central nervous system tumour (e.g., neuroglioma, glioblastoma multiforme, glioma or sarcoma), adenocarcinoma, prostate cancer or thyroid cancer.

[0624] In some embodiments, the cancer is a solid tumour.

[0625] In some embodiments, the cancer is an advanced cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is a recurrent cancer. In some embodiments, the cancer is an unresectable cancer. In some embodiments, the cancer is an inoperable cancer.

[0626] In some embodiments, the cancer is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, prostate cancer, cervical cancer, head and neck cancer.

[0627] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is advanced breast cancer. In some embodiments, the cancer is unresectable breast cancer. In some embodiments, the cancer is recurrent breast cancer. In some embodiments, the cancer is metastatic breast cancer.

[0628] In some embodiments, the breast cancer is triple negative breast cancer (TNBC). The term “triple-negative breast cancer” as used herein is used in the usual sense and refers to the cancer class that tests negative for estrogen receptors and progesterone receptors expression, and HER2 overexpression or gene amplification. TNBC is human epidermal growth factor receptor 2 (HER2) negative and has <1% expressionof estrogen receptors (ER) and progesterone receptors (PR) by immunostaining. It is a biologically aggressive tumour, characterized by moderate / high grade and highly proliferative cancer cells, which, together with limited treatment options leads to the poorest prognosis among the breast cancer subtypes. In some embodiments, the breast cancer is advanced triple negative breast cancer. In some embodiments, the breast cancer is unresectable triple negative breast cancer. In some embodiments, the breast cancer is recurrent triple negative breast cancer. In some embodiments, the breast cancer is metastatic triple negative breast cancer. In some embodiments, the cancer is TNBC and the combination is administered as a first line treatment.

[0629] In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is advanced lung cancer. In some embodiments, the cancer is unresectable lung cancer. In some embodiments, the cancer is recurrent lung cancer. In some embodiments, the cancer is metastatic lung cancer. In some embodiments, the lung cancer is non-smallcell lung cancer (NSCLC). In some embodiments, the cancer is advanced NSCLC. In some embodiments, the cancer is unresectable NSCLC. In some embodiments, the cancer is recurrent NSCLC. In some embodiments, the cancer is metastatic NSCLC. In some embodiments, the cancer is advanced non-squamous NSCLC. In some embodiments, the cancer is unresectable non-squamous NSCLC. In some embodiments, the cancer is recurrent non-squamous NSCLC. In some embodiments, the cancer is metastatic non-squamous NSCLC. In some embodiments, the lung cancer is non-small-cell lung cancer with or without actionable genomic alterations (AGA). In some embodiments, the lung cancer is AGA-positive non-squamous nonsmall-cell lung cancer. In some embodiments, the lung cancer is advanced AGA-positive non-squamous non-small-cell lung cancer. In some embodiments, the lung cancer is unresectable AGA-positive non-squamous non-small-cell lung cancer. In some embodiments, the lung cancer is recurrent AGA-positive non-squamous nonsmall-cell lung cancer. In some embodiments, the lung cancer is metastatic AGA-positive non-squamous non-small-cell lung cancer. In some embodiments, the lung cancer is AGA-negative non-squamous non-small-cell lung cancer. In some embodiments, the lung cancer is advanced, unresectable, recurrent, and / or metastatic NSCLC without actionable genomic alterations (AGAs). In some embodiments, the lung cancer is advanced / unresectable, recurrent, or metastatic (non-squamous) NSQNSCLC with AGAs (the AGAs may be EGFR, ALK, or other known AGAs). In some embodiments, the lung cancer is advanced, unresectable, recurrent, and / or metastatic NSCLC without AGAs. In some embodiments, the cancer is NSCLC without AGAs and the combination is administered as a first or second line treatment. In some embodiments, the cancer is non-squamous NSCLC with AGAs and the combination is administered as a second line treatment.

[0630] In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is advanced cervical cancer. In some embodiments, the cancer is unresectable cervical cancer. In some embodiments, the cancer is recurrent cervical cancer. In some embodiments, the cancer is metastatic cervical cancer. In some embodiments, the cancer is cervical cancer and the combination is administered as a first line treatment.

[0631] In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is platinum resistant ovarian cancer (PROC). In some embodiments, the cancer is PROC and the combination is administered as a first, second, third or fourth line treatment. In some embodiments, the cancer is PROC and the combination is administered as a first to fourth line treatment.

[0632] In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is advanced prostate cancer. In some embodiments, the cancer is unresectable prostate cancer. In some embodiments, the cancer is recurrent prostate cancer. In some embodiments, the cancer is metastatic prostate cancer. In some embodiments, the prostate cancer is castration resistant prostate cancer.

[0633] In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is head and neck squamous cell carcinoma.

[0634] In some embodiments, the binding agent (e.g. the bispecific antibody) and the antibody-drug conjugate are separately administered.In some embodiments, a dose of the binding agent (e.g. the bispecific antibody) and a dose of the antibody-drug conjugate are administered concurrently or consecutively. In some embodiments, a dose of the binding agent (e.g. the bispecific antibody) and a dose of the antibody-drug conjugate are administered concurrently. In some embodiments, a dose of the binding agent (e.g. the bispecific antibody) and a dose of the antibody-drug conjugate are administered consecutively.

[0635] The binding agent (e.g. the bispecific antibody) and / or the antibody-drug conjugate may be administered systemically, preferably the binding agent (e.g. the bispecific antibody) and the antibody-drug conjugate are administered systemically. In some embodiments, the binding agent (e.g. the bispecific antibody) and / or the antibodydrug conjugate are administered intravenously, preferably wherein the binding agent (e.g. the bispecific antibody) and the antibody-drug conjugate are administered intravenously. In some embodiments, the binding agent (e.g. the bispecific antibody) and / or the antibody-drug conjugate is administered via an IV injection or IV infusion.

[0636] Pharmaceutical Compositions and Kits

[0637] In some aspects of the disclosure, a medical preparation or composition is provided comprising:

[0638] a. a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction; and

[0639] b. an antibody-drug conjugate, as defined herein.

[0640] The embodiments for the combination therapy disclosed herein comprising the binding agent (e.g. the bispecific antibody) in combination with the antibody-drug conjugate can be used in the medical preparation or composition disclosed herein. Features described herein in more detail among others for the “binding agent” embodiments (e.g. the “bispecific antibody” embodiments), the “antibody-drug conjugate components” embodiments, the “linker and payload moieties” embodiments, the “linker-payload” embodiments, and the “antibody-drug conjugate composition” embodiments equally apply to the medical preparation or compositionembodiments disclosed herein which may contain mixtures of the binding agent (e.g. the bispecific antibody) and antibody-drug conjugates disclosed herein.

[0641] In some embodiments, the medical preparation or composition is a pharmaceutical composition. In these embodiments, the medical preparation or pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, diluents and / or excipients.

[0642] The term “carrier” refers to a component which may be natural, synthetic, organic, inorganic in which the active component is combined in order to facilitate, enhance or enable administration of the pharmaceutical composition. A carrier as used herein may be one or more compatible solid or liquid fillers, diluents or encapsulating substances, which are suitable for administration to subject. Suitable carriers include, without limitation, sterile water, Ringer, Ringer lactate, sterile sodium chloride solution, isotonic saline, polyalkylene glycols, hydrogenated naphthalenes and, in particular, biocompatible lactide polymers, lactide / glycolide copolymers or polyoxyethylene / polyoxy-propylene copolymers. In some embodiments, the pharmaceutical composition of the present disclosure includes isotonic saline.

[0643] Pharmaceutically acceptable carriers, excipients or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R Gennaro edit. 1985).

[0644] Pharmaceutical carriers, excipients or diluents can be selected with regard to the intended route of administration and standard pharmaceutical practice.

[0645] In some embodiments, the combination, medical preparation or composition of the aspects of the present disclosure, is a kit. In these embodiments, the ADC and the anti-PD-1 / PD-LlxVEGF / VEGFR binding agent preferably are in separate vials or containers, which may further comprise one or more pharmaceutically acceptable carriers, diluents and / or excipients as described herein. In case the combination, medical preparation or composition further comprises one or more further therapeutic agents (other than the ADC described herein and other than the anti-PD-l / PD-LlxVEGF / VEGFR binding agent described herein), it is also preferred for the kit that the one or more further therapeutic agents are in separate vials or containers (z.e., thatthe ADC, the anti-PD-1 / PD-LlxVEGF / VEGFR binding agent, and the one or more further therapeutic agents are in separate vials or containers, preferably the ADC, the anti-PD-1 / PD-LlxVEGF / VEGFR binding agent, and the one or more further therapeutic agents are in separate vials or containers), wherein each vial or container may further comprise one or more pharmaceutically acceptable carriers, diluents and / or excipients as described herein.

[0646] The agents described herein may be administered in combinations, pharmaceutical compositions or medicaments and may be administered in the form of any suitable pharmaceutical composition, medical preparation or combination.

[0647] In some embodiments, the agents described herein (such as ADC, anti-PD-l / PD-LlxVEGF / VEGFR binding agent, etc.) may be administered in a pharmaceutical composition or medical preparation. In one embodiment, the pharmaceutical composition or medical preparation is for therapeutic or prophylactic treatments, e.g., for inducing an immune response, preferably against cancer, e.g., for treating or preventing cancer.

[0648] In some embodiments, the combination, medical preparation or composition is for administration to a human. In one embodiment, the human subject to whom the combination, medical preparation or composition is to be administered has received prior cancer treatment, e.g., treatment with a PD-1 / PD-L1 inhibitor and / or a chemotherapeutic (such as a platinum compound). In one embodiment, the human subject to whom the combination, medical preparation or composition is to be administered has lung cancer (in particular, NSCLC, e.g., advanced unresectable Stage III or metastatic Stage IV NSCLC) and has received prior cancer treatment with a PD-1 / PD-L1 inhibitor and a platinum compound (but preferably is naive to VEGF or VEGFR targeted treatment).

[0649] In some embodiment, a kit of the invention comprises:

[0650] (a) a composition comprising a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction; and (b) a composition comprising an antibody-drug conjugate, as defined herein.

[0651] In some embodiments, a kit of the invention comprises: (a) a composition comprising an antibody-drug conjugate of formula (I), as defined herein; and (b) instructions for administering said antibody-drug conjugate of formula (I) with a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, for the treatment of cancer.

[0652] In some embodiments, a kit of the invention comprises: (a) a composition comprising a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction; and (b) instructions for administering said binding agent with an antibody-drug conjugate of formula (I) as defined herein, for the treatment of cancer.

[0653] In an embodiment, each composition of the kit is a pharmaceutical composition.

[0654] A kit of the invention typically includes instructions.

[0655] In some embodiments, administration of an effective amount (e.g., of a composition comprising the antibody-drug conjugate and / or the binding agent as described herein, e.g. the binding agent binding to (i) PD-1, PD-L1, or both and (ii) VEGF, VEGFR, or both) may: (i) reduce the number of cancer cells; (ii) reduce tumour size; (iii) inhibit, retard, slow to some extent and may stop cancer cell infiltration into peripheral organs; (iv) inhibit (e.g., slow to some extent and / or block or prevent) metastasis; (v) inhibit tumour growth; (vi) prevent or delay occurrence and / or recurrence of tumour; and / or (vii) relieve to some extent one or more of the symptoms associated with the cancer.The pharmaceutical compositions according to the present disclosure may contain salts, buffers, preservatives, and optionally other therapeutic agents. In one embodiment, the pharmaceutical compositions of the present disclosure comprise one or more pharmaceutically acceptable carriers, diluents, and / or excipients. Suitable preservatives for use in the pharmaceutical compositions of the present disclosure include, without limitation, benzalkonium chloride, chlorobutanol, paraben, and thimerosal.

[0656] A (pharmaceutical) composition may also comprise pharmaceutically acceptable antioxidants for instance (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0657] A (pharmaceutical) composition may also comprise isotonicity agents, such as sugars, polyalcohols, such as mannitol, sorbitol, glycerol or sodium chloride in the composition.

[0658] In one embodiment, the (pharmaceutical) composition comprising the binding agent of the present invention comprises salt, buffers, amino acids, stabilizers, and surfaceactive agents. In one embodiment, the (pharmaceutical) composition comprising the binding agent of the present invention comprises no preservative. In a more specific embodiment, the (pharmaceutical) composition comprising the binding agent of the present invention comprises L-histidine, histidine hydrochloride, sucrose, disodium edetate, polysorbate 80 and water for injection. In a more specific embodiment, the (pharmaceutical) composition comprising the binding agent of the present invention is diluted with sodium chloride prior to administration.

[0659] In one embodiment, pharmaceutical compositions according to the present disclosure may be administered intravenously. In a preferred embodiment, the pharmaceuticalcomposition is formulated for systemic administration. In another preferred embodiment, the systemic administration is by intravenous administration.

[0660] In some aspects of the disclosure, a kit-of-parts is provided comprising:

[0661] a. a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction; and

[0662] b. an antibody-drug conjugate, as defined herein.

[0663] In some aspects of the disclosure, a kit-of-parts is provided comprising:

[0664] a. a bispecific antibody that comprises:

[0665] (a) an antibody or fragment thereof that specifically binds to PD-L1, and

[0666] (b) an antibody or fragment thereof that specifically binds to VEGF; and

[0667] b. an antibody-drug conjugate, as defined herein.

[0668] The embodiments for the combination therapy disclosed herein comprising the binding agent (e.g. the bispecific antibody) in combination with the antibody-drug conjugate can be used in the kit-of-parts disclosed herein. Features described herein in more detail among others for the “binding agent” embodiments (e.g. the “bispecific antibody” embodiments), the “antibody-drug conjugate components” embodiments, the “linker and payload moieties” embodiments, the “linker-payload” embodiments, and the “antibody-drug conjugate composition” embodiments equally apply to the kit-of-parts embodiments disclosed herein which may include the binding agent (e.g. the bispecific antibody) and antibody-drug conjugates disclosed herein.

[0669] In some embodiments, the binding agent (e.g. the bispecific antibody) and the antibody-drug conjugate are comprised in separate containers. In some embodiments, the kit-of-parts further comprises instructions for use.

[0670] As used herein, an "instructional material" or "instructions" includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the compositions and methods described herein. Theinstructional material of the kit of the disclosure may, for example, be affixed to a container which contains the compositions of the disclosure or be shipped together with a container which contains the compositions. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the compositions be used cooperatively by the recipient.

[0671] The present invention further provides the combinations, medical preparations, compositions and kits described herein for use as a medicament. The medicament may be for administration to a subject. The use as a medicament may comprise a therapeutic or prophylactic treatment of a disease or disorder, for example comprising treating or preventing cancer. In some embodiments, the therapeutic or prophylactic treatment of a disease or disorder further comprises administering radiotherapy, preferably local radiotherapy.

[0672] In some embodiments, the medical preparation, kit, or kit-of-parts of the invention is formed at the point of use by the medical professional administering the treatment. For example, the antibody-drug conjugate of formula (I) as defined herein, or a pharmaceutical composition thereof; and the binding agent as defined herein, or a pharmaceutical composition thereof; may be packaged and sold separately, but labelled for use in combination, such that the medical preparation, kit or kit-of-parts of the invention is formed at the point of treatment of cancer in the subject, as described herein.

[0673] In this specification, the terms “subject” and “patient” are synonymous.

[0674] In some embodiments, the subject of the medical uses and methods of treatment according to the present invention may be a mammal.

[0675] In some embodiments, the subject may be a human.In some embodiments, the subject may alternatively be a non-human mammal, including for example, a primate, a monkey, a dog, a cat, a horse, a cow, a sheep, a pig, a rabbit, a rat, or a mouse.

[0676] In some embodiments, the subject may suffer from and / or have been diagnosed with one or more cancer(s).

[0677]

[0678] Treated

[0679] In some embodiments, the subject has not been previously treated for cancer. For example, with a treatment selected from the group comprising or consisting of chemotherapy, hormone therapy, immunotherapy, radiation therapy, surgery, or a targeted therapy or any combination thereof.

[0680] In some embodiments, the subject has been previously treated for cancer. In some embodiments, the subject has been previously treated with one or more other anticancer agents - for example, with a treatment selected from the group comprising or consisting of chemotherapy, hormone therapy, immunotherapy, radiation therapy, surgery, or a targeted therapy, or any combination thereof. For example, in some embodiments the subject has previously received a chemotherapy, hormone therapy, immunotherapy, radiation therapy, surgery to remove or destroy tumours, or a targeted therapy.

[0681] In some embodiments, the subject has not previously received a chemotherapy, hormone therapy, immunotherapy, radiation therapy, surgery to remove or destroy tumours, or a targeted therapy, or any combination thereof. In some embodiments, the subject has not previously received a chemotherapy, hormone therapy, immunotherapy, radiation therapy, and a targeted therapy. In some embodiments, the subject is treatment naive. In some embodiments, the subject has not received PD-1 / PD-L1, PD-L2, CTLA-4 directed immunotherapy.

[0682] In some embodiments, the anticancer agent is a platinum-based agent such as cisplatin, carboplatin and oxaliplatin.In some embodiments, the anticancer agent is a taxane, such as paclitaxel, docetaxel or cabazitaxel.

[0683] In some embodiments, the anticancer agent is an antibody or immunotherapy agent, such as atezolizumab, avelumab, balstilimab, bevacizumab, camrelizumab, cempilimab, cosibelimab, cetuximab, dostarlimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, retifanlimab, sintilimab, spartalizumab, tislelizumab, toripalimab, tremelimumab, vorpratelimab, or zalifrelimab. In some embodiments, the anticancer agent is a PD-1 and / or PD-L2 inhibitor, such as camrelizumab, cempilimab, dostarlimab, nivolumab, pembrolizumab, retifanlimab, sintilimab, spartalizumab, toripalimab, or vorpratelimab. In some embodiments, the anticancer agent is a PD-L1 inhibitor, such as atezolizumab, avelumab, cosibelimab or durvalumab. In some embodiments, the anticancer agent is a CTLA-4 inhibitor, such as ipilimumab or tremelimumab.

[0684] In some embodiments, the subject has previously received 1 line of systemic therapy for advanced or metastatic NSCLC. In some embodiments, the subject has not previously received systemic therapy for advanced or metastatic NSCLC. In some embodiments, the subject has NSCLC without AGAs and the subject has not previously received systemic therapy for NSCLC. In some embodiments, the subject has NSCLC without AGAs and the subject has previously received 1 line of systemic therapy for NSCLC.

[0685] In some embodiments, the subject has non-squamous NSCLC with AGAs and the subject has previously received 1 line of systemic therapy for NSCLC. In some embodiments, the subject has non-squamous NSCLC with AGAs and the subject has previously relapsed / progressed on or after treatment with at least one line of targeted therapy for the subject’s AGA. In some embodiments, the subject has non-squamous NSCLC with AGAs and the subject has previously relapsed / progressed on or after treatment with at least one line of targeted therapy for AGA for advanced or metastatic NSCLC.In some embodiments, the subject has cervical cancer and has not received prior systemic therapy for recurrent or metastatic cervical cancer. In some embodiments, the subject has not received PD-1 / PD-L1, PD-L2, CTLA-4 directed immunotherapy and not previously received systemic therapy for advanced / unresectable, recurrent, or metastatic cervical cancer.

[0686] In some embodiments, the subject has platinum resistant ovarian cancer and has previously received 1 to 3 lines of platinum therapy. In some embodiments, the subject has received 1 to 3 lines, such as 1, 2 or 3 lines, of platinum therapy. In some embodiments, the subject has progressed < 6 months after the last dose of platinum therapy. In some embodiments, the subject has platinum resistant ovarian cancer and has previously received 1 line and at least 4 cycles of platinum therapy. In some embodiments, the subject has platinum resistant ovarian cancer and has previously received 1 line and at least 4 cycles of platinum therapy and had a response and then progressed between 3 to 6 months after the last dose of platinum therapy. In some embodiments, the subject has platinum resistant ovarian cancer and has previously received 2 to 3 lines of platinum therapy and progressed within 6 months after the last dose of platinum therapy. In some embodiments, the subject has platinum resistant ovarian cancer and has previously received no more than 3 prior systemic lines of anticancer therapy. In some embodiments, the subject does not have primary platinum-refractory disease. In some embodiments, the subject has not previously (i) not responded to first-line platinum-containing chemotherapy, or (ii) progressed within 3 months of the last dose of first-line platinum-containing chemotherapy.

[0687] In some embodiments, the subject has not received PD-1 / PD-L1, PD-L2, CTLA-4 directed immunotherapy and not previously received systemic therapy for advanced or metastatic TNBC. In some embodiments, the subject has TNBC and has not previously received prior systemic therapy for unresectable, locally advanced or metastatic breast cancer.Example 1 - Compound 1 dose range finding studies

[0688] A Phase l / 2a, multicentre, 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.

[0689] Justification for selectins 3 mg / kg and 4 mg / kg, Q3W as randomization dose levels for ovarian cancer (OC).

[0690] As of 30 October 2023, ten subjects (2 mg / kg, N=2; 3 mg / kg, N=2; 4 mg / kg, N=4; 5 mg / kg, N=2) with OC / fallopian (9 / 10 subjects were platinum resistant OC) tube were treated with Compound 1 in doses ranging from 2 to 5 mg / kg. Preliminary antitumour activities were observed at all dose levels, with one subject having a partial response at each level. The confirmed ORR and DCR were 40% and 70%, respectively.

[0691] Twenty -nine subjects with various types of tumours were treated with Compound 1 at 4 mg / kg. Preliminary promising antitumour activity was observed, with a confirmed ORR of 20.7% and a DCR of 82.8%.

[0692] Although limited data exist, OC subjects appeared to respond to Compound 1 at lower doses [e.g., 2 mg / kg Q3W (1 PR out of N=2) and 3 mg / kg Q3W (1 PR out of N=2)] when compared to subjects with other tumour types.

[0693] Given that the PK of Compound 1 appears to be linear in the range of 3-6 mg / kg Q3W, there is roughly a 30% difference in mean exposure of Compound 1 (Cmax and AUC) between 3 mg / kg and 4 mg / kg. This difference was translated to more tolerable safety profiles in 3 mg / kg Q3W compared to 4 mg / kg Q3W in the current preliminary safety evaluation in patients with all tumour types.

[0694] Therefore, the doses of 3 mg / kg and 4 mg / kg Q3W or the intermediate dose of 3.5 mg / kg Q3W were selected to refine the Recommended Phase 2 Dose (RP2D) to understand the efficacy at these dose levels and further confirm the safety profiles in OC patients.Example 2 - Study to assess the therapeutic activity of an anti-hTR0P2-ADC (Compound 1) in combination with anti-mPDLlxmVEGF in a syngeneic mouse model.

[0695] To investigate the combination of the anti-hTROP2-ADC (Compound 1) and anti-mPDLlxmVEGF (mouse surrogate of Compound 2, in which the anti-VEGF part is changed to an anti-mouse- VEGF part and the anti-PDLl VHH domain is exchanged to a scFv of atezolizumab, which is mouse cross-reactive), a syngeneic mouse model was established as follows: C57BL / 6 mice were subcutaneously transplanted with hTROP2-MC38 cells. Treatments with the ADC / antibody indicated below were started when the tumour size was approximately 100 mm3. One day before treatment start 0.5 mg of an anti-mouse CD20 antibody were administered to deplete the B cells, in order to slow down anti-drug antibody development. 20 mg / kg of anti-hTROP2-ADC (Compound 1) were administered intravenously (i.v.) 4 times, once weekly (QW*4). 5 mg / kg or 20 mg / kg of the anti-mPDLlxmVEGF were administered intraperitoneally (i.p.) 4 times every second day (Q2D*4). Monotherapy control groups G2 to G4 were treated only either with the anti-mPDLlxmVEGF or the anti-hTROP2 ADC (Compound 1). The Vehicle control group G1 was treated with 0.9% sodium chloride only. Tumour volume and body weight were monitored. The study design is summarized in Table 4.

[0696] The combination of the anti-hTROP2-ADC and the anti-mPDLlxmVEGF resulted in complete tumour regression, whereas monotherapy treatments resulted only in shortterm tumour control and outgrowth of tumours (Figure 1). Tumour weights after study determination in the combination therapy group were lower than compared with the two monotherapy groups (Figure 2).

[0697] Table 4: Study design anti-hTROP2-ADC (Compound 1) + anti-mPDLlxmVEGF: Groups Treatment Dose Dosing Schedule Vehicle (0.9% sodium

[0698] G1 chloride) - QW*4 and Q2D*4 G2 Compound 1 20 mg / kg QW*4

[0699]

[0700] G3 anti-mPDL IxmVEGF 5 mg / kg Q2D*4 G4 anti-mPDL IxmVEGF 20 mg / kg Q2D*4

[0701] Compound 1 + anti- G5 mPDLIxmVEGF 20 mg / kg and 5 mg / kg QW*4 and Q2D*4 Compound 1+ anti- G6 mPDLIxmVEGF 20 mg / kg and 20 mg / kg QW*4 and Q2D*4

[0702]

[0703] Example 3 - Study to assess the therapeutic activity of an anti-hTR0P2-ADC (Compound 1) in combination with an anti-hPDLlxhVEGF (Compound 2) in a human xenograft PBMC mouse model.

[0704] To investigate the combination of the anti-hTROP2-ADC (Compound 1) and the anti-hPDLlxhVEGF (Compound 2), a A375 melanoma cancer xenograft mouse model engrafted with human PBMCs was established as follows: B-NDG B2M KO plus (vendor Biocytogen) mice were subcutaneously transplanted with A375 cells overexpressing hTROP2 and co-injected with human PBMCs. The human A375 cells endogenously express hPDLl and marginally hTROP2. Therefore, the cells were additionally transduced with human TROP2. Treatments with the ADC / antibody indicated below were started when the tumour size was approximately 300 mm3. 20 mg / kg of anti-hPDLlxhVEGF were administered 2 times (once every two days, Q2D*2). 1 mg / kg of the anti-hTROP2-ADC (Compound 1) was administered 5 times (once every two days, Q2D*5). Monotherapy control groups G2 and G3 were treated only either with the anti-hPDLlxhVEGF (Compound 2) or the anti-hTROP2 ADC (Compound 1). The Vehicle control group G1 was treated with PBS only. Tumour volume and body weight were monitored. The study design is summarized in Table 5.

[0705] The combination of the anti-hTROP2 ADC Compound 1 and the anti-hPDLlxhVEGF Compound 2 resulted in tumour regression and tumour control, whereas monotherapy treatments resulted at best in shorter-term tumour control followed by outgrowth of tumours (Figure 3). Tumour weights after study determination in the combination therapy group were lower than compared with the two monotherapy groups (Figure 4).Table 5: Study design anti-hTR0P2-ADC (Compound 1) + anti-hPDLlxhVEGF (Compound 2):

[0706] Groups Treatment Dose Dosing Schedule G1 Vehicle - Q2D*5

[0707] G2 Compound 2 20 mg / kg Q2D*2

[0708] G3 Compound 1 1 mg / kg Q2D*5

[0709] G4 Compound 2 + Compound 1 20 mg / kg and 1 mg / kg Q2D*2 and Q2D*5

[0710]

[0711] Example 4 - A Phase l / 2a, Multicentre, Open-Label, First in Human Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumour Activity of Compound 1 in combination with Compound 2 in Subjects with Advanced / Metastatic Solid Tumours

[0712] The combination of Compound 1 (TROP-2 ADC) and Compound 2 (the PD-L1 x vascular endothelial growth factor (VEGF) bispecific) provides a promising opportunity to increase the efficacy in a variety of solid tumour types such as nonsmall cell lung cancer (NSCLC), cervical cancer (CC) and ovarian cancer (OC), without inducing relevant overlapping toxicity.

[0713] Several ADCs have shown potent anti-tumour activity against treatment-resistant cancers. However, drug combinations that can overcome primary or acquired resistance by targeting distinct tumour clones without overlapping toxicities are the most appealing for development. The combination of ADCs with immunotherapy is one such promising approach, given increasing evidence that ADCs might increase the efficacy of immunotherapeutic agents (Nicolo et al. Cancer Treat Rev. 2022; 106:102395). In addition, anti-angiogenic agents, such as VEGF targeting drugs, may facilitate ADC penetration and exposure of tumour cells (Fuentes-Antras et al. Trends Cancer 2023; 9(4):339-354). Combining Compound 2 with ADCs may lead to better patient outcomes as it is suggested that ADCs could stimulate tumour immunity and increase the sensitivity of tumours to PD-L1 inhibition, including ‘cold tumours’. Additionally, increased sensitivity of tumours to ADCs could occur via targeting VEGF-A.Based on monotherapy data from early clinical trials of Compound 1 or Compound 2 their combination may allow for improved efficacy while maintaining a manageable safety profile with few overlapping toxicities. The safety profile of Compound 2 is mainly characterized by low-grade proteinuria, hypertension, and elevated transaminases, while the safety profile of Compound 1 is mainly characterized by stomatitis (Figure 5).

[0714] As such, the combination of Compound 1 with Compound 2, having a dual immunologic / anti-angiogenic mechanism of action, may lead to improved outcomes. This is supported by the pre-clinical data shown in Examples 2 and 3.

[0715] Dose rationale compound 1

[0716] Compound 1 is being studied in an ongoing Phase Vila clinical trial, which is assessing a range of doses including 3, 6, 9, 10.5 and 12 mg / kg Q3W. DLTs were observed at 12 and 10.5 mg / kg, and the maximum tolerated dose was 9 mg / kg. Based on tolerability, safety, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity data, Compound 1 was safe and demonstrated a promising antitumour activity. In Part 2 of the trial, there are currently several expansion dose optimization / expansion cohorts at 6 or 9 mg / kg ongoing including in HCC, CC, HNSCC, melanoma and NSCLC. In this trial, the Compound 1 dose will be tested at 3.0 mg / kg Q3W and 3.5 mg / kg Q3W. At the dose levels ranged 3-9 mg / kg Q3W, signs of efficacy and an acceptable and manageable safety profile were shown in the ongoing trial. The totality of data based on efficacy, safety, and PK support 3.0 mg / kg and 3.5 mg / kg as tolerable and efficacious dose levels of Compound 1 to be combined with Compound 2.

[0717] Dose rationale Compound 2

[0718] Compound 2 has been studied in nine clinical trials (one Phase I / IIa monotherapy and eight Phase lb, Phase II or Phase II / III combination therapy trials). The monotherapy trial evaluated a wide range of doses including 1, 3, 10, 20, 30, and 45 mg / kg every 2 weeks, as well as 20, 30, and 45 mg / kg Q3W. No Dose-Limiting Toxicity (DLT) was observed, and the maximum tolerated dose was not reached. Based on tolerability, safety, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity data ofall clinical trials, Compound 2 was safe and demonstrated promising anti-tumour activity. The target dose of 30 mg / kg Q3W of Compound 2 was explored extensively in previous and ongoing clinical trials and has shown signs of efficacy and an acceptable and manageable safety profile as well. The proposed target dose of Compound 2 of 30 mg / kg Q3W is supported by the totality of clinical data collected participants with advanced solid tumours from the ongoing monotherapy trial including a Phase la dose escalation part, and Phase lb and Ila dose expansion parts, conducted in China in combination therapy with paclitaxel in a clinical trial, and in combination therapy with nab-paclitaxel in a clinical trial.

[0719] This is a phase l / 2a, multicentre, open-label, trial to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumour activity of Compound 1 in combination with Compound 2 in subjects with advanced / metastatic solid tumours.

[0720] A 21 -day treatment cycle (Q3W) or 14-day treatment cycle (Q2W) will be used for Compound 1 and Compound 2. Both treatments will be intravenously administered on Day 1 of each cycle. The trial will be conducted into 2 parts (see Figure 6).

[0721] Part 1 (Dose escalation)

[0722] The primary objective of Part 1 is to evaluate the safety and tolerability of Compound 1 in combination with Compound 2 in subjects with advanced solid tumours. The secondary objectives of Part 1 are to assess the preliminary antitumour activity of Compound 1 in combination with Compound 2, to characterize the pharmacokinetics of the combination of Compound 1 and Compound 2 and to assess the immunogenicity of Compound 1 in combination with Compound 2.

[0723] Approximately three cohorts of advanced solid tumours will be treated with Compound 1 in combination with Compound 2 in Part 1. Part 1 will employ the classic "3+3" design to find an appropriate dose for expansion, as depicted in Figure 6.

[0724] Compound 1 and 2 will be tested in combination at the following dose levels:

[0725] A. Compound 1 DL1: 3 mg / kg Q3W + Compound 230 mg / kg Q3WB. Compound 2 DL2: 3.5 mg / kg Q3W + Compound 230 mg / kg Q3W Based upon emerging clinical data, lower, intermediate, and / or higher dose levels of Compound 1 may also be evaluated.

[0726] Enrolment in Part 1 will be limited to subjects with advanced or metastatic solid tumours for which there is no standard systemic treatment or who were intolerable to standard systemic treatment or who progressed after previous standard systemic treatment. Examples include but are not limited to non-small-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer (HR+ / HER2- BC), endometrial carcinoma (EC), pancreatic adenocarcinoma, gastric / gastroesophageal junction (G / GEJ) cancer, esophageal cancer, head and neck squamous cell carcinoma (HNSCC), transitional cell carcinoma of the urothelium, colorectal cancer (CRC), ovarian cancer (OC), cervical cancer (CC), and castrationresistant prostate cancer (CRPC).

[0727] Part 2 (Dose expansion)

[0728] The primary objectives of Part 2 are to assess the safety and tolerability of Compound 1 in combination with Compound 2 in targeted participant populations and to assess the preliminary efficacy of Compound 1 in combination with Compound 2. The secondary objectives of Part 2 are to assess the preliminary efficacy of Compound 1 in combination with Compound 2 and to characterize the pharmacokinetics of the combination of Compound 1 and Compound 2.

[0729] Cohort 1: Subjects with advanced / unresectable, recurrent, or metastatic NSCLC without Actionable Genomic Alterations (AGAs) who previously have received <1 line of systemic therapy for advanced or metastatic NSCLC.

[0730] Cohort 2: Subjects with advanced / unresectable, recurrent, or metastatic (non-squamous) NSQ NSCLC with AGAs (i.e., alterations in genes with approved therapies, such as EGFR, ALK, or other known AGAs) and have progressed on or after clinically available targeted systemic treatments.Cohort 3: Subjects with advanced / unresectable, recurrent, or metastatic CC who have not received PD-1 / PD-L1, PD-L2, CTLA-4 directed immunotherapy and previously not received systemic therapy for advanced / unresectable, recurrent, or metastatic CC.

[0731] Cohort 4: Subjects with advanced / unresectable, recurrent, or metastatic PROC who have received 1 to 3 lines of platinum therapy and must have progressed < 6 months after the last dose of platinum.

[0732] Cohort 5: Subjects with advanced / unresectable, recurrent, or metastatic TNBC who have not received PD-1 / PD-L1, PD-L2, CTLA-4 directed immunotherapy and previously have not received systemic therapy for advanced or metastatic TNBC.

[0733] Cohort 6: (Compound 1 Q2W + Compound 2 Q2W dose regimen) Subjects with advanced / unresectable, recurrent, or metastatic NSCLC without AGAs who previously have received <1 line of systemic therapy for advanced or metastatic NSCLC.

[0734] Based on results from Part 1, multiple dose regimens may be used for cohorts above. The subjects enrolled in Cohort 6 may be treated with 3 mg / kg Q2W Compound 1 combined with 20 mg / kg Q2W Compound 2 if the dose is confirmed to be safe in Part 1. Approximately 30 subjects will be enrolled in each cohort 1-6, with an additional 10 subjects potentially enrolled to further evaluate preliminary efficacy and safety.

[0735] Selected key inclusion criteria

[0736] NSCLC w / o AGA subjects (Cohort 1 and Cohort 6)

[0737] • No restriction on PD-L1 expression level.

[0738] • Pathologically documented Stage IIIB or IIIC NSCLC not amenable for radical surgery or definitive chemoradiation or Stage IV NSCLC (staging based on the American Joint Committee on Cancer, 8th Edition.

[0739] • Not harboring an EGFR-sensitizing mutation or ALK gene translocation or other onco-driver gene mutations which have available targeted therapies. NSQ NSCLC w AGA subjects (Cohort 2)

[0740] • No restriction on PD-L1 expression level.• Pathologically documented Stage IIIB or IIIC NSCLC not amenable for radical surgery or definitive chemoradiation or Stage IV non-squamous NSCLC (staging based on the American Joint Committee on Cancer, 8th Edition).

[0741] • Documented positive test results for one or more AGA: EGFR, ALK, ROS1, METexl4 skipping, RET, NTRK1 / 2 / 3, BRAF V600E, KRAS G12C, or other AGAs with available targeted therapies.

[0742] • Previously relapsed / progressed on or after the treatment with at least one line of clinically available targeted therapy for the subject’s actionable genomic alteration.

[0743] • Have not received PD-1 / PD-L1, PD-L2, CTLA-4 directed immunotherapy and previously have not received systemic therapy except clinically available targeted therapy for AGA for advanced or metastatic NSCLC.

[0744] CC subjects (Cohort 3)

[0745] • No restriction on PD-L1 expression level.

[0746] • Has recurrent or metastatic CC with squamous cell, adenocarcinoma, or adenosquamous histology, and:

[0747] • Have not received prior systemic therapy for recurrent or metastatic CC.

[0748] Chemotherapy administered in the adjuvant or neoadjuvant setting, or in combination with radiation therapy, should not be counted as a systemic therapy regimen. Single agent therapy with an anti-PDl / PD-Ll agent for recurrent or metastatic CC should be counted.

[0749] PROC subjects (Cohort 4)

[0750] • No restriction on PD-L1 expression level.

[0751] • Subjects must have a confirmed diagnosis of ovarian cancer, primary peritoneal cancer, or fallopian tube cancer, all of which with high-grade serous histology.

[0752] • Subjects with endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumours containing any of the above histologies, or low- grade / borderline tumour shall be excluded.

[0753] • Subjects must have platinum-resistant disease.• Subjects must have received at least 1 but no more than 3 prior systemic lines of anticancer therapy, including at least 1 line of therapy containing FRa targeted ADC if they are known to be FRa positive.

[0754] • Subjects must have progressed radiographically on or after their most recent line of anticancer therapy.

[0755] TNBC subjects (Cohort 5)

[0756] • No restriction on PD-L1 expression level.

[0757] • Pathologically documented unresectable advanced or metastatic BC with HR- (estrogen and progesterone receptor) negative disease and HER2-negative expression according to ASCO / CAP guidelines, based on the most recent analyzed biopsy or other pathology specimen.

[0758] • Has not received prior systemic therapy for unresectable, locally advanced or metastatic BC (adjuvant or neoadjuvant chemotherapy will qualify as line of therapy if the disease progression or relapse occurred within 12 months after its completion).

[0759] Selected key exclusion criteria

[0760] • Prior treatment with Trop-2 targeted therapy.

[0761] • Has experienced Grade 3 immune-related adverse events (irAEs) or irAEs that lead to permanent discontinuation of the prior immunotherapy.

[0762] • Prior treatment with antibody drug conjugate with topoisomerase inhibitor including but not limited to trastuzumab deruxtecan, patritumab deruxtecan [HER3-DXd; U31402] and sacituzumab govitecan.

[0763] • Presence of active autoimmune disease that has required systemic treatment in the past 2 years (e.g., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) except for hypothyroidism that only requires hormone replacement therapy).

[0764] • Has received immunosuppressive drugs (such as azathioprine, cyclosporine, thalidomide) within 2 weeks before the first dose, except for topical medications and systemic use of corticosteroids equivalent to < 10 mg / day of prednisone for treatment of disease, as long as the systemic use of corticosteroids is not for the treatment of autoimmune disease.Results

[0765] Early Clinical Safety

[0766] As of March 03, 2025, 67 patients have received Compound 1 + Compound 2 Q3W (21 in Part 1 and 46 in Part 2); 53 are still on treatment. No DLTs were reported in the DLT-evaluable period (first six patients). The safety profile (Figure 7) was manageable with low rate of Grade 3 TRAEs (32.8%) or TRAEs leading to discontinuation (n=3, 4.5%; one patient with Grade 3 stomatitis, one with Grade 2 Interstitial Lung Disease (ILD), one with Grade 5 pneumonia). Treatment with Compound 1 + Compound 2 (Figure 8) did not lead to an increase in TRAEs that have been previously reported with Compound 2 or Compound 1 alone. Stomatitis was reported in 38 (56.7%) patients (Grade 3 in 12 [17.9%]) and led to a dose reduction of Compound 1 in 12 (17.9%) patients. Other TRAEs commonly associated with Compound 2 monotherapy occurred infrequently: proteinuria (n=2, 3.0%), hypertension (n=l, 1.5%), ALT increased (n=3, 4.5%).

[0767] As of February 06, 2026, 143 patients have received Compound 1 + Compound 2 Q3W (22 in Part 1 and 121 in Part 2); 65 are still on treatment. No DLTs were reported in the DLT-evaluable period (first six patients). The safety profile was manageable with 55.2% of patients with Grade 3 TRAEs or TRAEs leading to discontinuation (n=18, 12.6%; most common event was stomatitis). Stomatitis was reported in 116 (81.1%) patients (Grade >3 in 34 patients [23.8%]) and led to a dose reduction of Compound 1 in 47 (32.9%) patients.

[0768] Early Clinical Efficacy

[0769] As of March 03, 2025, tumour response analyses are ongoing. In early efficacy data from Cohort 4 (2L-4L PROC), amongst 13 evaluable patients, 7 had a partial response and 3 had stable disease (Figure 9). Ten patients are still on treatment. Responses were also observed in patients with NSCLC or TNBC.

[0770] As of February 06, 2026, tumour response analyses are ongoing. In early efficacy data from Cohort 4 (2L-4L PROC), amongst 32 evaluable patients, 15 had a partial response and 10 had stable disease. Eleven patients are still on treatment.Early Clinical Safety and Efficacy in patients with TNBC

[0771] Patients with advanced or metastatic triple-negative breast cancer (a / mTNBC) and no prior systemic treatment received Compound 230 mg / kg plus Compound 1 3.5 mg / kg every 3 weeks. At data cutoff (December 22, 2025), 30 patients with a / mTNBC had received >1 doses of Compound 1 + Compound 2; 24 patients (80.0%) remain on treatment. Median patient age was 55.5 years (range 34-84 years), 83.3% were Chinese and 80.0% had an ECOG PS of 1. Median treatment duration was 4.9 months. At a median duration of follow-up of 5.5 months, 29 patients were evaluable for efficacy. Unconfirmed ORR was 82.8% (95% CI: 64.2, 94,1; 24 patients had a partial response); confirmed ORR was 75.9% (95% CI: 56.5, 89.7; two pending confirmation). DCR was 96.6% (95% CI: 56.5, 89.7); all cases of stable disease had tumor shrinkage (Figure 10). Most patients (96.7%) had treatment-emergent adverse events (TEAEs); grade >3 (43.3%). The most common TEAE was stomatitis (86.7%). TEAEs leading to dose reduction or interruption occurred in 30.0% of patients each. Discontinuations due to TEAEs were reported for one patient; no deaths occurred due to TEAEs. The combination of Compound 1 and Compound 2 showed encouraging efficacy and manageable safety profile as IL treatment for patients with a / mTNBC.

[0772] Example 5 - The combination of Compound 1 and Compound 2 shows superior tumor killing effect on tumor tissue slices from ovarian cancer patients.

[0773] Precision-cut tumor tissue slices from seven ovarian cancer patients were cultured and treated with control media, Compound 1 (500 ng / mL), Compound 2 (35 pg / mL), or a combination of Compound 1 and Compound 2. Viability was assessed on days 1, 4, and 8. Combination treatments demonstrated superior tumor killing in three out of seven samples, with statistically significant reductions in viability (p<0.05) (Figure 11)

[0774] All publications mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described 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 ofthe described modes for carrying out the invention which are obvious to those skilled in the art or related fields are intended to be within the scope of the following claims.

Claims

1. CLAIMS1. A combination ofa. a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, andb. an antibody-drug conjugate having the formula (I):or a tautomer, mesomer, enantiomer thereof, or a pharmaceutically acceptable salt thereof wherein:Ab is sacituzumab;L is -La-Lb-Lc-;La- iso- Lb- is:-Lc- is -CH2-;R1is selected from the group consisting of: -O-, -(R2)N-, -P(=O)(R2)- and -S-;X is -L1-CH2-C(O)-;L1is -(C(R3a)(R3b))m-, wherein 0 or at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-;wherein each R2, each R3a, each R3band each R4bare 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 C1-6 aliphatic 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;m is selected from the group consisting of integers > 0,when R1is -O- or -HN-, at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-, or each R3aand each R3bare not both hydrogen; andn is a connection number and is an integer from 1 to 10;for use in treating cancer in a subject,wherein the use comprises administering the antibody-drug conjugate of formula (I) at a dose of from about 2 mg / kg to about 5 mg / kg.

2. A binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction,for use in treating cancer in a subject, the use comprising administering to the subject: a. the binding agent; andb. an antibody-drug conjugate having the formula (I):or a tautomer, mesomer, enantiomer thereof, or a pharmaceutically acceptable salt thereof wherein:Ab is sacituzumab;L IS -La-Lb-Lc-^La- iso- Lb- is:-Lc- is -CH2-;R1is selected from the group consisting of: -O-, -(R2)N-, -P(=O)(R2)- and -S-; X is -LJ-CH2-C(0)-;L1is -(C(R3a)(R3b))m-, wherein 0 or at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-;wherein each R2, each R3a, each R3band each R4bare 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 C1-6 aliphatic 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)S02H or a C1-6 aliphatic group;m is selected from the group consisting of integers > 0,when R1is -O- or -HN-, at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-, or each R3aand each R3bare not both hydrogen;n is a connection number and is an integer from 1 to 10; wherein the use comprises administering the antibody-drug conjugate of formula (I) at a dose of from about 2 mg / kg to about 5 mg / kg.

3. An antibody-drug conjugate having the formula (I):or a tautomer, mesomer, enantiomer thereof, or a pharmaceutically acceptable salt thereof wherein:Ab is sacituzumab;L is -La-Lb-Lc-;La- iso- Lb- is:-Lc- is -CH2-;R1is selected from the group consisting of: -O-, -(R2)N-, -P(=O)(R2)- and -S-;X is -LJ-CH2-C(0)-;L1is -(C(R3a)(R3b))m-, wherein 0 or at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-;wherein each R2, each R3a, each R3band each R4bare 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 C1-6 aliphatic 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)S02H or a C1-6 aliphatic group;m is selected from the group consisting of integers > 0,when R1is -O- or -HN-, at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-, or each R3aand each R3bare not both hydrogen;n is a connection number and is an integer from 1 to 10,for use in treating cancer in a subject, the use comprising administering to the subject: a. a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction; andb. the antibody-drug conjugate;wherein the use comprises administering the antibody-drug conjugate of formula (I) at a dose of from about 2 mg / kg to about 5 mg / kg.

4. An antibody-drug conjugate having the formula (I):or a tautomer, mesomer, enantiomer thereof, or a pharmaceutically acceptable salt thereof wherein:Ab is sacituzumab;L IS -La-Lb-Lc-^La- iso- Lb- is:-Lc- is -CH2-;R1is selected from the group consisting of: -O-, -(R2)N-, -P(=O)(R2)- and -S-; X is -LJ-CH2-C(0)-;L1is -(C(R3a)(R3b))m-, wherein 0 or at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-;wherein each R2, each R3a, each R3band each R4bare 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 C1-6 aliphatic 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)S02H or a C1-6 aliphatic group;m is selected from the group consisting of integers > 0,when R1is -O- or -HN-, at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-, or each R3aand each R3bare not both hydrogen; andn is a connection number and is an integer from 1 to 10;and a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction,for use in treating cancer in a subject, the use comprising administering to the subject: a. the binding agent; andb. the antibody-drug conjugate at a dose of from about 2 mg / kg to about 5 mg / kg.

5. The combination for use according to claim 1, binding agent for use according to claim 2, antibody-drug conjugate for use according to claim 3, or antibody-drug conjugate and binding agent for use according to claim 4, wherein X is -L1-CH2-C(O)-, L1is -(C(R3a)(R3b))m-, m is not 0, and each R3aand each R3bare not both hydrogen.

6. The combination for use according to claim 1 or 5, binding agent for use according to claim 2 or 5, antibody-drug conjugate for use according to claim 3 or 5, or antibody-drug conjugate and binding agent for use according to claim 4 or 5, wherein m is 1, and L1is -C(R3a)(R3b)-.

7. The combination for use according to claim 1 or 5-6, binding agent for use according to claim 2 or 5-6, antibody-drug conjugate for use according to claim 3 or 5-6, or antibody-drug conjugate and binding agent for use according to claim 4 or 5-6, wherein R3ais a C1-6 aliphatic group, and R3bis hydrogen.

8. The combination for use according to claim 1 or 5-7, binding agent for use according to claim 2 or 5-7, antibody-drug conjugate for use according to claim 3 or 5-7, or antibody-drug conjugate and binding agent for use according to claim 4 or 5-7, wherein R3ais methyl, and R3bis hydrogen.

9. The combination for use according to claim 1 or 5-8, binding agent for use according to claim 2 or 5-8, antibody-drug conjugate for use according to claim 3 or 5-8, or antibody-drug conjugate and binding agent for use according to claim 4 or 5-8, wherein R1is -O-.

10. The combination for use according to claim 1 or 5-9, binding agent for use according to claim 2 or 5-9, antibody-drug conjugate for use according to claim 3 or 5-9, or antibody-drug conjugate and binding agent for use according to claim 4 or 5-9, wherein the antibody-drug conjugate comprises the following structure:

11. The combination for use according to claim 1 or 5-10, binding agent for use according to claim 2 or 5-10, antibody-drug conjugate for use according to claim 3 or 5-10, or antibody-drug conjugate and binding agent for use according to claim 4 or 5-10, wherein the antibody-drug conjugate comprises the following structure:

12. The combination for use according to any one of claims 1 or 5-11, binding agent for use according to any one of claims 2 or 5-11, antibody-drug conjugate for use according to any one of claims 3 or 5-11, or antibody-drug conjugate and binding agent for use according to any one of claims 4-11, wherein, the antibody-drug conjugate has the structural formula (II):n(II)wherein n represents a connection number, and q is selected from the group consisting of 1 to 8, preferably integers from 2 to 6, more preferably integers from 3 to 5, for example, n is an integer of 3, 4 or 5.

13. The combination for use according to any one of claims 1 or 5-12, binding agent for use according to any one of claims 2 or 5-12, antibody-drug conjugate for use according to any one of claims 3 or 5-12, or antibody-drug conjugate and binding agent for use according to any one of claims 4-12, wherein the binding agent is a bispecific antibody that comprises (a) an antibody or fragment thereof that specifically binds to PD-L1 and (b) an antibody or fragment thereof that specifically binds to VEGF.

14. The combination for use according to claim 13, binding agent for use according to claim 13, antibody-drug conjugate for use according to claim 13, or antibody-drug conjugate and binding agent for use according to claim 13, wherein the antibody or fragment thereof that specifically binds to PD-L1 is an anti-PD-Ll single domain antibody, preferably an anti-PD-Ll VHH.

15. The combination for use according to claim 13 or 14, binding agent for use according to claim 13 or 14, antibody-drug conjugate for use according to claim 13 or 14, or antibody-drug conjugate and binding agent for use according to claim 13 or 14, wherein the bispecific antibody comprises two anti-PD-Ll single domain antibodies, preferably two anti-PD-Ll VHHs, preferably wherein each VHH is terminally-fused to an anti -VEGF antibody.

16. The combination for use according to any one of claims 13-15, binding agent for use according to any one of claims 13-15, antibody-drug conjugate for use according to any one of claims 13-15, or antibody-drug conjugate and binding agent for use according to any one of claims 13-15, wherein the antibody or fragment thereof that specifically binds to PD-L1 comprises:(i) a HCDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 1, a HCDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 2, and a HCDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 3, wherein the CDRs are defined according to the Kabat numbering system; and / or(ii) a HCDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 4, a HCDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 5, and a HCDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 6, wherein the CDRs are defined according to the IMGT numbering system.

17. The combination for use according to any one of claims 13-16, binding agent for use according to any one of claims 13-16, antibody-drug conjugate for use according to any one of claims 13-16, or antibody-drug conjugate and binding agent for use according to any one of claims 13-16, wherein the antibody or fragment thereof that specifically binds to PD-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 7.

18. The combination for use according to any one of claims 13-17, binding agent for use according to any one of claims 13-17, antibody-drug conjugate for use according to any one of claims 13-17, or antibody-drug conjugate and binding agent for use according to any one of claims 13-17, wherein the antibody or fragment thereof that specifically binds to VEGF specifically binds to VEGF-A.

19. The combination for use according to any one of claims 13-18, binding agent for use according to any one of claims 13-18, antibody-drug conjugate for use according to any one of claims 13-18, or antibody-drug conjugate and binding agent for use according to any one of claims 13-18, wherein the antibody or fragment thereof that specifically binds to VEGF comprises:(i) a heavy chain variable region comprising: (i) a HCDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 8, (ii) a HCDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 9, and (iii) a HCDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 10; and a light chain variable region comprising: (i) a LCDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 11, (ii) a LCDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 12, and (iii) a LCDR3comprising or consisting of the amino acid sequence shown in SEQ ID NO: 13, 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 shown in SEQ ID NO: 14, (ii) a HCDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 15, and (iii) a HCDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 16; and a light chain variable region comprising: (i) a LCDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 17, (ii) a LCDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 18, and (iii) a LCDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO: 19, wherein the CDRs are defined according to the IMGT numbering system.

20. The combination for use according to any one of claims 13-19, binding agent for use according to any one of claims 13-19, antibody-drug conjugate for use according to any one of claims 13-19, or antibody-drug conjugate and binding agent for use according to any one of claims 13-19, wherein the antibody or fragment thereof that specifically binds to VEGF comprises: a heavy chain variable region comprising or consisting of the amino acid sequence shown in SEQ ID NO: 20 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and a light chain variable region comprising or consisting of the amino acid sequence shown in SEQ ID NO: 21 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

21. The combination for use according to any one of claims 13-20, binding agent for use according to any one of claims 13-20, antibody-drug conjugate for use according to any one of claims 13-20, or antibody-drug conjugate and binding agent for use according to any one of claims 13-20, wherein the antibody or fragment thereof that specifically binds to VEGF comprises: a heavy chain comprising or consisting of the amino acid sequence shown in SEQ ID NO: 25 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and a light chain comprising or consisting of the amino acid sequence shownin SEQ ID NO: 26 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

22. The combination for use according to any one of claims 13-21, binding agent for use according to any one of claims 13-21, antibody-drug conjugate for use according to any one of claims 13-21, or antibody-drug conjugate and binding agent for use according to any one of claims 13-21, wherein the bispecific antibody comprises an anti-VEGF antibody and at least one anti-PD-Ll single domain antibody, preferably an anti-VEGF antibody and two anti-PD-Ll single domain antibodies, more preferably an anti-VEGF antibody and two anti-PD-Ll VHHs, optionally wherein each heavy chain of the anti-VEGF antibody is terminally fused to an anti-PD-Ll single domain antibody, preferably via a linker.

23. The combination for use according to any one of claims 13-22, binding agent for use according to any one of claims 13-22, antibody-drug conjugate for use according to any one of claims 13-22, or antibody-drug conjugate and binding agent for use according to any one of claims 13-22, wherein the bispecific antibody comprises: a heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 27 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto; and a light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 28 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity thereto.

24. The combination for use according to any one of claims 1 or 5-23, binding agent for use according to any one of claims 2 or 5-23, antibody-drug conjugate for use according to any one of claims 3 or 5-23, or antibody-drug conjugate and binding agent for use according to any one of claims 4-23, wherein the binding agent and the antibody-drug conjugate are separately administered.

25. The combination for use according to any one of claims 1 or 5-24, binding agent for use according to any one of claims 2 or 5-24, antibody-drug conjugate for use according to any one of claims 3 or 5-24, or antibody-drug conjugate and binding agent for use according to any one of claims 4-24, wherein the cancer is positive forone or more target(s) expressed on the surface of a tumour cell, preferably wherein the cancer is positive for TROP2.

26. The combination for use according to any one of claims 1 or 5-25, binding agent for use according to any one of claims 2 or 5-25, antibody-drug conjugate for use according to any one of claims 3 or 5-25, or antibody-drug conjugate and binding agent for use according to any one of claims 4-25, wherein the cancer is a solid tumour.

27. The combination for use according to any one of claims 1 or 5-26, binding agent for use according to any one of claims 2 or 5-26, antibody-drug conjugate for use according to any one of claims 3 or 5-26, or antibody-drug conjugate and binding agent for use according to any one of claims 4-26, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, prostate cancer, cervical cancer, head and neck cancer.

28. The combination for use according to claim 27, binding agent for use according to claim 27, antibody-drug conjugate for use according to claim 27, or antibody-drug conjugate and binding agent for use according to claim 27, wherein the cancer is breast cancer, more preferably triple negative breast cancer.

29. The combination for use according to claim 27, binding agent for use according to claim 28, antibody-drug conjugate for use according to claim 27, or antibody-drug conjugate and binding agent for use according to claim 27, wherein the cancer is cervical cancer.

30. The combination for use according to claim 27, binding agent for use according to claim 27, antibody-drug conjugate for use according to claim 27, or antibody-drug conjugate and binding agent for use according to claim 27, wherein the cancer is lung cancer.

31. The combination for use according to claim 30, binding agent for use according to claim 30, antibody-drug conjugate for use according to claim 30, orantibody-drug conjugate and binding agent for use according to claim 30, wherein the lung cancer is non-small-cell lung cancer.

32. The combination for use according to claim 30, binding agent for use according to claim 30, antibody-drug conjugate for use according to claim 30, or antibody-drug conjugate and binding agent for use according to claim 30, wherein the lung cancer is non-small-cell lung cancer with or without actionable genomic alterations (AGA).

33. The combination for use according to claim 30, binding agent for use according to claim 30, antibody-drug conjugate for use according to claim 30, or antibody-drug conjugate and binding agent for use according to claim 30, wherein the lung cancer is AGA-positive non-squamous non-small-cell lung cancer.

34. The combination for use according to claim 30, binding agent for use according to claim 30, antibody-drug conjugate for use according to claim 30, or antibody-drug conjugate and binding agent for use according to claim 30, wherein the lung cancer is AGA-negative non-squamous non-small-cell lung cancer.

35. The combination for use according to claim 27, binding agent for use according to claim 27, antibody-drug conjugate for use according to claim 27, or antibody-drug conjugate and binding agent for use according to claim 27, wherein the cancer is ovarian cancer.

36. The combination for use according to claim 35, binding agent for use according to claim 35, antibody-drug conjugate for use according to claim 35, or antibody-drug conjugate and binding agent for use according to claim 35, wherein the cancer is platinum resistant ovarian cancer.

37. The combination for use according to claim 27, binding agent for use according to claim 27, antibody-drug conjugate for use according to claim 27, or antibody-drug conjugate and binding agent for use according to claim 27, wherein the cancer is prostate cancer.

38. The combination for use according to any one of claims 1 or 5-37, binding agent for use according to any one of claims 2 or 5-37, antibody-drug conjugate for use according to any one of claims 3 or 5-37, or antibody-drug conjugate and binding agent for use according to any one of claims 4-37, wherein the use comprises administering the antibody-drug conjugate at a dose of from about 2.5 mg / kg to about 4.5 mg / kg.

39. The combination for use according to any one of claims 1 or 5-37, binding agent for use according to any one of claims 2 or 5-37, antibody-drug conjugate for use according to any one of claims 3 or 5-37, or antibody-drug conjugate and binding agent for use according to any one of claims 4-37, wherein the use comprises administering the antibody-drug conjugate at a dose of from about 3 mg / kg to about 4 mg / kg.

40. The combination for use according to any one of claims 1 or 5-37, binding agent for use according to any one of claims 2 or 5-37, antibody-drug conjugate for use according to any one of claims 3 or 5-37, or antibody-drug conjugate and binding agent for use according to any one of claims 4-37, wherein the use comprises administering the antibody-drug conjugate at a dose of from about 3 mg / kg to about 3.5 mg / kg.

41. The combination for use according to any one of claims 1 or 5-37, binding agent for use according to any one of claims 2 or 5-37, antibody-drug conjugate for use according to any one of claims 3 or 5-37, or antibody-drug conjugate and binding agent for use according to any one of claims 4-37, wherein the use comprises administering the antibody-drug conjugate at a dose of from about 2.8 mg / kg to about 3.2 mg / kg, preferably from about 2.9 mg / kg to about 3.1 mg / kg, more preferably about 3 mg / kg.

42. The combination for use according to any one of claims 1 or 5-37, binding agent for use according to any one of claims 2 or 5-37, antibody-drug conjugate for use according to any one of claims 3 or 5-37, or antibody-drug conjugate and binding agent for use according to any one of claims 4-37, wherein the use comprisesadministering the antibody-drug conjugate at a dose of from about 3.3 mg / kg to about 3.7 mg / kg, preferably from about 3.4 mg / kg to about 3.6 mg / kg, more preferably about 3.5 mg / kg.

43. The combination for use according to any one of claims 1 or 5-42, binding agent for use according to any one of claims 2 or 5-42, antibody-drug conjugate for use according to any one of claims 3 or 5-42, or antibody-drug conjugate and binding agent for use according to any one of claims 4-42, wherein the use comprises administering the antibody-drug conjugate once every 3 weeks.

44. The combination for use according to any one of claims 1 or 5-42, binding agent for use according to any one of claims 2 or 5-42, antibody-drug conjugate for use according to any one of claims 3 or 5-42, or antibody-drug conjugate and binding agent for use according to any one of claims 4-42, wherein the use comprises administering the antibody-drug conjugate once every 2 weeks.

45. The combination for use according to any one of claims 1 or 5-44, binding agent for use according to any one of claims 2 or 5-44, antibody-drug conjugate for use according to any one of claims 3 or 5-44, or antibody-drug conjugate and binding agent for use according to any one of claims 4-44, wherein the use comprises administering the binding agent at a dose of about 15 mg / kg to about 35 mg / kg.

46. The combination for use according to any one of claims 1 or 5-44, binding agent for use according to any one of claims 2 or 5-44, antibody-drug conjugate for use according to any one of claims 3 or 5-44, or antibody-drug conjugate and binding agent for use according to any one of claims 4-44, wherein the use comprises administering the binding agent at a dose of from about 25 mg / kg to about 35 mg / kg.

47. The combination for use according to any one of claims 1 or 5-44, binding agent for use according to any one of claims 2 or 5-44, antibody-drug conjugate for use according to any one of claims 3 or 5-44, or antibody-drug conjugate and binding agent for use according to any one of claims 4-44, wherein the use comprisesadministering the binding agent at a dose of from about 28 mg / kg to about 32 mg / kg, preferably from about 29 mg / kg to about 31 mg / kg, more preferably about 30 mg / kg.

48. The combination for use according to any one of claims 1 or 5-44, binding agent for use according to any one of claims 2 or 5-44, antibody-drug conjugate for use according to any one of claims 3 or 5-44, or antibody-drug conjugate and binding agent for use according to any one of claims 4-44, wherein the use comprises administering the binding agent at a dose of from about 18 mg / kg to about 22 mg / kg, preferably from about 19 mg / kg to about 21 mg / kg, more preferably about 20 mg / kg.

49. The combination for use according to any one of claims 1 or 5-48, binding agent for use according to any one of claims 2 or 5-48, antibody-drug conjugate for use according to any one of claims 3 or 5-48, or antibody-drug conjugate and binding agent for use according to any one of claims 4-48, wherein the use comprises administering the binding agent once every 3 weeks.

50. The combination for use according to any one of claims 1 or 5-48, binding agent for use according to any one of claims 2 or 5-48, antibody-drug conjugate for use according to any one of claims 3 or 5-48, or antibody-drug conjugate and binding agent for use according to any one of claims 4-48, wherein the use comprises administering the binding agent once every 2 weeks.

51. The combination for use according to any one of claims 1 or 5-50, binding agent for use according to any one of claims 2 or 5-50, antibody-drug conjugate for use according to any one of claims 3 or 5-50, or antibody-drug conjugate and binding agent for use according to any one of claims 4-50, wherein the use comprises: administering the binding agent at a dose of about 30 mg / kg; andadministering the antibody-drug conjugate at a dose of about 3 mg / kg.

52. The combination for use according to claim 51, binding agent for use according to claim 51, antibody-drug conjugate for use according to claim 51, or antibody-drug conjugate and binding agent for use according to claim 51, wherein the cancer is ovarian cancer.

53. The combination for use according to any one of claims 1 or 5-50 binding agent for use according to any one of claims 2 or 5-50, antibody-drug conjugate for use according to any one of claims 3 or 5-50, or antibody-drug conjugate and binding agent for use according to any one of claims 4-50, wherein the use comprises: administering the binding agent at a dose of about 30 mg / kg; andadministering the antibody-drug conjugate at a dose of about 3.5 mg / kg.

54. The combination for use according to claim 53, binding agent for use according to claim 53, antibody-drug conjugate for use according to claim 53, or antibody-drug conjugate and binding agent for use according to claim 53, wherein the cancer is breast cancer, more preferably, triple negative breast cancer.

55. The combination for use according to claim 53, binding agent for use according to claim 53, antibody-drug conjugate for use according to claim 53, or antibody-drug conjugate and binding agent for use according to claim 53, wherein the cancer is NSCLC.

56. The combination for use according to claim 53, binding agent for use according to claim 53, antibody-drug conjugate for use according to claim 53, or antibody-drug conjugate and binding agent for use according to claim 53, wherein the cancer is cervical cancer.

57. The combination for use according to any one of claims 1 or 5-56, binding agent for use according to any one of claims 2 or 5-56, antibody-drug conjugate for use according to any one of claims 3 or 5-56, or antibody-drug conjugate and binding agent for use according to any one of claims 4-56, wherein the subject has been previously treated with one or more other anticancer agents.

58. The combination for use according to claim 57, binding agent for use according to claim 57, antibody-drug conjugate for use according to claim 57, or antibody-drug conjugate and binding agent for use according to claim 57, wherein the anticancer agent is a platinum-based agent.

59. The combination for use according to claim 57, binding agent for use according to claim 57, antibody-drug conjugate for use according to claim 57, or antibody-drug conjugate and binding agent for use according to claim 57, wherein the anti cancer agent is a taxane.

60. The combination for use according to claim 57, binding agent for use according to claim 5, antibody-drug conjugate for use according to claim 57, or antibody-drug conjugate and binding agent for use according to claim 57, wherein the anticancer agent is an antibody or immunotherapy agent.

61. A method of treating cancer in a subject, comprising administering to the subject:a. a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, andb. an antibody-drug conjugate having the formula (I):or a tautomer, mesomer, enantiomer thereof, or a pharmaceutically acceptable salt thereof wherein:Ab is sacituzumab;L is -La-Lb-Lc-;La- is-Lc- is -CH2-;R1is selected from the group consisting of: -O-, -(R2)N-, -P(=O)(R2)- and -S-;X is -L1-CH2-C(O)-;L1is -(C(R3a)(R3b))m-, wherein 0 or at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-;wherein each R2, each R3a, each R3band each R4bare 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 C1-6 aliphatic 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)S02H or a C1-6 aliphatic group;m is selected from the group consisting of integers > 0,when R1is -O- or -HN-, at least 1 methylene unit of L1is independently replaced by -C(O)-, -C(=S)-, -C(=NR4b)- or -C(=N2)-, or each R3aand each R3bare not both hydrogen; andn is a connection number and is an integer from 1 to 10;wherein the antibody-drug conjugate is administered at a dose of from about 2 mg / kg to about 5 mg / kg.

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