Bispecific antibody against PD-l1 and CD137 in combination therapy

Abstract

The present disclosure relates to a method of treating non-small cell lung cancer in human subjects using a combination therapy of a bispecific antibody binding to PD-L1 and to CD 137 and a PD-1 antagonist.

Description

[0001] BISPECIFIC ANTIBODY AGAINST PD-L1 AND CD137 IN COMBINATION THERAPY

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 691,832, filed September 6, 2024, U.S. Provisional Application No. 63 / 669,876, filed July 11, 2024, and U.S. Provisional Application No. 63 / 650,871, filed May 22, 2024, the disclosures of which are explicitly incorporated by reference herein in their entireties.

[0004] REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0005] This application is being filed electronically and includes an electronically submitted sequence listing. The sequence listing is entitled "24-0730-WO-Sequence-Listing.xml" and was created on May 21, 2025 and has a size of 36,879 bytes. The sequence listing contained in this .xml file is part of the specification and is herein incorporated by reference in its entirety.

[0006] FIELD OF THE DISCLOSURE

[0007] The present invention relates to a method of treating non-small cell lung cancer in human subjects using a combination therapy of a bispecific antibody binding to PD-L1 and to CD 137 and a PD-1 antagonist.

[0008] BACKGROUND

[0009] Lung cancer is one of the common cancer types, with an estimated nearly 2.1 million new cases diagnosed in 2018, resulting in an estimated 1.8 million deaths worldwide (Bray et al., CA Cancer J. Clin. 68(6): 394-24 (2018)). The American Cancer Society estimates about 235,760 new cases of lung cancer and 131,880 deaths from lung cancer will occur in 2021 in the United States (ACS, 2021). Non- small cell lung cancer (NSCLC) represents approximately 85% of lung cancers and includes adenocarcinomas, which account for approximately 50% of lung cancers, squamous cell carcinomas, which account for approximately 20%, and large cell carcinomas, which account for approximately 10% of lung cancers.

[0010] Progress has been made in the clinical management of early-stage NSCLC by establishing comprehensive, multi-modality treatment regimens. Current standard of care for first-line advanced NSCLC varies depending on the presence or absence of driver mutations, histology, and PD-L1 expression. Molecular profiling has established a definite role for EGFR, ALK, and ROS1 directed therapy in a subset of patients with non-squamous NSCLC. RET, BRAFV600E, MET exon 14 skipping mutation, and NTRK gene fusion are other targets, for which specific therapies are becoming available. In patients whose tumors have sensitizing EGFR mutations, osimertinib and erlotinib are recommended as first-line treatment. Gefitinib, afatinib, and dacomitinib are also indicated in this patient population. For patients whose tumors have an ALK mutation, alectinib, brigatinib, ceritinib, and crizotinib are recommended as first-line therapy. For patients with wild-type tumors having unknown, no, or low level of PD-L1 expression (tumor proportion score [TPS] 0% to 49%), the standard treatment for non- squamous disease is 4 to 6 cycles of platinum-based chemotherapy with or without PD-1 / PD-L1 inhibitors for squamous disease and the same with or without bevacizumab followed by possible maintenance therapy with pemetrexed for non-squamous disease. For patients whose tumors have higher levels of PD-L1 expression (TPS >50%), a single-agent PD-1 inhibitor is indicated. Subsequently, patients with metastatic lung cancer who have actionable driven mutations or are eligible for immunotherapies have longer survival, with 5-year survival rates ranging from 15% to 50% depending on the mutation status or biomarker status. Even though the death rate in lung cancer has declined, there are still more deaths from lung cancer than from breast, prostate, colorectal, and brain cancers combined (NCCN, 2021).

[0011] Despite the success of checkpoint inhibitors (CPIs) in first-line NSCLC, it is largely challenging to optimally treat patients who progress after immunotherapy. Currently recommended treatment options in this setting are docetaxel (with or without ramucirumab), pemetrexed (for non-squamous only), or gemcitabine. However, the outcome is poor, with an estimated average progression-free survival (PFS) of less than 6 months and overall survival (OS) of less than 1 year. The treatment options diminish with each line of therapy, as patients succumb to their cancer or experience deterioration of their health that makes further treatment impossible. This poor prognosis highlights the need for more agents across all lines of therapy and especially in later lines. Thus, there remains a need for further treatments and / or later lines of therapy for patients suffering from NSCLC, in particular patients with metastatic NSCLC and / or patients after failure of immunotherapies.

[0012] SUMMARY

[0013] The present inventors have surprisingly found that a combination of (i) a bispecific antibody binding to PD-L1 and CD 137 and (ii) a PD-1 antagonist treats non-small cell lung cancer (NSCLC) in human subjects.

[0014] Thus, in a first aspect, the present disclosure provides a method for treating NSCLC in a human subject, said method comprising administering to said human subject a bispecific antibody and a PD-1 antagonist. The bispecific antibody comprises a first binding region binding to CD 137 and a second binding region binding to PD-L1; the first binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, GAS, and SEQ ID NO: 7, respectively; and the second antigen-binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 13, DDN, and SEQ ID NO: 14, respectively. The PD-1 antagonist is an anti-PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 33, 34 and 35, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37 and 38, respectively.

[0015] In a second aspect, the present disclosure provides a bispecific antibody for use in a method for treating NSCLC according to the first aspect. The bispecific antibody comprises a first binding region binding to CD 137 and a second binding region binding to PD-L1; the first binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, GAS, and SEQ ID NO: 7, respectively; and the second antigen-binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 13, DDN, and SEQ ID NO: 14, respectively.

[0016] In a third aspect, the present disclosure provides a PD-1 antagonist for use in a method for treating NSCLC according to the first aspect. The PD-1 antagonist is an anti-PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 33, 34 and 35, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37 and 38, respectively.

[0017] In a fourth aspect, the present disclosure provides use of a bispecific antibody in a method for treating NSCLC according to the first aspect. The bispecific antibody comprises a first binding region binding to CD 137 and a second binding region binding to PD-L1; the first binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, GAS, and SEQ ID NO: 7, respectively; and the second antigen-binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 13, DDN, and SEQ ID NO: 14, respectively.

[0018] In a fifth aspect, the present disclosure provides use of a PD-1 antagonist in a method for treating NSCLC according to the first aspect. The PD-1 antagonist is an anti-PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 33, 34 and 35, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37 and 38, respectively.

[0019] In a sixth aspect, the present disclosure provides a kit comprising a bispecific antibody and a PD-1 antagonist. The bispecific antibody comprises a first binding region binding to CD 137 and a second binding region binding to PD-L1; the first binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, GAS, and SEQ ID NO: 7, respectively; and the second antigen-binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 13, DDN, and SEQ ID NO: 14, respectively. The PD-1 antagonist is an anti-PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 33, 34 and 35, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37 and 38, respectively.

[0020] BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The following detailed description of the embodiments of the present disclosure can best be understood when read in conjunction with the following drawings.

[0022] FIGURE 1 depicts a schematic overview of the GCT 1046-04 trial.

[0023] FIGURE 2A represents a graph of incidence percentages versus treatment emergent adverse events reported the Arm A trial cohort.

[0024] FIGURE 2B represents a graph of incidence percentages versus treatment emergent adverse events reported the Arm B trial cohort.

[0025] FIGURE 2C represents a graph of incidence percentages versus treatment emergent adverse events reported the Arm C trial cohort.

[0026] FIGURE 3A depicts a Kaplan-Meier plot of the duration of response versus time in months for all patients.

[0027] FIGURE 3B depicts a Kaplan-Meier plot of the duration of response versus time in months for PD-L 1 centrally positive patients.

[0028] FIGURE 3C depicts a Kaplan-Meier plot of the progression free survival (PFS) versus time in months for all patients.

[0029] FIGURE 3D depicts a Kaplan-Meier plot of the progression free survival (PFS) versus time in months for all PD-L1 centrally positive patients.

[0030] FIGURE 3E depicts a Kaplan-Meier plot of overall survival versus time in months for all patients. FIGURE 3F depicts a Kaplan-Meier plot of overall survival versus time in months for PD-L1 centrally positive patients.

[0031] FIGURE 4A depicts a line graph of the median fold-change of s4-lbb expression levels from C1D1 in Arm A (n=10). Error Bars Indicate interquartile range (IQR). Day 1 of each cycle specifies pre-dose sampling. CXDY=Cycle X Day Y.

[0032] FIGURE 4B depicts a line graph of the median fold-change of s4-lbb expression levels from C1D1 in Arm B (n=14). Error Bars Indicate interquartile range (IQR). Day 1 of each cycle specifies pre-dose sampling. CXDY=Cycle X Day Y.

[0033] FIGURE 4C depicts a line graph of the median fold-change of s4-lbb expression levels from C1D1 in Arm C (n=10). Error Bars Indicate interquartile range (IQR). Day 1 of each cycle specifies pre-dose sampling. CXDY=Cycle X Day Y.

[0034] FIGURE 5A depicts longitudinal dot plots of the percentage of CD8+ T effector memory cells (defined as CD45RA- / CCR7- / CD8+ cells) expressing the proliferation marker Ki67 for Arm B and Arm C. Paired longitudinal dot plots are shown with baseline levels for individual patients and as box and whiskers plots (box with median and 75th / 25th percentiles of the distribution and whiskers to min / max). (n=37 at CID 1). Cx=Cycle x.

[0035] FIGURE 5B depicts longitudinal dot plots of the percentage of CD8+ T effector memory cells (defined as CD45RA- / CCR7- / CD8+ cells) expressing the proliferation marker Ki67 for Arm A. Paired longitudinal dot plots are shown with baseline levels for individual patients and as box and whiskers plots (box with median and 75th / 25th percentiles of the distribution and whiskers to min / max). (n=l 1 at C1D1). Cx=Cycle x.

[0036] FIGURE 6A represents the fold-change from C ID 1 for individual patients over multiple cycles for Arm

[0037] B.

[0038] FIGURE 6B represents the fold-change from C1D1 for individual patients over multiple cycles for Arm

[0039] C.

[0040] FIGURE 6C depicts a box and whiskers plots of the fold change from cycle 1 day 1 of CD8+ T effector memory cells (defined as CD45RA- / CCR7- / CD8+ cells) expressing the proliferation marker Ki67 of Arm B (n=14 at C1D1) and Arm C (n=14 at C1D1). CxDy=Cycle x Day y.

[0041] FIGURE 7A depicts the fold-change from C1D1 of co-inhibitory marker TIM3 for Arm B (n=16 at C1D1) and Arm C (n=17 at CID 1). Day 1 of each cycle specifies pre-dose sampling. CxDy=Cycle x Day y.

[0042] FIGURE 7B depicts the fold-change from C1D1 of proliferation marker Ki67 for Arm B (n=16 at C1D1) and Arm C (n=17 at CID 1). Day 1 of each cycle specifies pre-dose sampling. CxDy=Cycle x Day y.

[0043] FIGURE 7C depicts the fold-change from C1D1 of T-cell activation marker HLA-DR for Arm B (n=16 at C1D1) and Arm C (n=17 at C1D1). Day 1 of each cycle specifies pre-dose sampling. CxDy=Cycle x Day y. FIGURE 8A depicts IL- 10 levels as a fold-change from CID 1 for individual patients over time and as a box and whiskers plot (box with median and 75 / 25 percentiles of the distribution and whiskers to the minimum / maximum) at week 6 for patients in Arm B (n=27 at C1D1). Day 1 of each cycle specifies pre-dose sampling. CxDy=Cycle x Day y.

[0044] FIGURE 8B depicts IL- 10 levels as a fold-change from C1D1 for individual patients over time and as a box and whiskers plot (box with median and 75 / 25 percentiles of the distribution and whiskers to the minimum / maximum) at week 6 for patients in Arm C (n=22 at C1D1). Day 1 of each cycle specifies pre-dose sampling. CxDy=Cycle x Day y.

[0045] FIGURE 8C depicts IL- 10 levels as a fold-change from C1D1 for all patients in Arm B (n=27 at CID 1) and Arm C (n=22 at C1D1) over time and as a box and whiskers plot (box with median and 75 / 25 percentiles of the distribution and whiskers to the minimum / maximum) at week 6 f Day 1 of each cycle specifies pre-dose sampling. CxDy=Cycle x Day y.

[0046] FIGURE 9A depicts a model-predicted relationship between acasunlimab exposure and probability of confirmed PR / CR at range of exposures in subjects who received acasunlimab in combination with pembrolizumab. Open circles represent observed outcomes with respect to response during treatment with acasunlimab in combination with pembrolizumab. Black squares represent observed probability of event (PR / CR) at each acasunlimab Cavg tertile and error bars represents associated 95% confidence interval (CI). Solid horizontal line and shaded region (z.e., hashed area) above and below solid line represent model predicted probability of event (PR / CR) and 95% CI, respectively.

[0047] FIGURE 9B depicts a model-predicted relationship between acasunlimab exposure and probability of unconfirmed PR / CR at range of exposures in subjects who received acasunlimab in combination with pembrolizumab. Open circles represent observed outcomes with respect to response during treatment with acasunlimab in combination with pembrolizumab. Black squares represent observed probability of event (PR / CR) at each acasunlimab Cavg tertile and error bars represents associated 95% confidence interval (CI). Solid horizontal line and shaded region (z.e., hashed area) above and below solid line represent model predicted probability of event (PR / CR) and 95% CI, respectively.

[0048] FIGURE 10 depicts a model-predicted relationship between acasunlimab exposure and risk of SMQ hepatic events at range of exposures where acasunlimab is given as Q3W or Q6W in combination with pembrolizumab. Open circles represent observed outcomes with respect to incidence of grade 3+ hepatic events during acasunlimab treatment in combination with pembrolizumab. Black squares represent observed probability of grade 3+ hepatic event at each acasunlimab Cavg tertile and error bars represent associated 95% CL Solid horizontal line represents model predicted probability of grade 3+ hepatic events and solid vertical lines represent 95% CL 1+B+C = Patients who received the combination of acasunlimab + pembrolizumab in GCT 1046-01, and GCT 1046-04 Arms B and C.

[0049] DETAILED DESCRIPTION Although the present disclosure is further described in more detail below, it is to be understood that this disclosure is not limited to the particular methodologies, protocols, and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present disclosure, which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0050] In the following, the elements of the present disclosure will be described in more detail. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present disclosure to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.

[0051] Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", H.G.W. Leuenberger, B. Nagel, and H. Kolbl, Eds., Helvetica Chimica Acta, CH-4010 Basel, Switzerland, (1995).

[0052] The practice of the present disclosure will employ, unless otherwise indicated, conventional chemistry, biochemistry, cell biology, immunology, and recombinant DNA techniques, which are explained in the literature in the field (cf. e.g., Organikum, Deutscher Verlag der Wissenschaften, Berlin 1990; Streitwieser / Heathcook, "Organische Chemie", VCH, 1990; Beyer / Walter, "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 et al., eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).

[0053] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g., "such as"), provided herein is intended merely to better illustrate the present disclosure and does not pose a limitation on the scope of the present disclosure otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the present disclosure. 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. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[0054] Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0055] Definitions

[0056] In the following, definitions will be provided which apply to all aspects of the present disclosure. The following terms have the following meanings unless otherwise indicated. Any undefined terms have their art recognized meanings.

[0057] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated member, integer or step or group of members, integers or steps but not the exclusion of any other member, integer or step or group of members, integers or steps. The term "consisting essentially of' means excluding other members, integers or steps of any essential significance. The term "comprising" encompasses the term "consisting essentially of' which, in turn, encompasses the term "consisting of'. Thus, at each occurrence in the present application, the term "comprising" may be replaced with the term "consisting essentially of' or "consisting of'. Likewise, at each occurrence in the present application, the term "consisting essentially of' may be replaced with the term "consisting of'.

[0058] The terms "a", "an", and "the" and similar references used in the context of describing the present disclosure (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 the context.

[0059] Where used herein, "and / or" is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, "X and / or Y" is to be taken as specific disclosure of each of (i) X, (ii) Y, and (iii) X and Y, just as if each is set out individually herein.

[0060] In the context of the present disclosure, the term "about" or term "approximate" denotes an interval of accuracy that the person of ordinary skill will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value by ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, and for example ±0.01%. As will be appreciated by the person of ordinary skill, the specific such deviation for a numerical value for a given technical effect will depend on the nature of the technical effect. For example, a natural or biological technical effect may generally have a larger such deviation than one for a man-made or engineering technical effect.

[0061] The term "binding agent" in the context of the present disclosure refers to any agent capable of binding to desired antigens. In certain embodiments of the present disclosure, 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 non-peptide 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.

[0062] As used herein, "immune checkpoint" refers to regulators of the immune system, and, in particular, costimulatory and inhibitory signals that regulate the amplitude and quality of T cell receptor recognition of an antigen. In certain embodiments, the immune checkpoint is an inhibitory signal. In certain embodiments, the inhibitory signal is the interaction between PD-1 and PD-L1 and / or PD-L2. In certain embodiments, the inhibitory signal is the interaction between CTLA-4 and CD80 or CD86 to displace CD28 binding. In certain embodiments the inhibitory signal is the interaction between LAG-3 and MHC class II molecules. In certain embodiments, the inhibitory signal is the interaction between TIM-3 and one or more of its ligands, such as galectin 9, PtdSer, HMGB 1 and CEACAM1. In certain embodiments, the inhibitory signal is the interaction between one or several KIRs and their ligands. In certain embodiments, the inhibitory signal is the interaction between TIGIT and one or more of its ligands, PVR, PVRL2 and PVRL3. In certain embodiments, the inhibitory signal is the interaction between CD94 / NKG2A and HLA-E. In certain embodiments, the inhibitory signal is the interaction between VISTA and its binding partner(s). In certain embodiments, the inhibitory signal is the interaction between one or more Siglecs and their ligands. In certain embodiments, the inhibitory signal is the interaction between GARP and one or more of its ligands. In certain embodiments, the inhibitory signal is the interaction between CD47 and SIRPa. In certain embodiments, the inhibitory signal is the interaction between PVRIG and PVRL2. In certain embodiments, the inhibitory signal is the interaction between CSF1R and CSF1. In certain embodiments, the inhibitory signal is the interaction between BTLA and HVEM. In certain embodiments, the inhibitory signal is part of the adenosinergic pathway, e.g., the interaction between A2AR and / or A2BR and adenosine, produced by CD39 and CD73. In certain embodiments, the inhibitory signal is the interaction between B7-H3 and its receptor and / or B7- H4 and its receptor. In certain embodiments, the inhibitory signal is mediated by IDO, CD20, NOX, or TDO. The terms "checkpoint inhibitor" (CPI) and "immune checkpoint (ICP) inhibitor" are used herein synonymously. The terms refer to molecules, such as binding agents, which totally or partially reduce, inhibit, interfere with or negatively modulate one or more checkpoint proteins or that totally or partially reduce, inhibit, interfere with or negatively modulate expression of one or more checkpoint proteins, like molecules, such as binding agents, which inhibit an immune checkpoint, in particular, which inhibit the inhibitory signal of an immune checkpoint. In one embodiment, the immune checkpoint inhibitor binds to one or more checkpoint proteins. In one embodiment, the immune checkpoint inhibitor binds to one or more molecules regulating checkpoint proteins. In one embodiment, the immune checkpoint inhibitor binds to precursors of one or more checkpoint proteins, e.g., on DNA- or RNA-level. Any agent that functions as a checkpoint inhibitor according to the present disclosure can be used. The term "partially" as used herein means at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% in the level, e.g., in the level of inhibition of a checkpoint protein.

[0063] In one embodiment, the checkpoint inhibitor can be any compound, such as any binding agent, which inhibits the inhibitory signal of an immune checkpoint, wherein the inhibitory signal is selected from the group consisting of: the interaction between PD-1 and PD-L1 and / or PD-L2; the interaction between CTLA-4 and CD80 or CD86 to displace CD28 binding; the interaction between LAG-3 and MHC class II molecules; the interaction between TIM-3 and one or more of its ligands, such as galectin 9, PtdSer, HMGB1, and CEACAM1; the interaction between one or several KIRs and their ligands; the interaction between TIGIT and one or more of its ligands, PVR, PVRL2, and PVRL3; the interaction between CD94 / NKG2A and HLA-E; the interaction between VISTA and its binding partner(s); the interaction between one or more Siglecs and their ligands; the interaction between GARP and one or more of its ligands; the interaction between CD47 and SIRPa; the interaction between PVRIG and PVRL2; the interaction between CSF1R and CSF1; the interaction between BTLA and HVEM; part of the adenosinergic pathway, e.g., the interaction between A2AR and / or A2BR and adenosine, produced by CD39 and CD73; the interaction between B7-H3 and its receptor and / or B7-H4 and its receptor; an inhibitory signal mediated by IDO, CD20, NOX, or TDO. In one embodiment, the checkpoint inhibitor is at least one selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, TIM-3 inhibitors, KIR inhibitors, LAG-3 inhibitors, TIGIT inhibitors, VISTA inhibitors, and GARP inhibitors. In one embodiment, the checkpoint inhibitor may be a blocking antibody, such as a PD-1 blocking antibody, a CTLA4 blocking antibody, a PD-L1 blocking antibody, a PD-L2 blocking antibody, a TIM-3 blocking antibody, a KIR blocking antibody, a LAG-3 blocking antibody, a TIGIT blocking antibody, a VISTA blocking antibody, or a GARP blocking antibody. Examples of a PD-1 blocking antibody include pembrolizumab, nivolumab, cemiplimab, and spartalizumab. Examples of a CTLA4 blocking antibody include ipilimumab and tremelimumab. Examples of a PD-L1 blocking antibody include atezolizumab, durvalumab, and avelumab. The term "immunoglobulin" relates to proteins of the immunoglobulin superfamily, preferably to antigen receptors such as antibodies or the B cell receptor (BCR). The immunoglobulins are characterized by a structural domain, z.e., the immunoglobulin domain, having a characteristic immunoglobulin (Ig) fold. The term encompasses membrane bound immunoglobulins as well as soluble immunoglobulins. Membrane bound immunoglobulins are also termed surface immunoglobulins or membrane immunoglobulins, which are generally part of the BCR. Soluble immunoglobulins are generally termed antibodies.

[0064] The structure of immunoglobulins has been well characterized. See, e.g., Fundamental Immunology Ch. 7 (Paul, W., ed., 2nded. Raven Press, N.Y. (1989)). Briefly, immunoglobulins generally comprise several chains, typically two identical heavy chains and two identical light chains which are linked via disulfide bonds. These chains are primarily composed of immunoglobulin domains or regions, such as the VL or VL (variable light chain) domain / region, CL or CL (constant light chain) domain / region, VH or VH (variable heavy chain) domain / region, and the CH or CH (constant heavy chain) domains / regions CHI (CHI), CH2 (CH2), CH3 (CH3), and CH4 (CH4). The heavy chain constant region typically is comprised of three domains, CHI, CH2, and CH3. The hinge region is the region between the CHI and CH2 domains of the heavy chain and is highly flexible. Disulfide bonds in the hinge region are part of the interactions between two heavy chains in an IgG molecule. Each light chain typically is comprised of a VL and a CL. The light chain constant region typically is comprised of one domain, CL. The VH and VL regions may be further subdivided into regions of hypervariability (or hypervariable regions which may be hypervariable in sequence and / or form of structurally defined loops), also termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and Lesk, J. Mol. Biol. 196(4): 901-17 (1987)). Unless otherwise stated or contradicted by context, CDR sequences herein are identified according to IMGT rules using DomainGapAlign (Lefranc et al., Nucleic Acids Res. 27(1): 209-12 (1999) and Ehrenmann et al., Nucleic Acids Res. 38(Database issue): D301-307 (2010); see also internet http address www.imgt.org. Unless otherwise stated or contradicted by context, reference to amino acid positions in the constant regions in the present disclosure is according to the EU-numbering (Edelman et al., Proc. Natl. Acad. Sci. U.S.A. 63(1): 78-85 (1969); Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition. 1991 NIH Publication No. 91-3242).

[0065] There are five types of mammalian immunoglobulin heavy chains, i.e., a, 5. a, y, and p, which account for the different classes of antibodies, i.e., IgA, IgD, IgE, IgG, and IgM. As opposed to the heavy chains of soluble immunoglobulins, the heavy chains of membrane or surface immunoglobulins comprise a transmembrane domain and a short cytoplasmic domain at their carboxy-terminus. In mammals there are two types of light chains, z.e., lambda and kappa. The immunoglobulin chains comprise a variable region and a constant region. The constant region is essentially conserved within the different isotypes of the immunoglobulins, wherein the variable part is highly divers and accounts for antigen recognition.

[0066] The term "amino acid" and "amino acid residue" may herein be used interchangeably, and are not to be understood as 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:

[0067] Table 1. Main classification based on structure and general chemical characterization of R group

[0068] Table 2. Alternative Physical and Functional Classifications of Amino Acid Residues

[0069] For the purposes of the present disclosure, "variants" of an amino acid sequence (peptide, protein or polypeptide) comprise amino acid insertion variants, amino acid addition variants, amino acid deletion variants and / or amino acid substitution variants. The term "variant" includes all mutants, splice variants, post-translationally modified variants, conformations, isoforms, allelic variants, species variants, and species homologs, in particular those which are naturally occurring. The term "variant" includes, in particular, fragments of an amino acid sequence.

[0070] Amino acid insertion variants comprise insertions of single or two or more amino acids in a particular amino acid sequence. In the case of amino acid sequence variants having an insertion, one or more amino acid residues are inserted into a particular site in an amino acid sequence, although random insertion with appropriate screening of the resulting product is also possible.

[0071] Amino acid addition variants comprise amino- and / or carboxy-terminal fusions of one or more amino acids, such as 1, 2, 3, 5, 10, 20, 30, 50, or more amino acids.

[0072] Amino acid deletion variants are characterized by the removal of one or more amino acids from the sequence, such as by removal of 1, 2, 3, 5, 10, 20, 30, 50, or more amino acids. The deletions may be in any position of the protein. Amino acid deletion variants that comprise the deletion at the N-terminal and / or C-terminal end of the protein are also called N-terminal and / or C-terminal truncation variants.

[0073] Amino acid substitution variants are characterized by at least one residue in the sequence being removed and another residue being inserted in its place. Substitution of one amino acid for another may be classified as a conservative or non-conservative substitution. Preference is given to the modifications being in positions in the amino acid sequence which are not conserved between homologous proteins or peptides and / or to replacing amino acids with other ones having similar properties. Preferably, amino acid changes in peptide and protein variants are conservative amino acid changes, z.e., substitutions of similarly charged or uncharged amino acids. A conservative amino acid change involves substitution of one of a family of amino acids which are related in their side chains. In the context of the present disclosure, a "conservative substitution" is a substitution of one amino acid with another amino acid having similar structural and / or chemical characteristics, such substitution of one amino acid residue for another amino acid residue of the same class as defined in any of the two tables above: for example, leucine may be substituted with isoleucine as they are both aliphatic, branched hydrophobes. Similarly, aspartic acid may be substituted with glutamic acid since they are both small, negatively charged residues. Naturally occurring amino acids may also be generally divided into four families: acidic (aspartate, glutamate), basic (lysine, arginine, histidine), non-polar (alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), and uncharged polar (glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine) amino acids. Phenylalanine, tryptophan, and tyrosine are sometimes classified jointly as aromatic amino acids. In one embodiment, conservative amino acid substitutions include substitutions within the following groups:

[0074] - glycine, alanine; - valine, isoleucine, leucine;

[0075] - aspartic acid, glutamic acid;

[0076] - asparagine, glutamine;

[0077] - serine, threonine;

[0078] - lysine, arginine; and

[0079] - phenylalanine, tyrosine.

[0080] The term "amino acid corresponding to position..." and similar expressions as used herein refer to an amino acid position number in a human IgGl heavy chain. Corresponding amino acid positions in other immunoglobulins may be found by alignment with human IgGl . Thus, an amino acid or segment in one sequence that "corresponds to" an amino acid or segment in another sequence is one that aligns with the other amino acid or segment using a standard sequence alignment program such as ALIGN, ClustalW or similar, typically at default settings and has at least 50%, at least 80%, at least 90%, or at least 95% identity to a human IgGl heavy chain. It is considered well-known in the art how to align a sequence or segment in a sequence and thereby determine the corresponding position in a sequence to an amino acid position according to the present disclosure.

[0081] The term "antibody" (Ab) in the context of the present disclosure refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or a derivative of either thereof, which has the ability to specifically bind to an antigen (in particular an epitope on an antigen) under typical physiological conditions, preferably with a half-life of significant periods of time, such as at least about 30 minutes, at least about 45 minutes, at least about one hour, at least about two hours, at least about four hours, at least about 8 hours, at least about 12 hours, about 24 hours or more, about 48 hours or more, about 3, 4, 5, 6, 7 or more days, etc., or any other relevant functionally-defined period (such as a time sufficient to induce, promote, enhance, and / or modulate a physiological response associated with antibody binding to the antigen and / or time sufficient for the antibody to recruit an effector activity). In particular, the term "antibody" refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. The term "antibody" includes monoclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, chimeric antibodies and combinations of any of the foregoing. Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (CH). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The variable regions and constant regions are also referred to herein as variable domains and constant domains, respectively. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The CDRs of a VH are termed HCDR1, HCDR2, and HCDR3 (or CDR-H1, CDR-H2, and CDR-H3), the CDRs of a VL are termed LCDR1, LCDR2, and LCDR3 (or CDR-L1, CDR-L2, and CDR-L3). The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of an antibody comprise the heavy chain constant region (CH) and the light chain constant region (CL), wherein CH can be further subdivided into constant domain CHI, a hinge region, and constant domains CH2 and CH3 (arranged from amino-terminus to carboxy-terminus in the following order: CHI, CH2, CH3). The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and components of the complement system such as Clq. Antibodies can be intact immunoglobulins derived from natural sources or from recombinant sources and can be immunoactive portions of intact immunoglobulins. Antibodies are typically tetramers of immunoglobulin molecules. Antibodies may exist in a variety of forms including, for example, polyclonal antibodies, monoclonal antibodies, Fv, Fab and F(ab)2, as well as single chain antibodies and humanized antibodies.

[0082] The variable regions of the heavy and light chains of the immunoglobulin molecule contain a binding domain that interacts with an antigen. The terms "binding region" and "antigen-binding region" are used herein interchangeably and refer to the region which interacts with the antigen and comprises both a VH region and a VL region. An antibody as used herein comprises not only monospecific antibodies, but also multispecific antibodies which comprise multiple, such as two or more, e.g., three or more, different antigen-binding regions.

[0083] As indicated above, the term antibody herein, unless otherwise stated or clearly contradicted by context, includes fragments of an antibody that are antigen-binding fragments, z.e., retain the ability to specifically bind to the antigen. It has been shown that the antigen-binding function of an antibody may be performed by fragments of a full-length antibody. Examples of antigen-binding fragments encompassed within the term "antibody" include (i) a Fab’ or Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains, or a monovalent antibody as described in International Publication No. WO 2007 / 059782 (Genmab); (ii) F(ab')2 fragments, bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting essentially of the VH and CHI domains; (iv) a Fv fragment consisting essentially of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment (Ward et al., Nature 341(6242): 544-46 (1989)), which consists essentially of a VH domain and also called domain antibodies (Holt et al., Trends Biotechnol. 21(11): 484-90 (2003)); (vi) camelid or Nanobody molecules (Revets et al., Expert. Opin. Biol. Ther. 5(1): 111-24 (2005)); and (vii) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they may be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain antibodies or single chain Fv (scFv), see for instance Bird et al., Science 242(4877): 423-26 (1988) and Huston et al., Proc. Natl. Acad. Set. U.S.A. 85(16): 5879-83 (1988)). Such single chain antibodies are encompassed within the term antibody unless otherwise noted or clearly indicated by context. Although such fragments are generally included within the meaning of antibody, they collectively and each independently are unique features of the present disclosure, exhibiting different biological properties and utility. These and other useful antibody fragments in the context of the present disclosure, as well as bispecific formats of such fragments, are discussed further herein. It also should be understood that the term antibody, unless specified otherwise, also includes polyclonal antibodies, monoclonal antibodies (mAbs), antibody-like polypeptides, such as chimeric antibodies and humanized antibodies, and antibody fragments retaining the ability to specifically bind to the antigen (antigen-binding fragments) provided by any known technique, such as enzymatic cleavage, peptide synthesis, and recombinant techniques.

[0084] An antibody as generated can possess any isotype. As used herein, the term "isotype" refers to the immunoglobulin class (for instance IgG (such as IgGl, IgG2, IgG3, IgG4), IgD, IgA (such as IgAl, IgA2), IgE, IgM, or IgY) that is encoded by heavy chain constant region genes. When a particular isotype, e.g., IgGl, is mentioned herein, the term is not limited to a specific isotype sequence, e.g., a particular IgGl sequence, but is used to indicate that the antibody is closer in sequence to that isotype, e.g., IgGl, than to other isotypes. Thus, e.g., an IgGl antibody disclosed herein may be a sequence variant of a naturally occurring IgGl antibody, including variations in the constant regions.

[0085] IgGl antibodies can exist in multiple polymorphic variants termed allotypes (reviewed in Jefferis and Lefranc, mAbs 1(4): 332-38 (2009)) any of which are suitable for use in some of the embodiments herein. Common allotypic variants in human populations are those designated by the letters a, f, n, z or combinations thereof. In any of the embodiments herein, the antibody may comprise a heavy chain Fc region comprising a human IgG Fc region. In further embodiments, the human IgG Fc region comprises a human IgGl.

[0086] The term "multispecific antibody" in the context of the present disclosure refers to an antibody having at least two different antigen-binding regions defined by different antibody sequences. In some embodiments, said different antigen-binding regions bind different epitopes on the same antigen. However, in preferred embodiments, said different antigen-binding regions bind different target antigens. In one embodiment, the multispecific antibody is a "bispecific antibody" or "bs". A multispecific antibody, such as a bispecific antibody, can be of any format, including any of the bispecific or multispecific antibody formats described herein below. The term "full-length" when used in the context of an antibody indicates that the antibody is not a fragment, but contains all of the domains of the particular isotype normally found for that isotype in nature, e.g., the VH, CHI, CH2, CH3, hinge, VL and CL domains for an IgGl antibody.

[0087] The term "human antibody", as used herein, is intended to include antibodies having variable and framework regions derived from human germline immunoglobulin sequences and a human immunoglobulin constant domain. The human antibodies disclosed herein may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations, insertions or deletions introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another non-human species, such as a mouse, have been grafted onto human framework sequences.

[0088] The term "chimeric antibody" as used herein, refers to an antibody wherein the variable region is derived from a non-human species (e.g., derived from rodents) and the constant region is derived from a different species, such as human. Chimeric antibodies may be generated by antibody engineering. "Antibody engineering" is a term used generically for different kinds of modifications of antibodies, and processes for antibody engineering are well-known for the skilled person. In particular, a chimeric antibody may be generated by using standard DNA techniques as described in Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Laboratory Press, Ch. 15. Thus, the chimeric antibody may be a genetically or an enzymatically engineered recombinant antibody. It is within the knowledge of the skilled person to generate a chimeric antibody, and thus, generation of the chimeric antibody may be performed by other methods than those described herein. Chimeric monoclonal antibodies for therapeutic applications in humans are developed to reduce anticipated antibody immunogenicity of non-human antibodies, e.g., rodent antibodies. They may typically contain non-human (e.g., murine or rabbit) variable regions, which are specific for the antigen of interest, and human constant antibody heavy and light chain domains. The terms "variable region" or "variable domain" as used in the context of chimeric antibodies, refer to a region which comprises the CDRs and framework regions of both the heavy and light chains of an immunoglobulin, as described below.

[0089] The term "humanized antibody" as used herein, refers to a genetically engineered non-human antibody, which contains human antibody constant domains and non-human variable domains modified to contain a high level of sequence homology to human variable domains. This can be achieved by grafting of the six non-human antibody complementarity-determining regions (CDRs), which together form the antigen binding site, onto a homologous human acceptor framework region (FR) (see International Publication No. WO 92 / 22653 and EP 0 629 240). In order to fully reconstitute the binding affinity and specificity of the parental antibody, the substitution of framework residues from the parental antibody (i.e., the non- human antibody) into the human framework regions (back-mutations) may be required. Structural homology modeling may help to identify the amino acid residues in the framework regions that are important for the binding properties of the antibody. Thus, a humanized antibody may comprise nonhuman CDR sequences, primarily human framework regions optionally comprising one or more amino acid back-mutations to the non-human amino acid sequence, and fully human constant regions. Optionally, additional amino acid modifications, which are not necessarily back-mutations, may be applied to obtain a humanized antibody with preferred characteristics, such as affinity and biochemical properties.

[0090] As used herein, a protein which is "derived from" another protein, e.g., a parent protein, means that one or more amino acid sequences of the protein are identical or similar to one or more amino acid sequences in the other or parent protein. For example, in an antibody, binding arm, antigen-binding region, constant region, or the like which is derived from another or a parent antibody, binding arm, antigen-binding region, or constant region, one or more amino acid sequences are identical or similar to those of the other or parent antibody, binding arm, antigen-binding region, or constant region. Examples of such one or more amino acid sequences include, but are not limited to, those of the VH and VL CDRs and / or one or more or all of the framework regions, VH, VL, CL, hinge, or CH regions. For example, a humanized antibody can be described herein as "derived from" a non-human parent antibody, meaning that at least the VL and VH CDR sequences are identical or similar to the VH and VL CDR sequences of said non- human parent antibody. A chimeric antibody can be described herein as being "derived from" a non- human parent antibody, meaning that typically the VH and VL sequences may be identical or similar to those of the non-human parent antibody. Another example is a binding arm or an antigen-binding region which may be described herein as being "derived from" a particular parent antibody, meaning that said binding arm or antigen-binding region typically comprises identical or similar VH and / or VL CDRs, or VH and / or VL sequences to the binding arm or antigen-binding region of said parent antibody. As described elsewhere herein, however, amino acid modifications such as mutations can be made in the CDRs, constant regions or elsewhere in the antibody, binding arm, antigen-binding region or the like, to introduce desired characteristics. When used in the context of one or more sequences derived from a first or parent protein, a "similar" amino acid sequence preferably has a sequence identity of at least about 50%, such as at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 97%, 98% or 99%.

[0091] Non-human antibodies can be generated in a number of different species, such as mouse, rabbit, chicken, guinea pig, llama and goat.

[0092] Monoclonal antibodies can be produced by a variety of techniques, including conventional monoclonal antibody methodology, e.g., the standard somatic cell hybridization technique of Kohler and Milstein, Nature 256(5517): 495-97 (1975). Other techniques for producing monoclonal antibodies can be employed, e.g., viral or oncogenic transformation of B-lymphocytes or phage display techniques using libraries of antibody genes, and such methods are well known to a person skilled in the art.

[0093] Hybridoma production in such non-human species is a very well-established procedure. Immunization protocols and techniques for isolation of splenocytes of immunized animals / non-human species for fusion are known in the art. Fusion partners (e.g., murine myeloma cells) and fusion procedures are also known.

[0094] When used herein, unless contradicted by context, the term "Fab-arm" or "arm" refers to one heavy chain-light chain pair and is used interchangeably with "half molecules" herein.

[0095] The term "binding arm comprising an antigen-binding region" means an antibody molecule or fragment that comprises an antigen-binding region. Thus, a binding arm can comprise, e.g., the six VH and VL CDR sequences, the VH and VL sequences, a Fab or Fab' fragment, or a Fab-arm.

[0096] When used herein, unless contradicted by context, the term "Fc region" refers to an antibody region consisting of the two Fc sequences of the heavy chains of an immunoglobulin, wherein said Fc sequences comprise at least a hinge region, a CH2 domain, and a CH3 domain. In one embodiment, the term "Fc region", as used herein, refers to a region comprising, in the direction from the N- to C-terminal end of the antibody, at least a hinge region, a CH2 region and a CH3 region. An Fc region of the antibody may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (such as effector cells) and components of the complement system.

[0097] In the context of the present disclosure, the term "induce Fc-mediated effector function to a lesser extent" used in relation to an antibody, including a multispecific antibody, means that the antibody induces Fc- mediated effector functions, such function in particular being selected from the list of IgG Fc receptor (FcgammaR, FcyR) binding, Clq binding, ADCC or CDC, to a lesser extent compared to a human IgGl antibody comprising (i) the same CDR sequences, in particular comprising the same first and second antigen-binding regions, as said antibody and (ii) two heavy chains comprising human IgGl hinge, CH2 and CH3 regions.

[0098] Fc-mediated effector function may be measured by binding to FcyRs, binding to Clq, or induction of Fc-mediated cross-linking via FcyRs.

[0099] The term "hinge region" as used herein refers to the hinge region of an immunoglobulin heavy chain. Thus, for example, the hinge region of a human IgGl antibody corresponds to amino acids 216-230 according to the EU numbering as set forth in Kabat (Kabat et al., Sequences of proteins of immunological interest. 5th Edition - US Department of Health and Human Services, NIH publication No. 91-3242, pp. 662, 680, 689 (1991). However, the hinge region may also be any of the other subtypes as described herein.

[0100] The term "CHI region" or "CHI domain" as used herein refers to the CHI region of an immunoglobulin heavy chain. Thus, for example, the CHI region of a human IgGl antibody corresponds to amino acids 118-215 according to the EU numbering as set forth in Kabat (ibid). However, the CHI region may also be any of the other subtypes as described herein.

[0101] The term "CH2 region" or "CH2 domain" as used herein refers to the CH2 region of an immunoglobulin heavy chain. Thus, for example, the CH2 region of a human IgGl antibody corresponds to amino acids 231-340 according to the EU numbering as set forth in Kabat (ibid). However, the CH2 region may also be any of the other subtypes as described herein.

[0102] The term "CH3 region" or "CH3 domain" as used herein refers to the CH3 region of an immunoglobulin heavy chain. Thus, for example, the CH3 region of a human IgGl antibody corresponds to amino acids 341-447 according to the EU numbering as set forth in Kabat (ibid). However, the CH3 region may also be any of the other subtypes as described herein.

[0103] The term "monovalent antibody" means in the context of the present disclosure that an antibody molecule is capable of binding a single molecule of the antigen, and thus is not capable of antigen crosslinking.

[0104] A "CD137 antibody" or "anti-CD137 antibody" is an antibody as described above, which binds specifically to the antigen CD 137.

[0105] A "CD137xPD-Ll antibody" or "anti-CD137xPD-Ll antibody" is a bispecific antibody, which comprises two different antigen-binding regions, one of which binds specifically to the antigen CD 137 and one of which binds specifically to the antigen PD-L1.

[0106] The term "biosimilar" (e.g., of an approved reference product / biological drug) as used herein refers to a biological product that is similar to the reference product based on data from (a) analytical studies demonstrating that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including the assessment of toxicity); and / or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is approved and intended to be used and for which approval is sought (e.g., that there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product). In some embodiments, the biosimilar biological product and reference product utilizes the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product. In some embodiments, the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product. In some embodiments, the route of administration, the dosage form, and / or the strength of the biological product are the same as those of the reference product. A biosimilar can be, e.g., a presently known antibody having the same primary amino acid sequence as a marketed antibody, but may be made in different cell types or by different production, purification, or formulation methods.

[0107] As used herein, the terms "binding" or "capable of binding" in the context of the binding of an antibody to a predetermined antigen or epitope typically is a binding with an affinity corresponding to a KD of about 10'7M or less, such as about 10'8M or less, such as about 10'9M or less, about IO10M or less, or about 1011M or even less, when determined using Bio-Layer Interferometry (BLI) or, for instance, when determined using surface plasmon resonance (SPR) technology in a BIAcore 3000 instrument using the antigen as the ligand and the antibody as the analyte. The antibody binds to the predetermined antigen with an affinity corresponding to a KD that is at least ten-fold lower, such as at least 100-fold lower, for instance at least 1,000-fold lower, such as at least 10,000-fold lower, for instance at least 100,000-fold lower than its KD for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely related antigen. The amount with which the affinity is higher is dependent on the KD of the antibody, so that when the KD of the antibody is very low (that is, the antibody is highly specific), then the degree to which the affinity for the antigen is lower than the affinity for a non-specific antigen may be at least 10,000-fold.

[0108] The term "kd" (sec1), as used herein, refers to the dissociation rate constant of a particular antibodyantigen interaction. Said value is also referred to as the kOff value.

[0109] The term "KD" (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction.

[0110] Two antibodies have the "same specificity" if they bind to the same antigen and to the same epitope. Whether an antibody to be tested recognizes the same epitope as a certain antigen-binding antibody, z.e., the antibodies bind to the same epitope, may be tested by different methods well known to a person skilled in the art.

[0111] The competition between the antibodies can be detected by a cross-blocking assay. For example, a competitive ELISA assay may be used as a cross-blocking assay, e.g., target antigen may be coated on the wells of a microtiter plate and antigen-binding antibody and candidate competing test antibody may be added. The amount of the antigen-binding antibody bound to the antigen in the well indirectly correlates with the binding ability of the candidate competing test antibody that competes therewith for binding to the same epitope. Specifically, the larger the affinity of the candidate competing test antibody is for the same epitope, the smaller the amount of the antigen-binding antibody bound to the antigen- coated well. The amount of the antigen-binding antibody bound to the well can be measured by labeling the antibody with detectable or measurable labeling substances.

[0112] An antibody competing for binding to an antigen with another antibody, e.g., an antibody comprising heavy and light chain variable regions as described herein, or an antibody having the specificity for an antigen of another antibody, e.g., an antibody comprising heavy and light chain variable regions as described herein, may be an antibody comprising variants of said heavy and / or light chain variable regions as described herein, e.g., modifications in the CDRs and / or a certain degree of identity as described herein.

[0113] An "isolated multispecific antibody" as used herein is intended to refer to a multispecific antibody which is substantially free of other antibodies having different antigenic specificities (for instance an isolated bispecific antibody that specifically binds to CD 137 and PD-L1 is substantially free of monospecific antibodies that specifically bind to CD137 or PD-L1).

[0114] The term "monoclonal antibody" as used herein refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

[0115] When used herein the term "heterodimeric interaction between the first and second CH3 regions" refers to the interaction between the first CH3 region and the second CH3 region in a first-CH3 / second-CH3 heterodimeric antibody.

[0116] When used herein the term "homodimeric interactions of the first and second CH3 regions" refers to the interaction between a first CH3 region and another first CH3 region in a first-CH3 / first-CH3 homodimeric antibody and the interaction between a second CH3 region and another second CH3 region in a second-CH3 / second-CH3 homodimeric antibody. When used herein the term "homodimeric antibody" refers to an antibody comprising two first Fab-arms or half-molecules, wherein the amino acid sequence of said Fab-arms or half-molecules is the same.

[0117] When used herein the term "heterodimeric antibody" refers to an antibody comprising a first and a second Fab-arm or half-molecule, wherein the amino acid sequence of said first and second Fab-arms or half-molecules are different. In particular, the CH3 region, or the antigen-binding region, or the CH3 region and the antigen-binding region of said first and second Fab-arms / half-molecules are different.

[0118] The term "reducing conditions" or "reducing environment" refers to a condition or an environment in which a substrate, such as a cysteine residue in the hinge region of an antibody, is more likely to become reduced than oxidized.

[0119] The present disclosure also describes multispecific antibodies, such as bispecific antibodies, comprising functional variants of the VL regions, VH regions, or one or more CDRs of the bispecific antibodies of the examples. A functional variant of a VL, VH, or CDR used in the context of a bispecific antibody still allows each antigen-binding region of the bispecific antibody to retain at least a substantial proportion (at least about 50%, 60%, 70%, 80%, 90%, 95% or more) of the affinity and / or the specificity / selectivity of the parent bispecific antibody and in some cases such a bispecific antibody may be associated with greater affinity, selectivity and / or specificity than the parent bispecific antibody.

[0120] Such functional variants typically retain significant sequence identity to the parent bispecific antibody. The percent identity between two sequences is a function of the number of identical positions shared by the sequences (i.e. , % 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 Meyers and Miller, Comput. Appl. Biosci. 4(1): 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(3); 444-53 (1970) algorithm.

[0121] In the context of the present disclosure, unless otherwise indicated, the following notations are used to describe a mutation: i) substitution of an amino acid in a given position is written as, e.g., K409R which means a substitution of a lysine in position 409 of the protein with an arginine; and ii) for specific variants the specific three or one letter codes are used, including the codes Xaa and X to indicate any amino acid residue. Thus, the substitution of lysine with arginine in position 409 is designated as: K409R, and the substitution of lysine with any amino acid residue in position 409 is designated as K409X. In case of deletion of lysine in position 409 it is indicated by K409*.

[0122] Exemplary variants include those which differ from the VH and / or VL and / or CDRs of the parent sequences mainly by conservative substitutions; for example, 12, such as 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 of the substitutions in the variant are conservative amino acid residue replacements.

[0123] In the context of the present disclosure, conservative substitutions may be defined by substitutions within the classes of amino acids as defined in Tables 1 and 2.

[0124] The term "CD137" as used herein, refers to CD137 (4-1BB), also referred to as tumor necrosis factor receptor superfamily member 9 (TNFRSF9), which is the receptor for the ligand TNFSF9 / 4-1BBL. CD137 (4-1BB) is believed to be involved in T-cell activation. Other synonyms for CD137 include, but are not limited to, 4- IBB ligand receptor, CDwl37, T-cell antigen 4- IBB homolog and T-cell antigen ILA. In one embodiment, CD137 (4-1BB) is human CD137 (4-1BB), having UniProt accession number Q07011. The sequence of human CD137 is also shown in SEQ ID NO: 19. Amino acids 1-23 of SEQ ID NO: 19 correspond to the signal peptide of human CD137; while amino acids 24-186 of SEQ ID NO: 19 correspond to the extracellular domain of human CD137; and the remainder of the protein, z.e., from amino acids 187-213 and 214-255 of SEQ ID NO: 19 are transmembrane and cytoplasmic domain, respectively.

[0125] 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. The sequence of human PD-1 is also shown in SEQ ID NO: 23. "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.

[0126] 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 nos. NP_054862.I, XP_005581836, XP_003413533, XP_005665023, and NP_068693, respectively), and analogs having at least one common epitope with hPD-Ll. The sequence of human PD-L1 is also shown in SEQ ID NO: 21, wherein amino acids 1-18 are predicted to be a signal peptide. The term "PD-L2" as used herein includes human PD-L2 (hPD-L2), variants, isoforms, and species homologs of hPD-L2, and analogs 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 tumor 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.

[0127] The term "dysfunctional", as used herein, refers to an immune cell that is in a state of reduced immune responsiveness to antigen stimulation. Dysfunctional includes unresponsive to antigen recognition and impaired capacity to translate antigen recognition into downstream T cell effector functions, such as proliferation, cytokine production (e.g., IL-2), and / or target cell killing.

[0128] The term "anergy", as used herein, refers to the state of unresponsiveness to antigen stimulation resulting from incomplete or insufficient signals delivered through the T cell receptor (TCR). T cell anergy can also result upon stimulation with antigen in the absence of co-stimulation, resulting in the cell becoming refractory to subsequent activation by the antigen even in the context of co-stimulation. The unresponsive state can often be overridden by the presence of IL-2. Anergic T cells do not undergo clonal expansion and / or acquire effector functions.

[0129] The term "exhaustion", as used herein, refers to immune cell exhaustion, such as T cell exhaustion as a state of T cell dysfunction that arises from sustained TCR signaling that occurs during many chronic infections and cancer. It is distinguished from anergy in that it arises not through incomplete or deficient signaling, but from sustained signaling. Exhaustion is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of diseases (e.g., infection and tumors). Exhaustion can result from both extrinsic negative regulatory pathways (e.g., immunoregulatory cytokines) as well as cell intrinsic negative regulatory pathways (inhibitory immune checkpoint pathways, such as described herein).

[0130] "Enhancing T cell function" means to induce, cause or stimulate a T cell to have a sustained or amplified biological function, or renew or reactivate exhausted or inactive T cells. Examples of enhancing T cell function include increased secretion of y-interferon from CD8+ T cells, increased proliferation, increased antigen responsiveness (e.g., tumor clearance) relative to such levels before the intervention. In one embodiment, the level of enhancement is as least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 200%, or more. Manners of measuring this enhancement are known to one of ordinary skill in the art.

[0131] The term "inhibitory nucleic acid" or "inhibitory nucleic acid molecule" as used herein refers to a nucleic acid molecule, e.g., DNA or RNA, that totally or partially reduces, inhibits, interferes with or negatively modulates one or more PD-1 proteins. Inhibitory nucleic acid molecules include, without limitation, oligonucleotides, siRNA, shRNA, antisense DNA or RNA molecules, and aptamers (e.g., DNA or RNA aptamers).

[0132] The term "oligonucleotide" as used herein refers to a nucleic acid molecule that is able to decrease protein expression, in particular expression of a PD-1 protein, such as the PD-lproteins described herein. Oligonucleotides are short DNA or RNA molecules, typically comprising from 2 to 50 nucleotides. Oligonucleotides maybe single-stranded or double-stranded. A PD-1 inhibitor oligonucleotide may be an antisense-oligonucleotide.

[0133] Antisense-oligonucleotides are single-stranded DNA or RNA molecules that are complementary to a given sequence, in particular to a sequence of the nucleic acid sequence (or a fragment thereof) of a PD- 1 protein. Antisense RNA is typically used to prevent protein translation of mRNA, e.g., of mRNA encoding a PD-1 protein, by binding to said mRNA. Antisense DNA is typically used to target a specific, complementary (coding or non-coding) RNA. If binding takes place, such a DNA / RNA hybrid can be degraded by the enzyme RNase H. Moreover, morpholino antisense oligonucleotides can be used for gene knockdowns in vertebrates. For example, Kryczek et al., J. Exp. Med. 203(4): 871-81 (2006)) designed B7-H4-specific morpholines that specifically blocked B7-H4 expression in macrophages, resulting in increased T cell proliferation and reduced tumor volumes in mice with tumor associated antigen (TAA)-specific T cells.

[0134] The terms "siRNA" or "small interfering RNA" or "small inhibitory RNA" are used interchangeably herein and refer to a double-stranded RNA molecule with a typical length of 20-25 base pairs that interferes with expression of a specific gene, such as a gene coding for a PD-1 protein, with a complementary nucleotide sequence. In one embodiment, siRNA interferes with mRNA therefore blocking translation, e.g., translation of a PD-1 protein. Transfection of exogenous siRNA may be used for gene knockdown, however, the effect maybe only transient, especially in rapidly dividing cells. Stable transfection may be achieved, e.g., by RNA modification or by using an expression vector. Useful modifications and vectors for stable transfection of cells with siRNA are known in the art. siRNA sequences may also be modified to introduce a short loop between the two strands resulting in a "small hairpin RNA" or "shRNA". shRNA can be processed into a functional siRNA by Dicer. shRNA has a relatively low rate of degradation and turnover. Accordingly, the PD-1 inhibitor may be a shRNA. The term "aptamer" as used herein refers to a single-stranded nucleic acid molecule, such as DNA or RNA, typically in a length of 25-70 nucleotides that is capable of binding to a target molecule, such as a polypeptide. In one embodiment, the aptamer binds to a PD-1 protein such as the PD-1 proteins described herein. For example, an aptamer according to the disclosure can specifically bind to a PD-1 protein or polypeptide, or to a molecule in a signaling pathway that modulates the expression of a PD-1 protein or polypeptide. The generation and therapeutic use of aptamers is well known in the art (see, e.g., U.S. Patent No. 5,475,096).

[0135] The terms "small molecule inhibitor" or "small molecule" are used interchangeably herein and refer to a low molecular weight organic compound, usually up to 1000 Daltons, that totally or partially reduces, inhibits, interferes with, or negatively modulates one or more PD-1 proteins as described above. Such small molecular inhibitors are usually synthesized by organic chemistry, but may also be isolated from natural sources, such as plants, fungi, and microbes. The small molecular weight allows a small molecule inhibitor to rapidly diffuse across cell membranes. For example, various A2AR antagonists known in the art are organic compounds having a molecular weight below 500 Daltons.

[0136] The term "cell based therapy" refers to the transplantation of cells (e.g., T lymphocytes, dendritic cells, or stem cells) into a subject for the purpose of treating a disease or disorder (e.g., a cancer disease).

[0137] The term "oncolytic virus" as used herein, refers to a virus capable of selectively replicating in and slowing the growth or inducing the death of a cancerous or hyperproliferative cell, either in vitro or in vivo, while having no or minimal effect on normal cells. An oncolytic virus for the delivery of a PD-1 inhibitor comprises an expression cassette that may encode a PD-1 inhibitor that is an inhibitory nucleic acid molecule, such as a siRNA, shRNA, an oligonucleotide, antisense DNA or RNA, an aptamer, an antibody or a fragment thereof or a soluble PD-1 protein or fusion. The oncolytic virus preferably is replication competent and the expression cassette is under the control of a viral promoter, e.g., synthetic early / late poxvirus promoter. Exemplary oncolytic viruses include vesicular stomatitis virus (VSV), rhabdoviruses (e.g., picomaviruses such as Seneca Valley virus; SVV-001), coxsackievirus, parvovirus, Newcastle disease virus (NDV), herpes simplex virus (HSV; OncoVEX GMCSF), retroviruses (e.g., influenza viruses), measles virus, reovirus, Sindbis virus, vaccinia virus, as exemplarily described in International Publication No. WO 2017 / 209053 (including Copenhagen, Western Reserve, Wyeth strains), and adenovirus (e.g., Delta-24, Delta-24-RGD, ICOVIR-5, ICOVIR-7, Onyx-015, ColoAdl, H101, AD5 / 3-D24-GMCSF). Generation of recombinant oncolytic viruses comprising a soluble form of a PD-1 inhibitor and methods for their use are disclosed in International Publication No. WO 2018 / 022831, herein incorporated by reference in its entirety. Oncolytic viruses can be used as attenuated viruses. "Treatment cycle" is herein defined as the time period, within the effects of separate dosages of the binding agent add on due to the pharmacodynamics of the binding agent, or in other words the time period after the subject's body is essentially cleared from the administrated binding agent. Multiple small doses in a short time window, e.g., within 2-24 few hours, such as 2-12 hours or on the same day, might be equal to a larger single dose.

[0138] In the present context, the term "treatment", "treating" or "therapeutic intervention" relates to the management and care of a subject for the purpose of combating a condition such as a disease or disorder. The term is intended to include the full spectrum of treatments for a given condition from which the subject is suffering, such as administration of the therapeutically effective compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and / or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of an individual for the purpose of combating the disease, condition or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. In one embodiment, "treatment" refers to the administration of an effective amount of a therapeutically active binding agent, such as of a therapeutically active antibody, of the present disclosure with the purpose of easing, ameliorating, arresting or eradicating (curing) symptoms or disease states.

[0139] The response to treatment as well as the resistance to, failure to respond to and / or relapse from treatment with a binding agent of the present disclosure may be determined according to the Response Evaluation Criteria in Solid Tumors; version 1. 1 (RECIST Criteria vl .1). The RECIST Criteria are set forth in the table below (LD: longest dimension).

[0140] Table 3. Definition of Response (RECIST Criteria vl.l)

[0141] The "best overall response" is the best response recorded from the start of the treatment until disease progression / recurrence (the smallest measurements recorded since the treatment started will be used as the reference for PD). Subjects with CR or PR are considered to have an objective response. Subjects with CR, PR, or SD are considered to be in disease control. Subjects with NE are counted as nonresponders. The best overall response is the best response recorded from the start of the treatment until disease progression / recurrence (the smallest measurements recorded since the treatment started will be used as the reference for PD). Subjects with CR, PR, or SD are considered to be in disease control. Subjects with NE are counted as non-responders.

[0142] "Objective response rate (ORR)" is defined as the proportion of subjects with a confirmed response of PR or CR according to RECIST vl .1 criteria.

[0143] "Disease control rate (DCR)" is defined as the proportion of subjects with SD or a confirmed response of PR or CR according to RECIST vl. 1 criteria.

[0144] "Duration of response (DOR)" only applies to subjects whose confirmed best overall response is CR or PR and is defined as the time from the first documentation of objective tumor response (CR or PR) to the date of first PD or death due to underlying cancer.

[0145] "Progression-free survival (PFS)" is defined as the number of days from Day 1 in Cycle 1 to the first documented progression, preferably radiographic progression, or death due to any cause.

[0146] "Overall survival (OS)" is defined as the number of days from Day 1 in Cycle 1 to death due to any cause. If a subject is not known to have died, then OS will be censored at the latest date the subject was known to be alive (on or before the cut-off date). Time to response (TTR)" is defined as the time from Day 1 in Cycle 1 to onset of response.

[0147] In the context of the present disclosure, the term "treatment regimen" refers to a structured treatment plan designed to improve and maintain health.

[0148] The term "effective amount" or "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount of a binding agent, such as an antibody, like a multispecific antibody or monoclonal antibody, may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the binding 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 binding agent or a fragment thereof, 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. It is a priori unpredictable which dose will have the highest benefit / risk (or benefit vs detrimental effects) ratio and thus be the preferred dose for a treatment with a new drug or combination of drugs, and the present invention discloses surprising results obtained with treatment methods and / or uses according to the invention.

[0149] As used herein, the term "cancer" includes a disease characterized by aberrantly regulated cellular growth, proliferation, differentiation, adhesion, and / or migration. By "cancer cell" is meant an abnormal cell that grows by a rapid, uncontrolled cellular proliferation and continues to grow after the stimuli that initiated the new growth cease.

[0150] The term "cancer" according to the present disclosure also comprises cancer metastases. By "metastasis" is meant the spread of cancer cells from its original site to another part of the body. The formation of metastasis is a very complex process and depends on detachment of malignant cells from the primary tumor, invasion of the extracellular matrix, penetration of the endothelial basement membranes to enter the body cavity and vessels, and then, after being transported by the blood, infiltration of target organs. Finally, the growth of a new tumor, i.e., a secondary tumor or metastatic tumor, at the target site depends on angiogenesis. Tumor metastasis often occurs even after the removal of the primary tumor because tumor cells or components may remain and develop metastatic potential. In one embodiment, the term "metastasis" according to the present disclosure relates to "distant metastasis" which relates to a metastasis which is remote from the primary tumor and the regional lymph node system. Terms such as "reduce", "inhibit", "interfere", and "negatively modulate" as used herein means the ability to cause an overall decrease, for example, of about 5% or greater, about 10% or greater, about 15% or greater, about 20% or greater, about 25% or greater, about 30% or greater, about 40% or greater, about 50% or greater, or about 75% or greater, in the level. The term "inhibit" or similar phrases includes a complete or essentially complete inhibition, z.e., a reduction to zero or essentially to zero.

[0151] Terms such as "increase" or "enhance" in one embodiment relate to an increase or enhancement by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 80%, or at least about 100%.

[0152] "Physiological pH" as used herein refers to a pH of 7.5 or about 7.5.

[0153] As used in the present disclosure, "% by weight" refers to weight percent, which is a unit of concentration measuring the amount of a substance in grams (g) expressed as a percent of the total weight of the total composition in grams (g).

[0154] The term “TPS” or “tumor proportion score,” refers to the percentage of tumor cells expressing PD-L1 on the cell membrane. TPS typically includes the percentage of neoplastic cells expressing PD-L1 at any intensity (weak, moderate, or strong), which can be determined using an immunohistochemical assay using a diagnostic anti-human PD-L1 mAb, e.g., antibody 20C3 and antibody 22C3, described in International Publication No. WO 2014 / 100079. Cells are considered to express PD-L1 if membrane staining is present, including cells with partial membrane staining.

[0155] The term "freezing" relates to the solidification of a liquid, usually with the removal of heat.

[0156] The term "lyophilizing" or "lyophilization" refers to the freeze-drying of a substance by freezing it and then reducing the surrounding pressure (e.g., below 15 Pa, such as below 10 Pa, below 5 Pa, or 1 Pa or less) to allow the frozen medium in the substance to sublimate directly from the solid phase to the gas phase. Thus, the terms "lyophilizing" and "freeze-drying" are used herein interchangeably.

[0157] The term "recombinant" in the context of the present disclosure means "made through genetic engineering". In one embodiment, a "recombinant object" in the context of the present disclosure is not occurring naturally.

[0158] The term "naturally occurring" as used herein refers to the fact that an object can be found in nature. For example, a peptide or nucleic acid that is present in an organism (including viruses) and can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory is naturally occurring. The term "found in nature" means "present in nature" and includes known objects as well as objects that have not yet been discovered and / or isolated from nature, but that may be discovered and / or isolated in the future from a natural source.

[0159] According to the present disclosure, the term "peptide" comprises oligo- and polypeptides and refers to substances which comprise about two or more, about 3 or more, about 4 or more, about 6 or more, about 8 or more, about 10 or more, about 13 or more, about 16 or more, about 20 or more, and up to about 50, about 100 or about 150, consecutive amino acids linked to one another via peptide bonds. The term "protein" refers to large peptides, in particular peptides having at least about 151 amino acids, but the terms "peptide" and "protein" are used herein usually as synonyms.

[0160] A "therapeutic protein" has a positive or advantageous effect on a condition or disease state of a subject when provided to the subject in a therapeutically effective amount. In one embodiment, a therapeutic protein has curative or palliative properties and may be administered to ameliorate, relieve, alleviate, reverse, delay onset of or lessen the severity of one or more symptoms of a disease or disorder. A therapeutic protein may have prophylactic properties and may be used to delay the onset of a disease or to lessen the severity of such disease or pathological condition. The term "therapeutic protein" includes entire proteins or peptides and can also refer to therapeutically active fragments thereof. It can also include therapeutically active variants of a protein. Examples of therapeutically active proteins include, but are not limited to, antigens for vaccination and immunostimulants such as cytokines.

[0161] The term "portion" refers to a fraction. With respect to a particular structure such as an amino acid sequence or protein the term "portion" thereof may designate a continuous or a discontinuous fraction of said structure.

[0162] The terms "part" and "fragment" are used interchangeably herein and refer to a continuous element. For example, a part of a structure such as an amino acid sequence or protein refers to a continuous element of said structure. When used in context of a composition, the term "part" means a portion of the composition. For example, a part of a composition may any portion from 0.1% to 99.9% (such as 0.1%, 0.5%, 1%, 5%, 10%, 50%, 90%, or 99%) of said composition.

[0163] "Fragment", with reference to an amino acid sequence (peptide or protein), relates to a part of an amino acid sequence, z.e., a sequence which represents the amino acid sequence shortened at the N-terminus and / or C-terminus. A fragment shortened at the C-terminus (N-terminal fragment) is obtainable, e.g., by translation of a truncated open reading frame that lacks the 3'-end of the open reading frame. A fragment shortened at the N-terminus (C-terminal fragment) is obtainable, e.g., by translation of a truncated open reading frame that lacks the 5'-end of the open reading frame, as long as the truncated open reading frame comprises a start codon that serves to initiate translation. A fragment of an amino acid sequence comprises, e.g., at least 50 %, at least 60 %, at least 70 %, at least 80%, at least 90% of the amino acid residues from an amino acid sequence. A fragment of an amino acid sequence preferably comprises at least 6, in particular at least 8, at least 12, at least 15, at least 20, at least 30, at least 50, or at least 100 consecutive amino acids from an amino acid sequence.

[0164] According to the present disclosure, a part or fragment of a peptide or protein preferably has at least one functional property of the peptide or protein from which it has been derived. Such functional properties comprise a pharmacological activity, the interaction with other peptides or proteins, an enzymatic activity, the interaction with antibodies, and the selective binding of nucleic acids. E.g., a pharmacological active fragment of a peptide or protein has at least one of the pharmacological activities of the peptide or protein from which the fragment has been derived. A part or fragment of a peptide or protein preferably comprises a sequence of at least 6, in particular at least 8, at least 10, at least 12, at least 15, at least 20, at least 30 or at least 50, consecutive amino acids of the peptide or protein. A part or fragment of a peptide or protein preferably comprises a sequence of up to 8, in particular up to 10, up to 12, up to 15, up to 20, up to 30 or up to 55, consecutive amino acids of the peptide or protein.

[0165] By "variant" herein is meant an amino acid sequence that differs from a parent amino acid sequence by virtue of at least one amino acid modification. The parent amino acid sequence may be a naturally occurring or wild type (WT) amino acid sequence, or may be a modified version of a wild type amino acid sequence. Preferably, the variant amino acid sequence has at least one amino acid modification compared to the parent amino acid sequence, e.g., from 1 to about 20 amino acid modifications, and preferably from 1 to about 10 or from 1 to about 5 amino acid modifications compared to the parent.

[0166] By "wild type" or "WT" or "native" herein is meant an amino acid sequence that is found in nature, including allelic variations. A wild type amino acid sequence, peptide or protein has an amino acid sequence that has not been intentionally modified.

[0167] Preferably the degree of similarity, preferably identity between a given amino acid sequence and an amino acid sequence which is a variant of said given amino acid sequence will be at least about 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. 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: meedle, Matrix: Blosum62, Gap Open 10.0, Gap Extend 0.5.

[0168] "Sequence similarity" indicates the percentage 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.

[0169] 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, Ads App. Math. 2(4): 482-89 (1981), with the aid of the local homology algorithm by Needleman and Wunsch, J. Mol. Biol. 48(3): 443-53 (1970), with the aid of the similarity search algorithm by Pearson and Lipman, Proc. Natl Acad. Sci. U.S.A. 85(8): 2444-48 (1988), 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 Center for Biotechnology Information (NCBI) website (e.g., at blast.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 is 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.

[0170] 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.

[0171] 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.

[0172] The amino acid sequence variants described herein may readily be prepared by the skilled person, for example, by recombinant DNA manipulation. The manipulation of DNA sequences for preparing peptides or proteins having substitutions, additions, insertions or deletions, is described in detail in Sambrook etal. (1989), for example. Furthermore, the peptides and amino acid variants described herein may be readily prepared with the aid of known peptide synthesis techniques such as, for example, by solid phase synthesis and similar methods.

[0173] In one embodiment, a fragment or variant of an amino acid sequence (peptide or protein) is preferably a "functional fragment" or "functional variant". The term "functional fragment" or "functional variant" of an amino acid sequence relates to any fragment or variant exhibiting one or more functional properties identical or similar to those of the amino acid sequence from which it is derived, z.e., it is functionally equivalent. With respect to antigens or antigenic sequences, one particular function is one or more immunogenic activities displayed by the amino acid sequence from which the fragment or variant is derived. The term "functional fragment" or "functional variant", as used herein, in particular refers to a variant molecule or sequence that comprises an amino acid sequence that is altered by one or more amino acids compared to the amino acid sequence of the parent molecule or sequence and that is still capable of fulfilling one or more of the functions of the parent molecule or sequence, e.g., inducing an immune response. In one embodiment, the modifications in the amino acid sequence of the parent molecule or sequence do not significantly affect or alter the characteristics of the molecule or sequence. In different embodiments, the function of the functional fragment or functional variant may be reduced but still significantly present, e.g., immunogenicity of the functional variant may be at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the parent molecule or sequence. However, in other embodiments, immunogenicity of the functional fragment or functional variant may be enhanced compared to the parent molecule or sequence.

[0174] An amino acid sequence (peptide, protein or polypeptide) "derived from" a designated amino acid sequence (peptide, protein or polypeptide) refers to the origin of the first amino acid sequence. Preferably, the amino acid sequence which is derived from a particular amino acid sequence has an amino acid sequence that is identical, essentially identical or homologous to that particular sequence or a fragment thereof. Amino acid sequences derived from a particular amino acid sequence may be variants of that particular sequence or a fragment thereof. For example, it will be understood by one of ordinary skill in the art that the antigens suitable for use herein may be altered such that they vary in sequence from the naturally occurring or native sequences from which they were derived, while retaining the desirable activity of the native sequences.

[0175] "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 binding agent used in the present disclosure is in substantially purified form.

[0176] The term "genetic modification" includes the transfection of cells with nucleic acid. The term "transfection" relates to the introduction of nucleic acids, in particular DNA or RNA, into a cell. For purposes of the present disclosure, the term "transfection" also includes the introduction of a nucleic acid into a cell or the uptake of a nucleic acid by such cell, wherein the cell may be present in a subject, e.g., a patient. Thus, according to the present disclosure, a cell for transfection of a nucleic acid described herein can be present in vitro or in vivo, e.g., the cell can form part of an organ, a tissue and / or an organism of a patient. According to the present disclosure, transfection can be transient or stable. For some applications of transfection, it is sufficient if the transfected genetic material is only transiently expressed. RNA can be transfected into cells to transiently express its coded protein. Since the nucleic acid introduced in the transfection process is usually not integrated into the nuclear genome, the foreign nucleic acid will be diluted through mitosis or degraded. Cells allowing episomal amplification of nucleic acids greatly reduce the rate of dilution. If it is desired that the transfected nucleic acid actually remains in the genome of the cell and its daughter cells, a stable transfection must occur. Such stable transfection can be achieved by using virus-based systems or transposon-based systems for transfection. Generally, nucleic acid encoding antigen is transiently transfected into cells. RNA can be transfected into cells to transiently express its coded protein. According to the present disclosure, an analog of a peptide or protein is a modified form of said peptide or protein from which it has been derived and has at least one functional property of said peptide or protein. E.g., a pharmacological active analog of a peptide or protein has at least one of the pharmacological activities of the peptide or protein from which the analog has been derived. Such modifications include any genetic and / or chemical modification and comprise single or multiple substitutions, deletions and / or additions of any molecules associated with the protein or peptide, such as carbohydrates, lipids and / or proteins or peptides. In one embodiment, "analogs" of proteins or peptides include those modified forms resulting from glycosylation, acetylation, phosphorylation, amidation, palmitoylation, myristoylation, isoprenylation, lipidation, alkylation, derivatization, introduction of protective / blocking groups, proteolytic cleavage or binding to an antibody or to another cellular ligand. The term "analog" also extends to all functional chemical equivalents of said proteins and peptides.

[0177] "Activation" or "stimulation", as used herein, refers to the state of an immune effector cell such as T cell that has been sufficiently stimulated to induce detectable cellular proliferation. Activation can also be associated with initiation of signaling pathways, induced cytokine production, and detectable effector functions. The term "activated immune effector cells" refers to, among other things, immune effector cells that are undergoing cell division.

[0178] The term "priming" refers to a process wherein an immune effector cell such as a T cell has its first contact with its specific antigen and causes differentiation into effector cells such as effector T cells.

[0179] The term "clonal expansion" or "expansion" refers to a process wherein a specific entity is multiplied. In the context of the present disclosure, the term is preferably used in the context of an immunological response in which immune effector cells are stimulated by an antigen, proliferate, and the specific immune effector cell recognizing said antigen is amplified. Preferably, clonal expansion leads to differentiation of the immune effector cells.

[0180] An "antigen" according to the present disclosure covers any substance that will elicit an immune response and / or any substance against which an immune response or an immune mechanism such as a cellular response is directed. This also includes situations wherein the antigen is processed into antigen peptides and an immune response or an immune mechanism is directed against one or more antigen peptides, in particular if presented in the context of MHC molecules. In particular, an "antigen" relates to any substance, preferably a peptide or protein, that reacts specifically with antibodies or T- lymphocytes (T-cells). According to the present disclosure, the term "antigen" comprises any molecule which comprises at least one epitope, such as a T cell epitope. Preferably, an antigen in the context of the present disclosure is a molecule which, optionally after processing, induces an immune reaction, which is preferably specific for the antigen (including cells expressing the antigen). In one embodiment, an antigen is a disease-associated antigen, such as a tumor antigen, a viral antigen, or a bacterial antigen, or an epitope derived from such antigen.

[0181] The term "epitope" refers to an antigenic determinant in a molecule such as an antigen, z.e., to a part in or fragment of the molecule that is recognized by the immune system, for example, that is recognized by antibodies T cells or B cells, in particular when presented in the context of MHC molecules. In one embodiment, "epitope" means a protein determinant capable of specific binding to an antibody. Epitopes usually consist of surface groupings of molecules such as amino acids or sugar side chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents. The epitope may comprise amino acid residues directly involved in the binding and other amino acid residues, which are not directly involved in the binding, such as amino acid residues which are effectively blocked or covered by the specifically antigen-binding peptide (in other words, the amino acid residue is within the footprint of the specifically antigen-binding peptide).

[0182] An epitope of a protein preferably comprises a continuous or discontinuous portion of said protein and is preferably between about 5 and about 100, preferably between about 5 and about 50, more preferably between about 8 and about 0, most preferably between about 10 and about 25 amino acids in length, for example, the epitope may be preferably 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acids in length. It is particularly preferred that the epitope in the context of the present disclosure is a T cell epitope.

[0183] The term "optional" or "optionally" as used herein means that the subsequently described event, circumstance or condition may or may not occur, and that the description includes instances where said event, circumstance, or condition occurs and instances in which it does not occur.

[0184] As used herein, the terms "linked", "fused", or "fusion" are used interchangeably. These terms refer to the joining together of two or more elements or components or domains.

[0185] The term "disease" (also referred to as "disorder" herein) refers to an abnormal condition that affects the body of an individual. A disease is often construed as a medical condition associated with specific symptoms and signs. A disease may be caused by factors originally from an external source, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune diseases. In humans, "disease" is often used more broadly to refer to any condition that causes pain, dysfunction, distress, social problems, or death to the individual afflicted, or similar problems for those in contact with the individual. In this broader sense, it sometimes includes injuries, disabilities, disorders, syndromes, infections, isolated symptoms, deviant behaviors, and atypical variations of structure and function, while in other contexts and for other purposes these may be considered distinguishable categories. Diseases usually affect individuals not only physically, but also emotionally, as contracting and living with many diseases can alter one's perspective on life, and one's personality.

[0186] The term "therapeutic treatment" relates to any treatment which improves the health status and / or prolongs (increases) the lifespan of an individual. Said treatment may eliminate the disease in an individual, arrest or slow the development of a disease in an individual, inhibit or slow the development of a disease in an individual, decrease the frequency or severity of symptoms in an individual, and / or decrease the recurrence in an individual who currently has or who previously has had a disease.

[0187] The terms "prophylactic treatment" or "preventive treatment" relate to any treatment that is intended to prevent a disease from occurring in an individual. The terms "prophylactic treatment" or "preventive treatment" are used herein interchangeably. Similarly, the term "method for preventing" in the context of progression of a disease, such as progression of a tumor or cancer, relates to any method that is intended to prevent the disease from progressing in an individual.

[0188] The terms "individual" and "subject" are used herein interchangeably. They refer to a human or another mammal (e.g., mouse, rat, rabbit, dog, cat, cattle, swine, sheep, horse or primate), or any other nonmammal-animal, including birds (chicken), fish or any other animal species that can be afflicted with or is susceptible to a disease or disorder (e.g., cancer). Unless otherwise stated, the terms "individual" and "subject" do not denote a particular age, and thus encompass adults, elderlies, children, and newborns. In embodiments of the present disclosure, the "individual" or "subject" is a "patient".

[0189] The term "patient" means an individual or subject for treatment, in particular a diseased individual or subject.

[0190] The term "adverse event" as used herein, refers to any untoward medical occurrence in a patient or clinical trial subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. AEs (including laboratory abnormalities that constitute AEs) can be described using a diagnosis whenever possible, rather than individual underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be reported as a separate AE. Toxicities can be graded for severity according to the National Cancer Institute CTCAE, v5.0, with the exception of CRS which can be graded according to the ASTCT criteria described by (Lee et al., Biol. Blood Marrow Transplant 25(4): 625-38 (2019)). The trial investigator can assess whether or not the adverse event is related to the trial drug.

[0191] Aspects and embodiments of the present disclosure

[0192] In a first aspect, the present disclosure provides a method for treating non-small cell lung cancer (NSCLC) in a human subject, said method comprising administering to said human subject a bispecific antibody and a PD-1 antagonist. The bispecific antibody comprises a first binding region binding to CD 137 and a second binding region binding to PD-L1; the first binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, GAS, and SEQ ID NO: 7, respectively; and the second antigenbinding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 13, DDN, and SEQ ID NO: 14, respectively. The PD-1 antagonist is an anti-PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 33, 34 and 35, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37, and 38, respectively.

[0193] Bispecific antibody binding to CD 137 and PD-L1

[0194] In one embodiment, CD 137 is human CD 137, in particular human CD 137 comprising the sequence set forth in SEQ ID NO: 20. In one embodiment, PD-L1 is human PD-L1, in particular human PD-L1 comprising the sequence set forth in SEQ ID NO: 22. In one embodiment, CD137 is human CD137 and PD-L1 is human PD-L1. In one embodiment, CD 137 is human CD 137 comprising the sequence set forth in SEQ ID NO: 20, and PD-L1 is human PD-L1 comprising the sequence set forth in SEQ ID NO: 22.

[0195] In one embodiment of the bispecific antibody according to the first aspect, the first binding region binding to human CD137 comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO: 1 and a light chain variable region (VL) region and comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO: 5.

[0196] In further embodiment of the bispecific antibody according to the first aspect, the second binding region binding to human PD-L1 comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO: 8 and a light chain variable region (VL) region comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO: 12.

[0197] In one embodiment of the bispecific antibody according to the first aspect, a) the first binding region binding to human CD 137 comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO: 1 and a light chain variable region (VL) region and comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO: 5; and b) the second binding region binding to human PD-L1 comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO: 8 and a light chain variable region (VL) region comprising an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO: 12.

[0198] In one embodiment of the bispecific antibody according to the first aspect, the first binding region binding to human CD137 comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 5.

[0199] In a further embodiment of the bispecific antibody according to the first aspect, the second binding region binding to human PD-L1 comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 8 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 12.

[0200] In one embodiment of the bispecific antibody according to the first aspect, a) the first binding region binding to human CD 137 comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 5; and b) the second binding region binding to human PD-L1 comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 8 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 12.

[0201] The bispecific antibody may be in the format of a full-length antibody or an antibody fragment, preferably a full-length antibody. It is further preferred that the bispecific antibody is a human antibody or a humanized antibody.

[0202] The bispecific antibody according to the first aspect is of an isotype selected from the group consisting of IgGl, IgG2, IgG3, and IgG4. In particular, the bispecific antibody may be a full-length IgGl antibody. In preferred embodiments of the first aspect, the bispecific antibody (in particular, antibody) is of the IgGlm(f) allotype.

[0203] In a preferred embodiment of the bispecific antibody according to the first aspect, the bispecific antibody comprises a first heavy chain and light chain comprising said first binding region binding to CD 137, wherein the first heavy chain comprising the sequence set forth in SEQ ID NO: 15, and the first light chain comprising the sequence set forth in SEQ ID NO: 16; and a second heavy chain and light chain comprising said second binding region binding to PD-L1, wherein the second heavy chain comprising the sequence set forth in SEQ ID NO: 17, and the second light chain comprising the sequence set forth in SEQ ID NO: 18.

[0204] The bispecific antibody according to the first aspect may in particular be acasunlimab or a biosimilar thereof. In a preferred embodiment, the bispecific antibody is acasunlimab. In one embodiment, the bispecific antibody is an acasunlimab biosimilar. Acasunlimab is previously known as GEN 1046 or BNT311.

[0205] In some embodiments, the amount of bispecific antibody administered in each dose and / or in each treatment cycle is a) about 0.3-5 mg / kg body weight or about 25-400 mg in total; and / or b) about 2.1 x 10'9- 3.4 x IO-8mol / kg body weight or about 1.7 x 10'7- 2.7 x 10'6mol in total.

[0206] According to these embodiments, the dose defined in mg / kg may be converted to flat dose, and vice versa, based on the median body weight of the subjects to whom the bispecific antibody is administered being 80 kg.

[0207] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be about 0.3-4.0 mg / kg body weight or about 25-320 mg in total; and / or about 2.1 x 10'9- 2.7 x 10'8mol / kg body weight or about 1.7 x 10'7- 2.2 x 10'6mol in total.

[0208] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be about 0.38-4.0 mg / kg body weight or about 30-320 mg in total; and / or about 2.6 x 10'9- 2.7 x 10'8mol / kg body weight or about 2.4 x 10'7- 2.2 x 10'6mol in total.

[0209] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be about 0.5-3.3 mg / kg body weight or about 40-260 mg in total; and / or about 3.4 x 10'9- 2.2 x 10'8mol / kg body weight or about 2.7 x 10'7- 1.8 x 10'6mol in total. The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be about 0.6-2.5 mg / kg body weight or about 50-200 mg in total; and / or about 4.3 x 10'9- 1.7 x IO-8mol / kg body weight or about 3.4 x 10'7- 1.4 x 10'6mol in total.

[0210] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be about 0.8-1.8 mg / kg body weight or about 60-140 mg in total; and / or about 5.1 x 10'9- 1.2 x 10'8mol / kg body weight or about 4.1 x 10'7- 9.5 x 10'7mol in total.

[0211] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be about 0.9-1.8 mg / kg body weight or about 70-140 mg in total; and / or about 6.0 x 10'9- 1.2 x 10'8mol / kg body weight or about 4.8 x 10'7- 9.5 x 10'7mol in total.

[0212] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be about 1-1.5 mg / kg body weight or about 80-120 mg in total; and / or about 6.8 x 10'9- 1.0 x 10'8mol / kg body weight or about 5.5 x 10'7- 8.2 x 10'7mol in total.

[0213] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be about 1.1-1.4 mg / kg body weight or about 90-110 mg in total; and / or about 7.7 x 10'9- 9.4 x 10'9mol / kg body weight or about 6.1 x 10'7- 7.5 x 10'7mol in total.

[0214] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be about 1.2-1.3 mg / kg body weight or about 95-105 mg in total; and / or about 6.8 x 10'9- 8.9 x 10'9mol / kg body weight or about 6.5 x 10'7- 7.2 x 10'7mol in total.

[0215] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be about 0.8-1.5 mg / kg body weight or about 65-120 mg in total; and / or about 5.5 x 10'9- 1.0 x 10'8mol / kg body weight or about 4.4 x 10'7- 8.2 x 10'7mol in total.

[0216] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be about 0.9-1.3 mg / kg body weight or about 70-100 mg in total; and / or about 6.0 x 10'9- 8.5 x 10'9mol / kg body weight or about 4.8 x 10'7- 6.8 x 10'7mol in total. about 0.9-1.1 mg / kg body weight or about 75-90 mg in total; and / or about 6.4 x 10'9- 7.7 x 10'9mol / kg body weight or about 5.1 x 10'7- 6.1 x 10'7mol in total.

[0217] Further, the amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be 0.3-4.0 mg / kg body weight or 25-320 mg in total; and / or

[0218] 2.1 x 10'9- 2.7 x 10'8mol / kg body weight or 1.7 x 10'7- 2.2 x 10'6mol in total.

[0219] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be 0.38-4.0 mg / kg body weight or 30-320 mg in total; and / or

[0220] 2.6 x 10'9- 2.7 x 10'8mol / kg body weight or 2.4 x 10'7- 2.2 x 10'6mol in total.

[0221] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be 0.5-3.3 mg / kg body weight or 40-260 mg in total; and / or

[0222] 3.4 x 10'9- 2.2 x 10'8mol / kg body weight or 2.7 x 10'7- 1.8 x 10'6mol in total.

[0223] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be 0.6-2.5 mg / kg body weight or 50-200 mg in total; and / or 4.3 x 10'9- 1.7 x IO-8mol / kg body weight or 3.4 x 10'7- 1.4 x 10'6mol in total.

[0224] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be 0.8-1.8 mg / kg body weight or 60-140 mg in total; and / or

[0225] 5.1 x 10'9- 1.2 x 10'8mol / kg body weight or 4.1 x 10'7- 9.5 x 10'7mol in total.

[0226] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be 0.9-1.8 mg / kg body weight or 70-140 mg in total; and / or

[0227] 6.0 x 10'9- 1.2 x 10'8mol / kg body weight or 4.8 x 10'7- 9.5 x 10'7mol in total.

[0228] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be 1-1.5 mg / kg body weight or 80-120 mg in total; and / or

[0229] 6.8 x 10'9- 1.0 x 10'8mol / kg body weight or 5.5 x 10'7- 8.2 x 10'7mol in total.

[0230] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be 1. 1-1.4 mg / kg body weight or 90-110 mg in total; and / or

[0231] 7.7 x 10'9- 9.4 x 10'9mol / kg body weight or 6.1 x 10'7- 7.5 x 10'7mol in total.

[0232] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be 1.2-1.3 mg / kg body weight or 95-105 mg in total; and / or

[0233] 6.8 x 10'9- 8.9 x 10'9mol / kg body weight or 6.5 x 10'7- 7.2 x 10'7mol in total.

[0234] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be 0,8-1.5 mg / kg body weight or 65-120 mg in total; and / or

[0235] 5.5 x 10'9- 1.0 x 10'8mol / kg body weight or 4.4 x 10'7- 8.2 x 10'7mol in total.

[0236] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be 0.9-1.3 mg / kg body weight or 70-100 mg in total; and / or

[0237] 6.0 x 10'9- 8.5 x 10'9mol / kg body weight or 4.8 x 10'7- 6.8 x 10'7mol in total.

[0238] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may in particular be 0.9- 1.1 mg / kg body weight or 75-90 mg in total; and / or

[0239] 6.4 x 10'9- 7.7 x 10'9mol / kg body weight or 5.1 x 10'7- 6.1 x 10'7mol in total.

[0240] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may be a) about 1.1 mg / kg body weight or about 80 mg in total; and / or b) about 6.8 x 10'9mol / kg body weight or about 5.5 x 10'7mol in total.

[0241] The amount of bispecific antibody administered in each dose and / or in each treatment cycle may be a) 1.1 mg / kg body weight or 80 mg in total; and / or b) 6.8 x 10'9mol / kg body weight or 5.5 x 10'7mol in total.

[0242] It is currently preferred that the amount of bispecific antibody administered in each dose and / or in each treatment cycle is a) about 1.25 mg / kg body weight or about 100 mg in total; and / or b) about 8.5 x 10'9mol / kg body weight or about 6.8 x 10'7mol in total.

[0243] It is equally preferred that the amount of bispecific antibody administered in each dose and / or in each treatment cycle is a) 1.25 mg / kg body weight or 100 mg in total; and / or b) 8.5 x 10'9mol / kg body weight or 6.8 x 10'7mol in total.

[0244] The bispecific antibody may be administered in any manner and by any route known in the art. In a preferred embodiment, the bispecific antibody is administered systemically, such as parenterally, in particular intravenously.

[0245] The bispecific antibody may be administered in the form of any suitable pharmaceutical composition as described herein. In a preferred embodiment, the bispecific antibody is administered in the form of an infusion.

[0246] The bispecific antibody according to the invention may be administered by using intravenous (IV) infusion, such as by intravenous infusion over a minimum of 30 minutes, such as over a minimum of 60 minutes e.g., by using intravenous infusion over 30 to 120 minutes. Preferably, the bispecific antibody according to the invention is administered by using intravenous (IV) infusion over 30 minutes.

[0247] The bispecific antibody can be administered prior to, simultaneously with, or after administration of the PD-1 antagonist.

[0248] In one embodiment, the bispecific antibody is administered prior to the administration of the PD-1 antagonist. For example, the gap between the end of the administration of the bispecific antibody and the beginning of the administration of the PD-1 antagonist can be at least about 10 minutes, such as at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes, and / or up to about 14 days (up to about 2 weeks), such as up to about 13 days, up to about 12 days, up to about 11 days, up to about 10 days, up to about 9 days, up to about 8 days, up to about 7 days (up to about 1 week), up to about 6 days, up to about 5 days, up to about 4 days, up to about 3 days, up to about 2 days, up to about 1 day (up to about 24 hours), up to about 18 hours, up to about 12 hours, up to about 6 hours, up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2.5 hours, or up to about 2 hours.

[0249] In one embodiment, the bispecific antibody is administered after the administration of the PD-1 antagonist. For example, the gap between the end of the administration of the PD-1 antagonist and the beginning of the administration of the bispecific antibody can be at least about 10 minutes, such as at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes, and / or up to about 14 days (up to about 2 weeks), such as up to about 13 days, up to about 12 days, up to about 11 days, up to about 10 days, up to about 9 days, up to about 8 days, up to about 7 days (up to about 1 week), up to about 6 days, up to about 5 days, up to about 4 days, up to about 3 days, up to about 2 days, up to about 1 day (up to about 24 hours), up to about 18 hours, up to about 12 hours, up to about 6 hours, up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2.5 hours, or up to about 2 hours. Preferably, the bispecific antibody according to the invention is administered after the administration of the PD-1 antagonist, and the time gap between the end of the administration of the PD-1 antagonist and the beginning of the administration of the bispecific antibody is approximately 30 minutes or longer.

[0250] In one embodiment, the bispecific antibody is administered simultaneously with the PD-1 antagonist. For example, the bispecific antibody and the PD-1 antagonist may be administered using a composition comprising both drugs. Alternatively, the bispecific antibody may be administered into one extremity of the subject, and the PD-1 antagonist may be administered into another extremity of the subject.

[0251] PD-1 antagonist

[0252] The PD-1 antagonist preferably comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity, such as at least 90% sequence identity, 95% sequence identity, 98% sequence identity, or 99% sequence identity, to the amino acid sequence of SEQ ID NO: 29 and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity, such as at least 90% sequence identity, 95% sequence identity, 98% sequence identity, or 99% sequence identity, to the amino acid sequence of SEQ ID NO: 30.

[0253] In a preferred embodiment, the PD-1 antagonist comprises a heavy chain variable region comprising, consisting of or consisting essentially of the amino acid sequence of SEQ ID NO: 29 and a light chain variable region comprising, consisting of or consisting essentially of the amino acid sequence of SEQ ID NO: 30.

[0254] The PD-1 antagonist may comprise a heavy chain comprising, consisting of or consisting essentially of the amino acid sequence of SEQ ID NO: 31 and a light chain comprising, consisting of or consisting essentially of the amino acid sequence of SEQ ID NO: 32.

[0255] The PD-1 antagonist used according to the present invention preferably prevents inhibitory signals associated with PD-1. The PD-1 antagonist preferably disrupts or inhibits inhibitory signaling associated with PD-1. Inhibiting or blocking of PD-1 signaling, as described herein, results in preventing or reversing immune- suppression and establishment or enhancement of T cell immunity against cancer cells. In one embodiment, inhibition of PD-1 signaling, as described herein, reduces or inhibits dysfunction of the immune system. In one embodiment, inhibition of PD-1 signaling, as described herein, renders dysfunctional immune cells less dysfunctional. In one embodiment, inhibition of PD-1 signaling, as described herein, renders a dysfunctional T cell less dysfunctional.

[0256] In one embodiment, the PD-1 antagonist prevents the interaction between PD-1 and PD-L1. In another embodiment, the PD-1 antagonist prevents the interaction between PD-1 and PD-L2.

[0257] The PD-1 antagonist may be in the format of a full-length antibody or an antibody fragment, preferably a full-length antibody.

[0258] In particular, the PD-1 antagonist is a chimerized, humanized or human antibody.

[0259] The PD-1 antagonist may in particular be pembrolizumab or a biosimilar thereof. In a preferred embodiment, the PD-1 antagonist is pembrolizumab. In one embodiment, the PD-1 antagonist is a pembrolizumab biosimilar.

[0260] In some embodiments, numbering of amino acid residues in CDR sequences of the PD-1 antagonist provided herein are according to the IMGT numbering scheme as described in Lefranc et al., Dev. Comp. Immunol. 27(1): 55-77 (2003). In these embodiments, the PD-1 antagonist is an anti-PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 24, 25 and 26, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 27, LAS and SEQ ID NO: 28, respectively.

[0261] In certain embodiments, the PD-1 antagonist is pembrolizumab and the amount of PD-1 antagonist administered, e.g., in each dose and / or in each treatment cycle, is about 10 - about 1000 mg in total such as about 100 - about 600 mg in total, e.g., about 150 - about 600 mg in total, about 150 - about 500 mg in total, about 175 - about 500 mg in total, about 175 - about 450 mg in total, about 200 - about 450 mg in total or such as about 200 - about 400 mg in total.

[0262] In certain embodiments, the PD-1 antagonist is pembrolizumab and the amount of PD-1 antagonist administered, e.g., in each dose and / or in each treatment cycle, is 10 - 1000 mg in total such as 100 - 600 mg in total, e.g., 150 - 600 mg in total, 150 - 500 mg in total, 175 - 500 mg in total, 175 - 450 mg in total, 200 - 450 mg in total or such as 200 - 400 mg in total. In certain embodiments, the PD-1 antagonist is pembrolizumab and the amount of PD-1 antagonist administered, e.g., in each dose and / or in each treatment cycle, is about 100 - 600 mg in total; and / or about 6.84 x 10'7- 4.11 x 10'7mol in total.

[0263] In certain embodiments, the PD-1 antagonist is pembrolizumab and the amount of PD-1 antagonist administered, e.g., in each dose and / or in each treatment cycle, is about 100 - 400 mg in total; and / or about 6.84 x 10'7- 2.73 x 10'6mol in total, such as 100 - 400 mg in total; and / or 6.84 x 10'7- 2.73 x 10"6mol in total.

[0264] In certain embodiments, the PD-1 antagonist is pembrolizumab and the amount of PD-1 antagonist administered, e.g., in each dose and / or in each treatment cycle, is about 200 - 400 mg in total; and / or about 6.84 x 10'7- 2.73 x 10'6mol in total, such as 200 - 400 mg in total; and / or 6.84 x 10'7- 2.73 x 10"6mol in total.

[0265] In certain embodiments, the amount of PD-1 antagonist administered, e.g., in each dose and / or in each treatment cycle, is about 200 mg or about 1.37 x 10'6mol in total, such as 200 mg or 1.37 x 10'6mol in total.

[0266] In certain embodiments, the PD-1 antagonist is pembrolizumab and the amount of PD-1 antagonist administered, e.g., in each dose and / or in each treatment cycle, is about 200 mg or about 1.37 x IO6mol in total, such as 200 mg or 1.37 x 10'6mol in total.

[0267] In certain embodiments, the amount of PD-1 antagonist administered, e.g., in each dose and / or in each treatment cycle, is about 400 mg in total or about 2.73 x 10'6in total, such as 400 mg in total or 2.73 x 10'6in total.

[0268] In certain embodiments, the PD-1 antagonist is pembrolizumab and the amount of PD-1 antagonist administered, e.g., in each dose and / or in each treatment cycle, is about 400 mg in total or about 2.73 x 10'6in total, such as 400 mg in total or 2.73 x 10'6in total.

[0269] The PD-1 antagonist may be administered in any manner and by any route known in the art. The mode and route of administration will depend on the type of antibody to be used. In a preferred embodiment, the PD-1 antagonist is administered systemically, such as parenterally, in particular intravenously. The PD-1 antagonist or may be administered in the form of any suitable pharmaceutical composition as described herein. In a preferred embodiment, the PD-1 antagonist is administered in the form of an infusion, such as an intravenous infusion.

[0270] Subject and cancer to be treated

[0271] The subject to be treated according to the present disclosure is a human subject.

[0272] The cancer to be treated according to the present disclosure is NSCLC, such as squamous or non- squamous NSCLC. The cancer may in particular be a metastatic cancer, such as metastatic NSCLC. In certain embodiments, the cancer is a histologically or cytologically confirmed stage 4 NSCLC.

[0273] Preferably, the cancer is PD-L1 positive. In certain embodiments, it is preferred that PD-L1 is expressed in >1% of the cancer cells or tumor cells. In a particular embodiment, the human subject has a tumor with PD-L1 expressed in > 1% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (TPS) > 1%. In one embodiment, the human subject has a tumor with PD-L1 expressed in > 1% and < 49% of the cancer or tumor cells, such as a tumor with a TPS > 1 and < 49%. In one embodiment, the human subject has a tumor with PD-L1 expressed in > 50% of the cancer or tumor cells, such as a tumor with a TPS > 50%. Such expression may be determined by any means and method known to the skilled person, such as by immunohistochemistry (IHC), such as determined by a local SOC testing (preferably an FDA-approved test) or at a central laboratory. In one embodiment, the expression of PD- L1 is measured using the Dako PD-L1 IHC 22C3 pharmDx assay. In one embodiment, the expression of PD-L1 is measured using VENTANA PD-L1 (SP263) assay.

[0274] In certain embodiments, the human subject may have received at least 1 prior line of systemic therapy, such as systemic therapy comprising a PD-1 inhibitor and / or a PD-L1 inhibitor, such as an anti-PD-1 antibody and / or an anti-PD-Ll antibody. In certain embodiments, the cancer may in particular have relapsed and / or is refractory after prior treatment of a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti PD-1 antibody or an anti-PD-Ll antibody. In certain embodiments, the human subject may in particular have demonstrated disease progression (PD), such as PD defined by RECIST vl. 1, after prior treatment of a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti PD-1 antibody or an anti-PD-Ll antibody. In certain embodiments, the PD-1 inhibitor or PD-L1 inhibitor may have been administered as monotherapy or as part of a combination therapy.

[0275] In particular embodiments the treatment according to the invention is provided to a human subject having received prior treatment; e.g. as defined above, wherein the last prior treatment was with a PD- 1 inhibitor or PD-L1 inhibitor, such as an anti PD-1 antibody or an anti-PD-Ll antibody, the PD-1 inhibitor or PD-L1 inhibitor being administered as monotherapy or as part of a combination therapy. The last prior treatment may be with a PD-1 inhibitor or PD-L1 inhibitor defined above.

[0276] Preferably, the therapy according to the invention is provided to a human subject when the time from progression of that subject on last treatment with a PD-1 inhibitor or PD-L1 inhibitor, such as an anti PD-1 antibody or an anti-PD-Ll antibody is 8 months or less, such as 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, 1 month or less, 3 weeks or less, or such as 2 weeks or less.

[0277] By analogy, it may be preferred to offer therapy according to the present invention to a human subjects when the time from last dosing of a PD-1 inhibitor or PD-L1 inhibitor, such as an anti PD-1 antibody or an anti-PD-Ll antibody as part of last prior treatment is 8 months or less, such as 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, 1 month or less, 3 weeks or less, or such as 2 weeks or less.

[0278] In further embodiments the cancer has relapsed and / or is refractory, or the subject has progressed during or after prior standard-of-care (SOC) treatment for metastatic NSCLC, such as a combination of a checkpoint inhibitor (CPI, such as a PD-1 inhibitor or a PD-L1 inhibitor) and a platinum-based chemotherapy. The PD-1 (or PD-L1) inhibitor and the platinum-based chemotherapy may be administrated concomitantly, or the PD-1 (or PD-L1) inhibitor and the platinum-based chemotherapy may be administrated sequentially, irrespective of the order.

[0279] In further embodiments the cancer has relapsed and / or is refractory, or the subject has progressed during or after i) platinum doublet chemotherapy following treatment with an anti-PD-1 antibody or an anti- PD-Ll antibody, or ii) treatment with an anti-PD-1 antibody or an anti-PD-Ll antibody following platinum doublet chemotherapy.

[0280] In certain embodiments, the human subject has had at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or preferably 6 weeks of prior treatment comprising a PD-1 inhibitor or a PD-L1 inhibitor. Preferably, said human subject has had clinical benefit, such as defined as documented radiographic stable disease (SD) or better, on said prior treatment comprising a PD-1 inhibitor or a PD-L1 inhibitor

[0281] In a particular embodiment, the human subject has a tumor with PD-L1 expressed in > 1% of the cancer or tumor cells, such as a tumor with a TPS > 1%; the human subject has received at least 1 prior line of systemic therapy comprising a PD-1 inhibitor and / or a PD-L1 inhibitor, such as an anti-PD-1 antibody and / or an anti-PD-Ll antibody; and the cancer has relapsed and / or is refractory, or said human subject has demonstrated disease progression, after prior treatment of a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti PD-1 antibody or an anti-PD-Ll antibody.

[0282] In a particular embodiment, the human subject has a PD-L1 positive tumor or a tumor with PD-L1 expressed in > 1% of the cancer or tumor cells, such as a tumor with a TPS > 1%, and the cancer has relapsed and / or is refractory, or the subject has progressed during or after prior standard-of-care (SOC) treatment for metastatic NSCLC, such as a combination of a checkpoint inhibitor (CPI, such as a PD-1 inhibitor or a PD-L1 inhibitor) and a platinum-based chemotherapy. The PD-1 (or PD-L1) inhibitor and the platinum-based chemotherapy may be administrated concomitantly, or the PD-1 (or PD-L1) inhibitor and the platinum-based chemotherapy may be administrated sequentially, irrespective of the order.

[0283] In further embodiments, the human subject has Eastern Cooperative Oncology Group (ECOG) performance status (PS) <1.

[0284] In further embodiments, the human subject has not received prior treatment with a 4- IBB (CD 137) targeting agent, such as an anti-4-lBB (CD137) antibody, with an antitumor vaccine, or with autologous cell immunotherapy.

[0285] In further embodiments, the human subject has a tumor that does not have, or the tumor has not been analyzed as having, the following alterations: (a) an EGFR sensitizing mutation, (b) a KRAS mutation, (c) a RET mutation, (d) a ROS1 mutation, (e) a BRAF mutation, (f) a NTRK gene infusion, (g) a RET rearrangement, (h) an ALK gene rearrangement, (i) a high-level MET amplification, (j) METex 14 skipping, or any combination thereof. In some embodiments, the human subject has a tumor that does not have an EGFR sensitizing mutation. In some embodiments, the human subject has a tumor that does not have a KRAS mutation. In some embodiments, the human subject has a tumor that does not have a RET mutation. In some embodiments, the human subject has a tumor that does not have a ROS1 mutation. In some embodiments, the human subject has a tumor that does not have a BRAF mutation. In some embodiments, the human subject has a tumor that does not have a NTRK gene infusion. In some embodiments, the human subject has a tumor that does not have a RET rearrangement. In some embodiments, the human subject has a tumor that does not have an ALK gene rearrangement. In some embodiments, the human subject has a tumor that does not have high-level a MET amplification. In some embodiments, the human subject has a tumor that does not have METex 14 skipping.

[0286] In further embodiments, the human subject has not received prior treatment with a taxane chemotherapeutic agent e.g., docetaxel, such as prior treatment for NSCLC with a taxane chemotherapeutic agent e.g., docetaxel. Treatment regimen

[0287] The bispecific antibody and the PD-1 antagonist can be administered by any suitable way, such as intravenously, intraarterially, subcutaneously, intradermally, intramuscularly, intranodally, or intratumorally.

[0288] In one embodiment of the first aspect, the bispecific antibody defined above is administered to the subject by systemic administration. Preferably, the bispecific antibody is administered to the subject by intravenous injection or infusion. In one embodiment, the bispecific antibody is administered in at least one treatment cycle.

[0289] In one embodiment, the PD-1 antagonist is in particular administered to the subject by systemic administration. Preferably, the PD-1 antagonist is administered to the subject by intravenous injection or infusion. In one embodiment, the PD-1 antagonist is administered in at least one treatment cycle.

[0290] In one embodiment, the bispecific antibody defined above and the PD-1 antagonist are in particular administered to the subject by systemic administration. Preferably, the bispecific antibody and the PD- 1 antagonist are administered to the subject by intravenous injection or infusion. In one embodiment, the bispecific antibody and the PD-1 antagonist are administered in at least one treatment cycle.

[0291] In one embodiment, each treatment cycle is about two weeks (14 days), three weeks (21 days), four weeks (28 days), five weeks (35 days), or 6 weeks (48 days). In preferred embodiments each treatment cycle is three weeks (21 days). In other preferred embodiments, each treatment cycle is 6 weeks (48 days).

[0292] In particular embodiments, one dose of the bispecific antibody defined above and one dose of the PD-1 antagonist are administered or infused every second week (Q2W), every third week (Q3W), every fourth week (Q4W), every fifth week (Q5W), or every sixth week (Q6W), preferably every third week (Q3W), or every sixth week (Q6W). In a preferred embodiment, one dose of the bispecific antibody defined above and one dose of the PD-1 antagonist are administered every six weeks (Q6W). The amount of bispecific antibody and the amount of PD-1 antagonist are preferably as defined above.

[0293] In some embodiments, one dose or each dose is administered or infused on day 1 of each treatment cycle. For example, one dose of the bispecific antibody defined above and one dose of the PD-1 antagonist may be administered on day 1 of each treatment cycle.

[0294] In some embodiments, an approximate 100 mg dose of the bispecific antibody defined above and an approximate 200 mg dose of the PD-1 antagonist are administered every three weeks (Q3W). In other embodiments, an approximate 100 mg dose of the bispecific antibody defined above and an approximate 400 mg dose of the PD-1 antagonist are administered every six weeks (Q6W).

[0295] In particular embodiments, an approximate 100 mg dose of acasunlimab or a biosimilar thereof and an approximate 200 mg dose of pembrolizumab or a biosimilar thereof, are administered every three weeks (Q3W), such as on day one of each three-week treatment cycle.

[0296] In particular embodiments, an approximate 100 mg dose of acasunlimab or a biosimilar thereof and an approximate 400 mg dose of pembrolizumab or a biosimilar thereof, are administered every six weeks (Q6W), such as on day one of each six- week treatment cycle.

[0297] In particular embodiments, a 100 mg dose of acasunlimab or a biosimilar thereof and a 200 mg dose of pembrolizumab or a biosimilar thereof, are administered every three weeks (Q3W), such as on day one of each three-week treatment cycle.

[0298] In particular embodiments, a 100 mg dose of acasunlimab or a biosimilar thereof and a 400 mg dose of pembrolizumab or a biosimilar thereof, are administered every six weeks (Q6W), such as on day one of each six- week treatment cycle.

[0299] It is preferred that the PD-1 antagonist is administered first, followed by the administration of the bispecific antibody. Alternatively, the bispecific antibody is administered first, followed by the administration of the PD-1 antagonist. The time between infusions maybe approximately 30 minutes or longer.

[0300] Each dose may be administered or infused over a minimum of 30 minutes, such as over a minimum of 60 minutes, a minimum of 90 minutes, a minimum of 120 minutes, or a minimum of 240 minutes.

[0301] The bispecific antibody may in particular be administered by using intravenous (IV) infusion over 30 minutes, such as over a minimum of 40 minutes, a minimum of 50 minutes, or such as over a minimum of 60 minutes.

[0302] The PD-1 antagonist may in particular be administered as an intravenous infusion over 30 minutes, such as over a minimum of 40 minutes, a minimum of 50 minutes, or such as over a minimum of 60 minutes.

[0303] In some embodiments, the bispecific antibody and the PD-1 antagonist are administered simultaneously. The bispecific antibody defined above and the PD-1 antagonist may be administered in any suitable form (e.g. , naked as such). However, it is preferred that the bispecific antibody and the PD-1 antagonist, are administered in the form of any suitable pharmaceutical composition as described herein. In one embodiment, at least the bispecific antibody and the PD-1 antagonist are administered in the form of separate pharmaceutical compositions (z.e., one pharmaceutical composition for the bispecific antibody and one pharmaceutical composition for the PD-1 antagonist), preferably the bispecific antibody and the PD-1 antagonist are administered in the form of separate pharmaceutical compositions (z.e., one pharmaceutical composition for the bispecific antibody and one pharmaceutical composition for the PD- 1 antagonist.

[0304] A composition or pharmaceutical composition may be formulated with a carrier, excipient and / or diluent as well as any other components suitable for pharmaceutical compositions, including known adjuvants, in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19thEdition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The pharmaceutically acceptable carriers or diluents as well as any known adjuvants and excipients should be suitable for the bispecific antibody and / or the PD-1 antagonist and the chosen mode of administration. Suitability for carriers and other components of pharmaceutical compositions is determined based on the lack of significant negative impact on the desired biological properties of the chosen compound or pharmaceutical composition (e.g., less than a substantial impact [10% or less relative inhibition, 5% or less relative inhibition, etc.] upon antigen binding).

[0305] A composition, in particular the pharmaceutical composition of the bispecific antibody defined above, the pharmaceutical composition of the PD-1 antagonist, may include diluents, fillers, salts, buffers, detergents (e.g., a nonionic detergent, such as Tween-20 or Tween-80), stabilizers (e.g., sugars or protein-free amino acids), preservatives, solubilizers, and / or other materials suitable for inclusion in a pharmaceutical composition.

[0306] 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).

[0307] Pharmaceutical carriers, excipients or diluents can be selected with regards to the intended route of administration and standard pharmaceutical practice.

[0308] Pharmaceutically acceptable carriers include any and all suitable solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents, antioxidants and absorption-delaying agents, and the like that are physiologically compatible with the active compound, in particular a bispecific antibody defined above and the PD-1 antagonist.

[0309] Examples of suitable aqueous and non-aqueous carriers which may be employed in the (pharmaceutical) compositions include water, saline, phosphate buffered saline, ethanol, dextrose, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, com oil, peanut oil, cottonseed oil, and sesame oil, carboxymethyl cellulose colloidal solutions, tragacanth gum and injectable organic esters, such as ethyl oleate, and / or various buffers. Other carriers are well known in the pharmaceutical arts.

[0310] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the (pharmaceutical) compositions is contemplated.

[0311] 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, flavoring agents, or colorants.

[0312] The term "diluent" relates 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

[0313] 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 (BEIT), 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.

[0314] A (pharmaceutical) composition may also comprise isotonicity agents, such as sugars, polyalcohols, such as mannitol, sorbitol, glycerol or sodium chloride in the composition.

[0315] A (pharmaceutical) composition may also contain one or more adjuvants appropriate for the chosen route of administration such as preservatives, wetting agents, emulsifying agents, dispersing agents, preservatives or buffers, which may enhance the shelf life or effectiveness of the composition. The composition as used herein may be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and micro- encapsulated delivery systems. Such carriers may include gelatin, glyceryl monostearate, glyceryl distearate, biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, poly-ortho esters, and polylactic acid alone or with a wax, or other materials well known in the art. Methods for the preparation of such formulations are generally known to those skilled in the art, see, e.g., Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

[0316] "Pharmaceutically acceptable salts" comprise, for example, acid addition salts which may, for example, be formed by using a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, suitable pharmaceutically acceptable salts may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); ammonium (NHZ); and salts formed with suitable organic ligands (e.g., quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, galactate, galacturonate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2- naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3 -phenylpropionate, phosphate / diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, e.g., Berge et al., J. Pharm. Sci. 66(1): 1-19 (1977)). Salts which are not pharmaceutically acceptable may be used for preparing pharmaceutically acceptable salts and are included in the present disclosure.

[0317] In one embodiment, the bispecific antibody, and the PD-1 antagonist, used herein may be formulated to ensure proper distribution in vivo. Pharmaceutically acceptable carriers for parenteral administration include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except in so far as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Other active or therapeutic compounds may also be incorporated into the compositions.

[0318] Pharmaceutical compositions for injection must typically be sterile and stable under the conditions of manufacture and storage. The composition may be formulated as a solution, micro-emulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier may be an aqueous or a nonaqueous solvent or dispersion medium containing for instance water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as glycerol, mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin. Sterile injectable solutions may be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients, e.g., as enumerated above, as required, followed by sterilization microfdtration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients, e.g., from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, examples of methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-fdtered solution thereof.

[0319] Sterile injectable solutions may be prepared by incorporating the active compounds in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, examples of methods of preparation are vacuum-drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0320] In certain embodiments the bispecific antibody according to the invention is formulated in a composition or formulation comprising histidine, sucrose and Polysorbate-80, and having a pH from about 5 to about 6. such as from 5 to 6. In particular, the bispecific antibody according to the invention may be in a composition or formulation comprising about 20 mM histidine, about 250 mM Sucrose, about 0.02% Polysorbate-80, and having a pH of about 5.5, such as a composition or formulation comprising 20 mM histidine, 250 mM Sucrose, 0.02% Polysorbate-80, and having a pH of 5.5. The formulation may in particular embodiments comprise about 10 to about 30 mg bispecific antibody / mL, such as 10-30 mg bispecific antibody / mL, in particular about 20 mg bispecific antibody / mL, such as 20 mg bispecific antibody / mL.

[0321] The bispecific antibody for use according to the invention may be provided in a composition as defined above and may then be diluted in 0.9% NaCl (saline) prior to administration.

[0322] Treatment Outcome

[0323] In one aspect, a method of treating NSCLC with an bispecific antibody and a PD-1 antagonist described herein results in an improvement, or in one or more therapeutic effects, in the human subject after administration of the bispecific antibody and the PD- 1 antagonist. In some embodiments, the one or more therapeutic effects is Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DOR), Progression-free Survival (PFS), Overall Survival (OS), Time to Response (TTR), the size of the tumor derived from NSCLC, or any combination thereof. In one embodiment, the one or more therapeutic effects is the size of the tumor derived from NSCLC. In one embodiment, the one or more therapeutic effects is decreased tumor size. In one embodiment, the one or more therapeutic effects is stable disease. In one embodiment, the one or more therapeutic effects is partial response. In one embodiment, the one or more therapeutic effects is complete response. In one embodiment, the one or more therapeutic effects is the ORR. In one embodiment, the one or more therapeutic effects is the DCR. In one embodiment, the one or more therapeutic effects is the DOR. In one embodiment, the one or more therapeutic effects is the PFS. In one embodiment, the one or more therapeutic effects is the OS. In one embodiment, the one or more therapeutic effects is the TTR. In one embodiment, the one or more therapeutic effects is cancer regression.

[0324] In one embodiment of the method described herein, response to treatment with the bispecific antibody and the PD-1 antagonist described herein is assessed by measuring the time of overall survival after administration of the bispecific antibody and the PD-1 antagonist. Methods for analyzing OS are well known to a person skilled in the art. In some embodiments, OS is analyzed using the Kaplan-Meier method censoring at last contact date in case of no observed death. In some embodiments, the human subject exhibits median overall survival of at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, at least about 26 weeks, at least about 28 weeks, at least about 30 weeks, at least about 32 weeks, at least about 34 weeks, at least about 36 weeks, at least about 38 weeks, at least about 40 weeks, at least about 42 weeks, at least about 44 weeks, at least about 46 weeks, at least about 48 weeks, at least about 50 weeks, at least about 52 weeks, at least about 54 weeks, at least about 56 weeks, at least about 58 weeks, at least about 60 weeks, at least about 62 weeks, at least about 64 weeks, at least about 66 weeks, at least about 68 weeks, at least about 70 weeks, at least about 72 weeks, at least about 74 weeks, at least about 76 weeks, at least about 78 weeks, or at least about 80 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 40 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 42 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 44 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 46 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 48 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 50 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 52 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 54 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 56 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 58 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 60 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 62 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 64 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 66 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 68 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 70 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 72 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 74 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 76 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 78 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median overall survival of at least about 80 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 40%, at least about 42%, at least about 44%, at least about 46%, at least about 48%, at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, or at least about 70% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 40% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 42% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 44% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 46% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 48% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 50% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 52% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 54% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 56% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 58% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 60% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 62% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 64% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 66% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 68% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 12-month overall survival of at least about 70% after administration of said bispecific antibody and said PD-1 antagonist. In one embodiment of the method described herein, response to treatment with the bispecific antibody and the PD-1 antagonist described herein is assessed by measuring the time of progression-free survival (PFS) after administration of the bispecific antibody and the PD-1 antagonist. Methods for analyzing PFS are well known to a person skilled in the art. In some embodiments, PFS is analyzed using the Kaplan-Meier method. In some embodiments, PFS is analyzed using the Kaplan-Meier method censoring at the date of the last evaluable response assessment before the earliest of start of new anticancer therapy, two consecutive missing radiographic assessments, trial discontinuation, and data cutoff date in case of no prior progression event (death or radiographic progression). In some embodiments, the human subject exhibits median PFS of at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least about 20 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median PFS of at least about 8 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median PFS of at least about 9 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median PFS of at least about 10 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median PFS of at least about 11 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median PFS of at least about 12 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median PFS of at least about 13 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median PFS of at least about 14 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median PFS of at least about 15 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median PFS of at least about 16 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median PFS of at least about 17 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median PFS of at least about 18 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median PFS of at least about 19 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median PFS of at least about 20 weeks after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, or at least about 40% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 20% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 21% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6- month PFS of at least about 22% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 23% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 24% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 25% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 26% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 27% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 28% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6- month PFS of at least about 29% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 30% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 31% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 32% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 33% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 34% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 35% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6- month PFS of at least about 36% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 37% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 38% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 39% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits 6-month PFS of at least about 40% after administration of said bispecific antibody and said PD-1 antagonist. In one embodiment of the method described herein, response to treatment with the bispecific antibody and the PD-1 antagonist described herein is assessed by measuring the ORR after administration of the bispecific antibody and the PD-1 antagonist. Methods for analyzing ORR are well known to a person skilled in the art. In some embodiments, ORR is analyzed using with an exact 1 -sided lower 95% confidence limit based on the Clopper-Pearson method. In some embodiments, the ORR is at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, or at least about 30% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 6% after administration of said bispecific antibody and said PD- 1 antagonist. In some embodiments, the ORR is at least about 7% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 8% after administration of said bispecific antibody and said PD- 1 antagonist. In some embodiments, the ORR is at least about 9% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 10% after administration of said bispecific antibody and said PD- 1 antagonist. In some embodiments, the ORR is at least about 11% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 12% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 13% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 14% after administration of said bispecific antibody and said PD- 1 antagonist. In some embodiments, the ORR is at least about 15% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 16% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 17% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 18% after administration of said bispecific antibody and said PD- 1 antagonist. In some embodiments, the ORR is at least about 19% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 20% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 21% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 22% after administration of said bispecific antibody and said PD- 1 antagonist. In some embodiments, the ORR is at least about 23% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 24% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 25% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 26% after administration of said bispecific antibody and said PD- 1 antagonist. In some embodiments, the ORR is at least about 27% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 28% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 29% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the ORR is at least about 30% after administration of said bispecific antibody and said PD-1 antagonist.

[0325] In one embodiment of the method described herein, response to treatment with the bispecific antibody and the PD-1 antagonist described herein is assessed by measuring the DCR after administration of the bispecific antibody and the PD-1 antagonist. Methods for analyzing DCR are well known to a person skilled in the art. In some embodiments, DCR is analyzed using with an exact 1 -sided lower 95% confidence limit based on the Clopper-Pearson method. In some embodiments, the DCR is at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, at least about 70%, at least about 72%, at least about 74%, at least about 76%, at least about 78%, or at least about 80% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 50% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 52% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 54% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 56% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 58% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 60% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 62% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 64% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 66% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 68% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 70% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 72% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 74% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 76% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 78% after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the DCR is at least about 80% after administration of said bispecific antibody and said PD-1 antagonist. In one embodiment of the method described herein, response to treatment with the bispecific antibody and the PD-1 antagonist described herein is assessed by measuring the DOR after administration of the bispecific antibody and the PD-1 antagonist. Methods for analyzing DOR are well known to a person skilled in the art. In some embodiments, DOR is analyzed using with the Kaplan-Meier method. In some embodiments, DOR is analyzed using with the Kaplan-Meier method, censoring at the date of the last evaluable response assessment before the earliest of start of new anti-cancer therapy, two consecutive missing radiographic assessments, trial discontinuation, and data cutoff date in case of no prior progression event (death or radiographic progression). In some embodiments, the human subject exhibits median DOR of at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, or at least about 18 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 2 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 3 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 4 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 5 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 6 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 7 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 8 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 9 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 10 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 11 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 12 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 13 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 14 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 15 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 16 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 17 months after administration of said bispecific antibody and said PD-1 antagonist. In some embodiments, the human subject exhibits median DOR of at least about 18 months after administration of said bispecific antibody and said PD-1 antagonist.

[0326] In one embodiment, the human subject treated with a method of treating NSCLC with an bispecific antibody and a PD-1 antagonist described herein exhibits treatment-related adverse events (TRAEs), such as liver-related adverse events (AEs). In some embodiments, the method of treating NSCLC exhibits improved safety, such as shown by a lower incidence of TRAEs for the treated human subject or a faster resolution of the TRAEs. In some embodiments, the human subject exhibits lower incidence of liver-related AEs, such as grade >3 liver-related AEs. In some embodiments, the incidence of grade >3 liver-related AEs for the treated human subject is about 16% or lower, such as about 15% or lower, about 14% or lower, about 13% or lower, about 12% or lower, about 11% or lower, or about 10% or lower. In some embodiments, the human subject exhibits faster resolution of grade >3 liver-related AEs. In some embodiments, the median time to resolution of the grade >3 liver-related AEs is about 15 days or less, such as about 14 days or less, about 13 days or less, about 12 days or less, about 11 days or less, or about 10 days or less.

[0327] In a second aspect, the present disclosure provides a bispecific antibody for use in a method for treating NSCLC according to the first aspect. The bispecific antibody comprises a first binding region binding to CD 137 and a second binding region binding to PD-L1; the first binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, GAS, and SEQ ID NO: 7, respectively; and the second antigen-binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 13, DDN, and SEQ ID NO: 14, respectively.

[0328] In a third aspect, the present disclosure provides a PD-1 antagonist for use in a method for treating NSCLC according to the first aspect. The PD-1 antagonist is an anti-PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 33, 34 and 35, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37 and 38, respectively.

[0329] In a fourth aspect, the present disclosure provides use of a bispecific antibody in a method for treating NSCLC according to the first aspect. The bispecific antibody comprises a first binding region binding to CD 137 and a second binding region binding to PD-L1; the first binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, GAS, and SEQ ID NO: 7, respectively; and the second antigen-binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 13, DDN, and SEQ ID NO: 14, respectively.

[0330] In a fifth aspect, the present disclosure provides use of aPD-1 antagonist in a method for treating NSCLC according to the first aspect. The PD-1 antagonist is an anti-PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 33, 34 and 35, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37 and 38, respectively.

[0331] In a sixth aspect, the present disclosure provides a kit comprising a bispecific antibody and a PD-1 antagonist. The bispecific antibody comprises a first binding region binding to CD 137 and a second binding region binding to PD-L1; the first binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, GAS, and SEQ ID NO: 7, respectively; and the second antigen-binding region comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 13, DDN, and SEQ ID NO: 14, respectively. The PD-1 antagonist is an anti-PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 33, 34 and 35, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37 and 38, respectively. In one embodiment, the kit comprises at least two containers, wherein one thereof contains the bispecific antibody (as such or in the form of a (pharmaceutical) composition) and the second container contains the PD-1 antagonist (as such or in the form of a (pharmaceutical) composition).

[0332] The embodiments disclosed herein with respect to the first aspect also apply to all other aspects disclosed herein.

[0333] Embodiments Embodiment 1 : A method for treating cancer in a human subject, said method comprising administering to said human subject a bispecific antibody and a PD-1 antagonist, wherein:

[0334] (a) the bispecific antibody comprises a first binding region binding to CD 137 and a second binding region binding to PD-L1, wherein the first binding region comprises a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, GAS, and SEQ ID NO: 7, respectively, and the second binding region comprises a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 13, DDN, and SEQ ID NO: 14, respectively; and

[0335] (b) the PD-1 antagonist is an anti -PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 33, 34 and 35, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37 and 38, respectively; wherein said cancer is non-small cell lung cancer (NSCLC).

[0336] Embodiment 2 : The method of embodiment 1 , wherein the first binding region of the bispecific antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 5; and the second binding region of the bispecific antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 8 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 12.

[0337] Embodiment 3 : The method of either embodiment 1 or embodiment 2, wherein said bispecific antibody comprises a first heavy chain and a first light chain comprising said first binding region binding to CD137, wherein the first heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 15, and the first light chain comprises the amino acid sequence set forth in SEQ ID NO: 16; and a second heavy chain and a second light chain comprising said second binding region binding to PD-L1, wherein the second heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 17, and the second light chain comprises the amino acid sequence set forth in SEQ ID NO: 18.

[0338] Embodiment 4: The method of any one of the preceding embodiments, wherein said bispecific antibody is acasunlimab or a biosimilar thereof.

[0339] Embodiment 5 : The method of any one of the preceding embodiments, wherein the bispecific antibody is in a composition or formulation comprising histidine, sucrose, and Polysorbate-80, and having a pH from 5 to 6. preferably in a composition or formulation comprising about 20 mM histidine, about 250 mM sucrose, about 0.02% Polysorbate-80, and having a pH of about 5.5.

[0340] Embodiment 6: The method of any one of the preceding embodiments, wherein said PD-1 antagonist comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 29, and a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 30.

[0341] Embodiment 7: The method of any one of the preceding embodiments, wherein said PD-1 antagonist comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 31, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 32.

[0342] Embodiment 8: The method of any one of the preceding embodiments, wherein said PD-1 antagonist is pembrolizumab or a biosimilar thereof.

[0343] Embodiment 9: The method of any one of the preceding embodiments, wherein said human subject exhibits median progression-free survival (PFS) of at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least about 20 weeks after administration of said bispecific antibody and said PD-1 antagonist.

[0344] Embodiment 10: The method of any one of the preceding embodiments, wherein said human subject exhibits 6-month PFS of at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, or at least about 40% after administration of said bispecific antibody and said PD-1 antagonist.

[0345] Embodiment 11: The method of any one of the preceding embodiments, wherein said human subject exhibits median overall survival (OS) of at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, at least about 26 weeks, at least about 28 weeks, at least about 30 weeks, at least about 32 weeks, at least about 34 weeks, at least about 36 weeks, at least about 38 weeks, at least about 40 weeks, at least about 42 weeks, at least about 44 weeks, at least about 46 weeks, at least about 48 weeks, at least about 50 weeks, at least about 52 weeks, at least about 54 weeks, at least about 56 weeks, at least about 58 weeks, at least about 60 weeks, at least about 62 weeks, at least about 64 weeks, at least about 66 weeks, at least about 68 weeks, at least about 70 weeks, at least about 72 weeks, at least about 74 weeks, at least about 76 weeks, at least about 78 weeks, or at least about 80 weeks after administration of said bispecific antibody and said PD-1 antagonist.

[0346] Embodiment 12: The method of any one of the preceding embodiments, wherein said human subject exhibits 12-month overall survival of at least about 40%, at least about 42%, at least about 44%, at least about 46%, at least about 48%, at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, or at least about 70% after administration of said bispecific antibody and said PD-1 antagonist.

[0347] Embodiment 13: The method of any one of the preceding embodiments, wherein the objective response rate (ORR) is at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, or at least about 30% after administration of said bispecific antibody and said PD-1 antagonist.

[0348] Embodiment 14: The method of any one of the preceding embodiments, wherein the disease control rate (DCR) is at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, at least about 70%, at least about 72%, at least about 74%, at least about 76%, at least about 78%, or at least about 80% after administration of said bispecific antibody and said PD-1 antagonist.

[0349] Embodiment 15: The method of any one of the preceding embodiments, wherein said human subject exhibits median duration of response (DOR) of at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, or at least about 18 months after administration of said bispecific antibody and said PD-1 antagonist.

[0350] Embodiment 16: The method of any one of the preceding embodiments, wherein the incidence of grade >3 liver-related adverse events (AEs) for the treated human subject is about 16% or lower, about 15% or lower, about 14% or lower, about 13% or lower, about 12% or lower, about 11% or lower, or about 10% or lower. Embodiment 17: The method of any one of the preceding embodiments, wherein the human subject exhibits median time to resolution of grade >3 liver-related adverse events (AEs) of about 15 days or less, about 14 days or less, about 13 days or less, about 12 days or less, about 11 days or less, or about 10 days or less.

[0351] Embodiment 18: The method of any one of the preceding embodiments, wherein the bispecific antibody and / or the PD-1 antagonist are administered in at least one treatment cycle, each treatment cycle being three weeks (21 days) or six weeks (42 days).

[0352] Embodiment 19: The method of any one of the preceding embodiments, wherein one dose of the bispecific antibody and / or one dose of the PD-1 antagonist are administered every third week (Q3W).

[0353] Embodiment 20: The method of any one of embodiments 1 to 18, wherein one dose of the bispecific antibody and / or one dose of the PD-1 antagonist are administered every six weeks (Q6W).

[0354] Embodiment 21: The method of any one of the preceding embodiments, wherein one dose of the bispecific antibody and one dose of the PD-1 antagonist are administered on day 1 of each treatment cycle.

[0355] Embodiment 22: The method of any one of the preceding embodiments, wherein the amount of said bispecific antibody administered in each dose and / or in each treatment cycle is about 100 mg.

[0356] Embodiment 23: The method of any one of the preceding embodiments, wherein the amount of said PD-1 antagonist administered in each dose and / or in each treatment cycle is about 200 mg.

[0357] Embodiment 24: The method of any one of embodiments 1 to 22, wherein the amount of said PD-1 antagonist administered in each dose and / or in each treatment cycle is about 400 mg.

[0358] Embodiment 25: The method of any one of embodiments 1 to 18, wherein an approximate 100 mg dose of the bispecific antibody and an approximate 200 mg dose of the PD-1 antagonist are administered every three weeks (Q3W).

[0359] Embodiment 26: The method of any one of embodiments 1 to 18, wherein an approximate 100 mg dose of the bispecific antibody and an approximate 400 mg dose of the PD-1 antagonist are administered every six weeks (Q6W). Embodiment 27: The method of any one of embodiments 1 to 18, wherein an approximate 100 mg dose of acasunlimab or a biosimilar thereof and an approximate 200 mg dose of pembrolizumab or a biosimilar thereof are administered every three weeks (Q3W), such as on day 1 of each three-week treatment cycle.

[0360] Embodiment 28: The method of any one of embodiments 1 to 18, wherein an approximate 100 mg dose of acasunlimab or a biosimilar thereof and an approximate 400 mg dose of pembrolizumab or a biosimilar thereof are administered every six weeks (Q6W), such as on day 1 of every six-week treatment cycle.

[0361] Embodiment 29: The method of any one of the preceding embodiments, wherein the bispecific antibody and / or the PD-1 antagonist are administered systemically, such as by injection or infusion, in particular by intravenous (IV) infusion.

[0362] Embodiment 30: The method of any one of the preceding embodiments, wherein the PD-1 antagonist is administered first, followed by the bispecific antibody, preferably wherein the time between infusions is approximately 30 minutes or longer.

[0363] Embodiment 31: The method of any one of the preceding embodiments, wherein said cancer is squamous or non-squamous NSCLC.

[0364] Embodiment 32: The method of any one of the preceding embodiments, wherein the cancer is metastatic, such as metastatic NSCLC (mNSCLC).

[0365] Embodiment 33: The method of any one of the preceding embodiments, wherein the cancer is a histologically or cytologically confirmed stage 4 NSCLC.

[0366] Embodiment 34: The method of any one of the preceding embodiments, wherein the cancer has relapsed and / or is refractory after prior treatment, such as systemic treatment with a checkpoint inhibitor.

[0367] Embodiment 35: The method of any one of the preceding embodiments, wherein the human subject has demonstrated disease progression (PD), such as PD defined by RECIST v 1. 1 , after prior treatment, such as systemic treatment with a checkpoint inhibitor.

[0368] Embodiment 36: The method of any one of the preceding embodiments, wherein the human subject has received at least 1 prior line of systemic therapy, such as systemic therapy comprising a PD-1 inhibitor and / or a PD-L1 inhibitor, such as an anti-PD-1 antibody and / or an anti-PD-Ll antibody. Embodiment 37: The method of any one of the preceding embodiments, wherein the human subject has demonstrated disease progression (PD) after prior treatment with a PD-1 inhibitor or PD-L1 inhibitor, such as an anti-PD-1 antibody or an anti-PD-Ll antibody, the PD-1 inhibitor or PD-L1 inhibitor being administered as monotherapy or as part of a combination therapy.

[0369] Embodiment 38: The method of any one of the preceding embodiments, wherein last prior treatment was with a PD-1 inhibitor or PD-L1 inhibitor, such as an anti-PD-1 antibody or an anti-PD-Ll antibody, the PD-1 inhibitor or PD-L1 inhibitor being administered as monotherapy or as part of a combination therapy, such as a combination therapy with a platinum-based chemotherapy.

[0370] Embodiment 39: The method of any one of the preceding embodiments, wherein the human subject has demonstrated disease progression (PD) during or after platinum doublet chemotherapy following treatment with an anti-PD-1 antibody or an anti-PD-Ll antibody.

[0371] Embodiment 40: The method of any one of the preceding embodiments, wherein the human subject has demonstrated disease progression (PD) during or after prior treatment with an anti-PD-1 antibody or an anti-PD-Ll antibody following platinum doublet chemotherapy.

[0372] Embodiment 41 : The method of any one of the preceding embodiments, wherein the human subject has relapsed or refractory mNSCLC after prior treatment with an immune checkpoint inhibitor, such as an anti-PD-1 antibody or an anti-PD-Ll antibody.

[0373] Embodiment 42: The method of any one of the preceding embodiments, wherein the cancer has relapsed and / or is refractory, or the human subject has progressed during or after prior standard-of-care (SOC) treatment for metastatic NSCLC, such as a combination of a checkpoint inhibitor (CPI), such as a PD-1 inhibitor or PD-L1 inhibitor, and a platinum-based chemotherapy.

[0374] Embodiment 43 : The method of embodiment 42, wherein the PD- 1 or PD-L 1 inhibitor and the platinumbased chemotherapy are administrated concomitantly, or the PD-1 or PD-L1 inhibitor and the platinumbased chemotherapy are administrated sequentially, irrespective of the order.

[0375] Embodiment 44: The method of any one of the preceding embodiments, wherein the human subject has had at least 6 weeks of prior treatment comprising a PD-1 inhibitor or PD-L1 inhibitor, and preferably said human subject has had clinical benefit, such as defined as documented radiographic stable disease (SD) or better, on said prior treatment comprising a PD-1 inhibitor or PD-L1 inhibitor. Embodiment 45: The method of any one of the preceding embodiments, wherein the human subject has a PD-L1 positive tumor, preferably as determined by an FDA-approved test.

[0376] Embodiment 46: The method of any one of the preceding embodiments, wherein the human subject has a tumor with PD-L1 expressed in > 1% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (TPS) > 1%.

[0377] Embodiment 47: The method of any one of the preceding embodiments, wherein the human subject has a tumor with PD-L1 expressed in > 50% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (TPS) > 50%.

[0378] Embodiment 48: The method of any one of the preceding embodiments, wherein the human subject has a tumor with PD-L1 expressed in > 1% and < 49% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (TPS) > 1 and < 49%.

[0379] Embodiment 49: The method of any one of the preceding embodiments, wherein the human subject has a PD-L1 positive tumor as determined by an FDA-approved test, such as a tumor with a TPS > 1%, and the human subject has progressed during or after prior treatment with a combination of a PD-1 inhibitor or PD-L1 inhibitor and a platinum-based chemotherapy.

[0380] Embodiment 50: The method of any one of the preceding embodiments, wherein the PD-1 inhibitor or PD-L1 inhibitor and the platinum-based chemotherapy are administrated concomitantly or sequentially, irrespective of the order.

[0381] Embodiment 51 : The method of any one of the preceding embodiments, wherein the human subject has Eastern Cooperative Oncology Group (ECOG) performance status (PS) <1.

[0382] Embodiment 52: The method of any one of the preceding embodiments, wherein the human subject has a tumor that does not have EGFR sensitizing mutation, KRAS mutation, RET mutation, ROS1 mutation, BRAF mutation, NTRK gene infusion, RET rearrangement, ALK gene rearrangement, high-level MET amplification, or METex 14 skipping.

[0383] Embodiment 53: The method of any one of the preceding embodiments, wherein the human subject has not received prior treatment with a 4- IBB (CD 137) targeting agent, such as an anti-4- IBB (CD 137) antibody, with an antitumor vaccine, or with autologous cell immunotherapy. Embodiment 54: The method of any one of the preceding embodiments, wherein the human subject has not received prior treatment with a taxane chemotherapeutic agent, such as docetaxel, such as prior treatment for NSCLC with a taxane chemotherapeutic agent, such as docetaxel.

[0384] Embodiment 55 : The method of any one of the preceding embodiments, wherein the bispecific antibody is administered prior to, simultaneously with, or after administration of the PD-1 antagonist.

[0385] Embodiment 56: The method of embodiment 55, wherein when the administration of the bispecific antibody is prior to the administration of the PD-1 antagonist, the gap between the end of the administration of the bispecific antibody and the beginning of the administration of the PD-1 antagonist is at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes, and / or up to about 14 days (up to about 2 weeks), up to about 13 days, up to about 12 days, up to about 11 days, up to about 10 days, up to about 9 days, up to about 8 days, up to about 7 days (up to about 1 week), up to about 6 days, up to about 5 days, up to about 4 days, up to about 3 days, up to about 2 days, up to about 1 day (up to about 24 hours), up to about 18 hours, up to about 12 hours, up to about 6 hours, up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2.5 hours, or up to about 2 hours.

[0386] Embodiment 57: The method of embodiment 55, wherein when the administration of the bispecific antibody is after the administration of the PD-1 antagonist, the gap between the end of the administration of the PD-1 antagonist and the beginning of the administration of the bispecific antibody is at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes, and / or up to about 14 days (up to about 2 weeks), up to about 13 days, up to about 12 days, up to about 11 days, up to about 10 days, up to about 9 days, up to about 8 days, up to about 7 days (up to about 1 week), up to about 6 days, up to about 5 days, up to about 4 days, up to about 3 days, up to about 2 days, up to about 1 day (up to about 24 hours), up to about 18 hours, up to about 12 hours, up to about 6 hours, up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2.5 hours, or up to about 2 hours.

[0387] Embodiment 58: A bispecific antibody for use in a method for treating non-small cell lung cancer (NSCLC) in a human subject, said method comprising administering to said subject the bispecific antibody with a PD-1 antagonist, wherein: (a) the bispecific antibody comprises a first binding region binding to CD 137 and a second binding region binding to PD-L1, wherein the first binding region comprises a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, GAS, and SEQ ID NO: 7, respectively, and the second binding region comprises a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 13, DDN, and SEQ ID NO: 14, respectively; and

[0388] (b) the PD-1 antagonist is an anti-PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 33, 34 and 35, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37 and 38, respectively.

[0389] Embodiment 59: The bispecific antibody for use of embodiment 58, wherein the first binding region of the bispecific antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 5; and the second binding region of the bispecific antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 8 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 12.

[0390] Embodiment 60: The bispecific antibody for use of either embodiment 58 or embodiment 59, wherein said bispecific antibody comprises a first heavy chain and a first light chain comprising said first binding region binding to CD 137, wherein the first heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 15, and the first light chain comprises the amino acid sequence set forth in SEQ ID NO: 16; and a second heavy chain and a second light chain comprising said second binding region binding to PD-L1, wherein the second heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 17, and the second light chain comprises the amino acid sequence set forth in SEQ ID NO: 18.

[0391] Embodiment 61: The bispecific antibody for use of any one of embodiments 58 to 60, wherein said bispecific antibody is acasunlimab or a biosimilar thereof.

[0392] Embodiment 62: The bispecific antibody for use of any one of embodiments 58 to 61, wherein the bispecific antibody is in a composition or formulation comprising histidine, sucrose, and Polysorbate- 80, and having a pH from 5 to 6, preferably in a composition or formulation comprising about 20 mM histidine, about 250 mM sucrose, about 0.02% Polysorbate-80, and having a pH of about 5.5. Embodiment 63: The bispecific antibody for use of any one of embodiments 58 to 62, wherein said PD- 1 antagonist comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 29, and a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 30.

[0393] Embodiment 64: The bispecific antibody for use of any one of embodiments 58 to 63, wherein said PD- 1 antagonist comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 31, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 32.

[0394] Embodiment 65: The bispecific antibody for use of any one of embodiments 58 to 64, wherein said PD- 1 antagonist is pembrolizumab or a biosimilar thereof.

[0395] Embodiment 66: The bispecific antibody for use of any one of embodiments 58 to 65, wherein said human subject exhibits median progression-free survival (PFS) of at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least about 20 weeks after administration of said bispecific antibody and said PD-1 antagonist.

[0396] Embodiment 67: The bispecific antibody for use of any one of embodiments 58 to 66, wherein said human subject exhibits 6-month PFS of at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, or at least about 40% after administration of said bispecific antibody and said PD-1 antagonist.

[0397] Embodiment 68: The bispecific antibody for use of any one of embodiments 58 to 67, wherein said human subject exhibits median overall survival (OS) of at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, at least about 26 weeks, at least about 28 weeks, at least about 30 weeks, at least about 32 weeks, at least about 34 weeks, at least about 36 weeks, at least about 38 weeks, at least about 40 weeks, at least about 42 weeks, at least about 44 weeks, at least about 46 weeks, at least about 48 weeks, at least about 50 weeks, at least about 52 weeks, at least about 54 weeks, at least about 56 weeks, at least about 58 weeks, at least about 60 weeks, at least about 62 weeks, at least about 64 weeks, at least about 66 weeks, at least about 68 weeks, at least about 70 weeks, at least about 72 weeks, at least about 74 weeks, at least about 76 weeks, at least about 78 weeks, or at least about 80 weeks after administration of said bispecific antibody and said PD-1 antagonist.

[0398] Embodiment 69: The bispecific antibody for use of any one of embodiments 58 to 68, wherein said human subject exhibits 12-month overall survival of at least about 40%, at least about 42%, at least about 44%, at least about 46%, at least about 48%, at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, or at least about 70% after administration of said bispecific antibody and said PD-1 antagonist.

[0399] Embodiment 70: The bispecific antibody for use of any one of embodiments 58 to 69, wherein the objective response rate (ORR) is at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, or at least about 30% after administration of said bispecific antibody and said PD-1 antagonist.

[0400] Embodiment 71: The bispecific antibody for use of any one of embodiments 58 to 70, wherein the disease control rate (DCR) is at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, at least about 70%, at least about 72%, at least about 74%, at least about 76%, at least about 78%, or at least about 80% after administration of said bispecific antibody and said PD-1 antagonist.

[0401] Embodiment 72: The bispecific antibody for use of any one of embodiments 58 to 71, wherein said human subject exhibits median duration of response (DOR) of at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, or at least about 18 months after administration of said bispecific antibody and said PD-1 antagonist.

[0402] Embodiment 73: The bispecific antibody for use of any one of embodiments 58 to 72, wherein the incidence of grade A3 liver-related adverse events (AEs) for the treated human subject is about 16% or lower, about 15% or lower, about 14% or lower, about 13% or lower, about 12% or lower, about 11% or lower, or about 10% or lower. Embodiment 74: The bispecific antibody for use of any one of embodiments 58 to 73, wherein the human subject exhibits median time to resolution of grade A3 liver-related adverse events (AEs) of about 15 days or less, about 14 days or less, about 13 days or less, about 12 days or less, about 11 days or less, or about 10 days or less.

[0403] Embodiment 75: The bispecific antibody for use of any one of embodiments 58 to 74, wherein the bispecific antibody and / or the PD-1 antagonist are administered in at least one treatment cycle, each treatment cycle being three weeks (21 days) or six weeks (42 days).

[0404] Embodiment 76: The bispecific antibody for use of any one of embodiments 58 to 75, wherein one dose of the bispecific antibody and / or one dose of the PD-1 antagonist are administered every third week (Q3W).

[0405] Embodiment 77: The bispecific antibody for use of any one of embodiments 58 to 75, wherein one dose of the bispecific antibody and / or one dose of the PD-1 antagonist are administered every six weeks (Q6W).

[0406] Embodiment 78: The bispecific antibody for use of any one of embodiments 58 to 77, wherein one dose of the bispecific antibody and one dose of the PD-1 antagonist are administered on day 1 of each treatment cycle.

[0407] Embodiment 79: The bispecific antibody for use of any one of embodiments 58 to 78, wherein the amount of said bispecific antibody administered in each dose and / or in each treatment cycle is about 100 mg.

[0408] Embodiment 80: The bispecific antibody for use of any one of embodiments 58 to 79, wherein the amount of said PD-1 antagonist administered in each dose and / or in each treatment cycle is about 200 mg.

[0409] Embodiment 81: The bispecific antibody for use of any one of embodiments 58 to 79, wherein the amount of said PD-1 antagonist administered in each dose and / or in each treatment cycle is about 400 mg.

[0410] Embodiment 82: The bispecific antibody for use of any one of embodiments 58 to 75, wherein an approximate 100 mg dose of the bispecific antibody and an approximate 200 mg dose of the PD-1 antagonist are administered every three weeks (Q3W). Embodiment 83: The bispecific antibody for use of any one of embodiments 58 to 75, wherein an approximate 100 mg dose of the bispecific antibody and an approximate 400 mg dose of the PD-1 antagonist are administered every six weeks (Q6W).

[0411] Embodiment 84: The bispecific antibody for use of any one of embodiments 58 to 75, wherein an approximate 100 mg dose of acasunlimab or a biosimilar thereof and an approximate 200 mg dose of pembrolizumab or a biosimilar thereof are administered every three weeks (Q3W), such as on day 1 of each three-week treatment cycle.

[0412] Embodiment 85: The bispecific antibody for use of any one of embodiments 58 to 75, wherein an approximate 100 mg dose of acasunlimab or a biosimilar thereof and an approximate 400 mg dose of pembrolizumab or a biosimilar thereof are administered every six weeks (Q6W), such as on day 1 of every six- week treatment cycle.

[0413] Embodiment 86: The bispecific antibody for use of any one of embodiments 58 to 85, wherein the bispecific antibody and / or the PD-1 antagonist are administered systemically, such as by injection or infusion, in particular by intravenous (IV) infusion.

[0414] Embodiment 87: The bispecific antibody for use of any one of embodiments 58 to 86, wherein the PD- 1 antagonist is administered first, followed by the bispecific antibody, preferably wherein the time between infusions is approximately 30 minutes or longer.

[0415] Embodiment 88: The bispecific antibody for use of any one of embodiments 58 to 87, wherein said cancer is squamous or non-squamous NSCLC.

[0416] Embodiment 89: The bispecific antibody for use of any one of embodiments 58 to 88, wherein the cancer is metastatic, such as metastatic NSCLC (mNSCLC).

[0417] Embodiment 90: The bispecific antibody for use of any one of embodiments 58 to 89, wherein the cancer is a histologically or cytologically confirmed stage 4 NSCLC.

[0418] Embodiment 91: The bispecific antibody for use of any one of embodiments 58 to 90, wherein the cancer has relapsed and / or is refractory after prior treatment, such as systemic treatment with a checkpoint inhibitor. Embodiment 92: The bispecific antibody for use of any one of embodiments 58 to 91, wherein the human subject has demonstrated disease progression (PD), such as PD defined by RECIST vl.l, after prior treatment, such as systemic treatment with a checkpoint inhibitor.

[0419] Embodiment 93: The bispecific antibody for use of any one of embodiments 58 to 92, wherein the human subject has received at least 1 prior line of systemic therapy, such as systemic therapy comprising a PD-1 inhibitor and / or a PD-L1 inhibitor, such as an anti-PD-1 antibody and / or an anti-PD-Ll antibody.

[0420] Embodiment 94: The bispecific antibody for use of any one of embodiments 58 to 93, wherein the human subject has demonstrated disease progression (PD) after prior treatment with a PD-1 inhibitor or PD-L1 inhibitor, such as an anti-PD-1 antibody or an anti-PD-Ll antibody, the PD-1 inhibitor or PD- L1 inhibitor being administered as monotherapy or as part of a combination therapy.

[0421] Embodiment 95: The bispecific antibody for use of any one of embodiments 58 to 94, wherein last prior treatment was with a PD-1 inhibitor or PD-L1 inhibitor, such as an anti-PD-1 antibody or an anti-PD- Ll antibody, the PD-1 inhibitor or PD-L1 inhibitor being administered as monotherapy or as part of a combination therapy, such as a combination therapy with a platinum-based chemotherapy.

[0422] Embodiment 96: The bispecific antibody for use of any one of embodiments 58 to 95, wherein the human subject has demonstrated disease progression (PD) during or after platinum doublet chemotherapy following treatment with an anti-PD-1 antibody or an anti-PD-Ll antibody.

[0423] Embodiment 97: The bispecific antibody for use of any one of embodiments 58 to 96, wherein the human subject has demonstrated disease progression (PD) during or after prior treatment with an anti- PD-1 antibody or an anti-PD-Ll antibody following platinum doublet chemotherapy.

[0424] Embodiment 98: The bispecific antibody for use of any one of embodiments 58 to 97, wherein the human subject has relapsed or refractory mNSCLC after prior treatment with an immune checkpoint inhibitor, such as an anti-PD-1 antibody or an anti-PD-Ll antibody.

[0425] Embodiment 99: The bispecific antibody for use of any one of embodiments 58 to 98, wherein the cancer has relapsed and / or is refractory, or the human subject has progressed during or after prior standard-of-care (SOC) treatment for metastatic NSCLC, such as a combination of a checkpoint inhibitor (CPI), such as a PD-1 inhibitor or PD-L1 inhibitor, and a platinum-based chemotherapy. Embodiment 100: The bispecific antibody for use of embodiment 99, wherein the PD-1 or PD-L1 inhibitor and the platinum-based chemotherapy are administrated concomitantly, or the PD-1 or PD-L1 inhibitor and the platinum-based chemotherapy are administrated sequentially, irrespective of the order.

[0426] Embodiment 101: The bispecific antibody for use of any one of embodiments 58 to 100, wherein the human subject has had at least 6 weeks of prior treatment comprising a PD-1 inhibitor or PD-L1 inhibitor, and preferably said human subject has had clinical benefit, such as defined as documented radiographic stable disease (SD) or better, on said prior treatment comprising a PD-1 inhibitor or PD- L1 inhibitor.

[0427] Embodiment 102: The bispecific antibody for use of any one of embodiments 58 to 101, wherein the human subject has a PD-L1 positive tumor, preferably as determined by an FDA-approved test.

[0428] Embodiment 103: The bispecific antibody for use of any one of embodiments 58 to 102, wherein the human subject has a tumor with PD-L1 expressed in A 1% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (TPS) 1%.

[0429] Embodiment 104: The bispecific antibody for use of any one of embodiments 58 to 103, wherein the human subject has a tumor with PD-L1 expressed in 50% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (TPS) 50%.

[0430] Embodiment 105: The bispecific antibody for use of any one of embodiments 58 to 104, wherein the human subject has a tumor with PD-L1 expressed in A I % and 49% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (TPS) 49%.

[0431] Embodiment 106: The bispecific antibody for use of any one of embodiments 58 to 105, wherein the human subject has a PD-L1 positive tumor as determined by an FDA-approved test, such as a tumor with a TPS 1%, and the human subject has progressed during or after prior treatment with a combination of a PD-1 inhibitor or PD-L1 inhibitor and a platinum-based chemotherapy.

[0432] Embodiment 107: The bispecific antibody for use of any one of embodiments 58 to 106, wherein the PD-1 inhibitor or PD-L1 inhibitor and the platinum-based chemotherapy are administrated concomitantly or sequentially, irrespective of the order.

[0433] Embodiment 108: The bispecific antibody for use of any one of embodiments 58 to 107, wherein the human subject has Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1. Embodiment 109: The bispecific antibody for use of any one of embodiments 58 to 108, wherein the human subject has a tumor that does not have EGFR sensitizing mutation, KRAS mutation, RET mutation, ROS1 mutation, BRAF mutation, NTRK gene infusion, RET rearrangement, ALK gene rearrangement, high-level MET amplification, or METex 14 skipping.

[0434] Embodiment 110: The bispecific antibody for use of any one of embodiments 58 to 109, wherein the human subject has not received prior treatment with a 4- IBB (CD 137) targeting agent, such as an anti- 4-1BB (CD137) antibody, with an antitumor vaccine, or with autologous cell immunotherapy.

[0435] Embodiment 111: The bispecific antibody for use of any one of embodiments 58 to 110, wherein the human subject has not received prior treatment with a taxane chemotherapeutic agent, such as docetaxel, such as prior treatment for NSCLC with a taxane chemotherapeutic agent, such as docetaxel.

[0436] Embodiment 112: The bispecific antibody for use of any one of embodiments 58 to 111, wherein the bispecific antibody is administered prior to, simultaneously with, or after administration of the PD-1 antagonist.

[0437] Embodiment 113: The bispecific antibody for use of embodiment 112, wherein when the administration of the bispecific antibody is prior to the administration of the PD-1 antagonist, the gap between the end of the administration of the bispecific antibody and the beginning of the administration of the PD-1 antagonist is at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes, and / or up to about 14 days (up to about 2 weeks), up to about 13 days, up to about 12 days, up to about 11 days, up to about 10 days, up to about 9 days, up to about 8 days, up to about 7 days (up to about 1 week), up to about 6 days, up to about 5 days, up to about 4 days, up to about 3 days, up to about 2 days, up to about 1 day (up to about 24 hours), up to about 18 hours, up to about 12 hours, up to about 6 hours, up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2.5 hours, or up to about 2 hours.

[0438] Embodiment 114: The bispecific antibody for use of embodiment 112, wherein when the administration of the bispecific antibody is after the administration of the PD-1 antagonist, the gap between the end of the administration of the PD-1 antagonist and the beginning of the administration of the bispecific antibody is at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes, and / or up to about 14 days (up to about 2 weeks), up to about 13 days, up to about 12 days, up to about 11 days, up to about 10 days, up to about 9 days, up to about 8 days, up to about 7 days (up to about 1 week), up to about 6 days, up to about 5 days, up to about 4 days, up to about 3 days, up to about 2 days, up to about 1 day (up to about 24 hours), up to about 18 hours, up to about 12 hours, up to about 6 hours, up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2.5 hours, or up to about 2 hours.

[0439] Embodiment 115: A PD-1 antagonist for use in a method for treating non-small cell lung cancer (NSCLC) in a human subject, said method comprising administering to said subject the PD-1 antagonist with a bispecific antibody, wherein:

[0440] (a) the PD-1 antagonist is an anti -PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 33, 34 and 35, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37 and 38, respectively; and

[0441] (b) the bispecific antibody comprises a first binding region binding to CD 137 and a second binding region binding to PD-L1, wherein the first binding region comprises a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, GAS, and SEQ ID NO: 7, respectively, and the second binding region comprises a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 13, DDN, and SEQ ID NO: 14, respectively.

[0442] Embodiment 116: The PD-1 antagonist for use of embodiment 115, wherein the first binding region of the bispecific antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 5; and the second binding region of the bispecific antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 8 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 12.

[0443] Embodiment 117: The PD-1 antagonist for use of either embodiment 115 or embodiment 116, wherein said bispecific antibody comprises a first heavy chain and a first light chain comprising said first binding region binding to CD 137, wherein the first heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 15, and the first light chain comprises the amino acid sequence set forth in SEQ ID NO: 16; and a second heavy chain and a second light chain comprising said second binding region binding to PD-L1, wherein the second heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 17, and the second light chain comprises the amino acid sequence set forth in SEQ ID NO: 18.

[0444] Embodiment 118: The PD-1 antagonist for use of any one of embodiments 115 to 117, wherein said bispecific antibody is acasunlimab or a biosimilar thereof.

[0445] Embodiment 119: The PD-1 antagonist for use of any one of embodiments 115 to 118, wherein the bispecific antibody is in a composition or formulation comprising histidine, sucrose, and Polysorbate- 80, and having a pH from 5 to 6, preferably in a composition or formulation comprising about 20 mM histidine, about 250 mM sucrose, about 0.02% Polysorbate-80, and having a pH of about 5.5.

[0446] Embodiment 120: The PD-1 antagonist for use of any one of embodiments 115 to 119, wherein said PD-1 antagonist comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 29, and a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 30.

[0447] Embodiment 121: The PD-1 antagonist for use of any one of embodiments 115 to 120, wherein said PD-1 antagonist comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 31, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 32.

[0448] Embodiment 122: The PD-1 antagonist for use of any one of embodiments 115 to 121, wherein said PD-1 antagonist is pembrolizumab or a biosimilar thereof.

[0449] Embodiment 123: The PD-1 antagonist for use of any one of embodiments 115 to 122, wherein said human subject exhibits median progression-free survival (PFS) of at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least about 20 weeks after administration of said bispecific antibody and said PD-1 antagonist.

[0450] Embodiment 124: The PD-1 antagonist for use of any one of embodiments 115 to 123, wherein said human subject exhibits 6-month PFS of at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, or at least about 40% after administration of said bispecific antibody and said PD-1 antagonist. Embodiment 125: The PD-1 antagonist for use of any one of embodiments 115 to 124, wherein said human subject exhibits median overall survival (OS) of at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, at least about 26 weeks, at least about 28 weeks, at least about 30 weeks, at least about 32 weeks, at least about 34 weeks, at least about 36 weeks, at least about 38 weeks, at least about 40 weeks, at least about 42 weeks, at least about 44 weeks, at least about 46 weeks, at least about 48 weeks, at least about 50 weeks, at least about 52 weeks, at least about 54 weeks, at least about 56 weeks, at least about 58 weeks, at least about 60 weeks, at least about 62 weeks, at least about 64 weeks, at least about 66 weeks, at least about 68 weeks, at least about 70 weeks, at least about 72 weeks, at least about 74 weeks, at least about 76 weeks, at least about 78 weeks, or at least about 80 weeks after administration of said bispecific antibody and said PD-1 antagonist.

[0451] Embodiment 126: The PD-1 antagonist for use of any one of embodiments 115 to 125, wherein said human subject exhibits 12-month overall survival of at least about 40%, at least about 42%, at least about 44%, at least about 46%, at least about 48%, at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, or at least about 70% after administration of said bispecific antibody and said PD-1 antagonist.

[0452] Embodiment 127: The PD-1 antagonist for use of any one of embodiments 115 to 126, wherein the objective response rate (ORR) is at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, or at least about 30% after administration of said bispecific antibody and said PD-1 antagonist.

[0453] Embodiment 128: The PD-1 antagonist for use of any one of embodiments 115 to 127, wherein the disease control rate (DCR) is at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, at least about 70%, at least about 72%, at least about 74%, at least about 76%, at least about 78%, or at least about 80% after administration of said bispecific antibody and said PD-1 antagonist.

[0454] Embodiment 129: The PD-1 antagonist for use of any one of embodiments 115 to 128, wherein said human subject exhibits median duration of response (DOR) of at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, or at least about 18 months after administration of said bispecific antibody and said PD-1 antagonist.

[0455] Embodiment 130: The PD-1 antagonist for use of any one of embodiments 115 to 129, wherein the incidence of grade A3 liver-related adverse events (AEs) for the treated human subject is about 16% or lower, about 15% or lower, about 14% or lower, about 13% or lower, about 12% or lower, about 11% or lower, or about 10% or lower.

[0456] Embodiment 131: The PD-1 antagonist for use of any one of embodiments 115 to 130, wherein the human subject exhibits median time to resolution of grade A3 liver-related adverse events (AEs) of about 15 days or less, about 14 days or less, about 13 days or less, about 12 days or less, about 11 days or less, or about 10 days or less.

[0457] Embodiment 132: The PD-1 antagonist for use of any one of embodiments 115 to 131, wherein the bispecific antibody and / or the PD-1 antagonist are administered in at least one treatment cycle, each treatment cycle being three weeks (21 days) or six weeks (42 days).

[0458] Embodiment 133: The PD-1 antagonist for use of any one of embodiments 115 to 132, wherein one dose of the bispecific antibody and / or one dose of the PD-1 antagonist are administered every third week (Q3W).

[0459] Embodiment 134: The PD-1 antagonist for use of any one of embodiments 115 to 132, wherein one dose of the bispecific antibody and / or one dose of the PD-1 antagonist are administered every six weeks (Q6W).

[0460] Embodiment 135: The PD-1 antagonist for use of any one of embodiments 115 to 134, wherein one dose of the bispecific antibody and one dose of the PD-1 antagonist are administered on day 1 of each treatment cycle.

[0461] Embodiment 136: The PD-1 antagonist for use of any one of embodiments 115 to 135, wherein the amount of said bispecific antibody administered in each dose and / or in each treatment cycle is about 100 mg. Embodiment 137: The PD-1 antagonist for use of any one of embodiments 115 to 136, wherein the amount of said PD-1 antagonist administered in each dose and / or in each treatment cycle is about 200 mg.

[0462] Embodiment 138: The PD-1 antagonist for use of any one of embodiments 115 to 136, wherein the amount of said PD-1 antagonist administered in each dose and / or in each treatment cycle is about 400 mg.

[0463] Embodiment 139: The PD-1 antagonist for use of any one of embodiments 115 to 132, wherein an approximate 100 mg dose of the bispecific antibody and an approximate 200 mg dose of the PD-1 antagonist are administered every three weeks (Q3W).

[0464] Embodiment 140: The PD-1 antagonist for use of any one of embodiments 115 to 132, wherein an approximate 100 mg dose of the bispecific antibody and an approximate 400 mg dose of the PD-1 antagonist are administered every six weeks (Q6W).

[0465] Embodiment 141: The PD-1 antagonist for use of any one of embodiments 115 to 132, wherein an approximate 100 mg dose of acasunlimab or a biosimilar thereof and an approximate 200 mg dose of pembrolizumab or a biosimilar thereof are administered every three weeks (Q3W), such as on day 1 of each three-week treatment cycle.

[0466] Embodiment 142: The PD-1 antagonist for use of any one of embodiments 115 to 132, wherein an approximate 100 mg dose of acasunlimab or a biosimilar thereof and an approximate 400 mg dose of pembrolizumab or a biosimilar thereof are administered every six weeks (Q6W), such as on day 1 of every six- week treatment cycle.

[0467] Embodiment 143: The PD-1 antagonist for use of any one of embodiments 115 to 142, wherein the bispecific antibody and / or the PD-1 antagonist are administered systemically, such as by injection or infusion, in particular by intravenous (IV) infusion.

[0468] Embodiment 144: The PD-1 antagonist for use of any one of embodiments 115 to 143, wherein the PD- 1 antagonist is administered first, followed by the bispecific antibody, preferably wherein the time between infusions is approximately 30 minutes or longer.

[0469] Embodiment 145: The PD-1 antagonist for use of any one of embodiments 115 to 144, wherein said cancer is squamous or non-squamous NSCLC. Embodiment 146: The PD-1 antagonist for use of any one of embodiments 115 to 145, wherein the cancer is metastatic, such as metastatic NSCLC (mNSCLC).

[0470] Embodiment 147: The PD-1 antagonist for use of any one of embodiments 115 to 146, wherein the cancer is a histologically or cytologically confirmed stage 4 NSCLC.

[0471] Embodiment 148: The PD-1 antagonist for use of any one of embodiments 115 to 147, wherein the cancer has relapsed and / or is refractory after prior treatment, such as systemic treatment with a checkpoint inhibitor.

[0472] Embodiment 149: The PD-1 antagonist for use of any one of embodiments 115 to 148, wherein the human subject has demonstrated disease progression (PD), such as PD defined by RECIST vl.l, after prior treatment, such as systemic treatment with a checkpoint inhibitor.

[0473] Embodiment 150: The PD-1 antagonist for use of any one of embodiments 115 to 149, wherein the human subject has received at least 1 prior line of systemic therapy, such as systemic therapy comprising a PD-1 inhibitor and / or a PD-L1 inhibitor, such as an anti-PD-1 antibody and / or an anti-PD-Ll antibody.

[0474] Embodiment 151: The PD-1 antagonist for use of any one of embodiments 115 to 150, wherein the human subject has demonstrated disease progression (PD) after prior treatment with a PD-1 inhibitor or PD-L1 inhibitor, such as an anti-PD-1 antibody or an anti-PD-Ll antibody, the PD-1 inhibitor or PD- L1 inhibitor being administered as monotherapy or as part of a combination therapy.

[0475] Embodiment 152: The PD-1 antagonist for use of any one of embodiments 115 to 151, wherein last prior treatment was with a PD-1 inhibitor or PD-L1 inhibitor, such as an anti-PD-1 antibody or an anti- PD-Ll antibody, the PD-1 inhibitor or PD-L1 inhibitor being administered as monotherapy or as part of a combination therapy, such as a combination therapy with a platinum-based chemotherapy.

[0476] Embodiment 153: The PD-1 antagonist for use of any one of embodiments 115 to 152, wherein the human subject has demonstrated disease progression (PD) during or after platinum doublet chemotherapy following treatment with an anti-PD-1 antibody or an anti-PD-Ll antibody.

[0477] Embodiment 154: The PD-1 antagonist for use of any one of embodiments 115 to 153, wherein the human subject has demonstrated disease progression (PD) during or after prior treatment with an anti- PD-1 antibody or an anti-PD-Ll antibody following platinum doublet chemotherapy. Embodiment 155: The PD-1 antagonist for use of any one of embodiments 115 to 154, wherein the human subject has relapsed or refractory mNSCLC after prior treatment with an immune checkpoint inhibitor, such as an anti-PD-1 antibody or an anti-PD-Ll antibody.

[0478] Embodiment 156: The PD-1 antagonist for use of any one of embodiments 115 to 155, wherein the cancer has relapsed and / or is refractory, or the human subject has progressed during or after prior standard-of-care (SOC) treatment for metastatic NSCLC, such as a combination of a checkpoint inhibitor (CPI), such as a PD-1 inhibitor or PD-L1 inhibitor, and a platinum-based chemotherapy.

[0479] Embodiment 157: The PD-1 antagonist for use of embodiment 156, wherein the PD-1 or PD-L1 inhibitor and the platinum-based chemotherapy are administrated concomitantly, or the PD-1 or PD-L1 inhibitor and the platinum-based chemotherapy are administrated sequentially, irrespective of the order.

[0480] Embodiment 158: The PD-1 antagonist for use of any one of embodiments 115 to 157, wherein the human subject has had at least 6 weeks of prior treatment comprising a PD-1 inhibitor or PD-L1 inhibitor, and preferably said human subject has had clinical benefit, such as defined as documented radiographic stable disease (SD) or better, on said prior treatment comprising a PD-1 inhibitor or PD- L1 inhibitor.

[0481] Embodiment 159: The PD-1 antagonist for use of any one of embodiments 115 to 158, wherein the human subject has a PD-L1 positive tumor, preferably as determined by an FDA-approved test.

[0482] Embodiment 160: The PD-1 antagonist for use of any one of embodiments 115 to 159, wherein the human subject has a tumor with PD-L1 expressed in A 1% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (TPS) 1%.

[0483] Embodiment 161: The PD-1 antagonist for use of any one of embodiments 115 to 160, wherein the human subject has a tumor with PD-L1 expressed in 50% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (TPS) 50%.

[0484] Embodiment 162: The PD-1 antagonist for use of any one of embodiments 115 to 161, wherein the human subject has a tumor with PD-L1 expressed in A I % and 49% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (TPS) 49%.

[0485] Embodiment 163: The PD-1 antagonist for use of any one of embodiments 115 to 162, wherein the human subject has a PD-L1 positive tumor as determined by an FDA-approved test, such as a tumor with a TPS 1%, and the human subject has progressed during or after prior treatment with a combination of a PD-1 inhibitor or PD-L1 inhibitor and a platinum-based chemotherapy.

[0486] Embodiment 164: The PD-1 antagonist for use of any one of embodiments 115 to 163, wherein the PD- 1 inhibitor or PD-L1 inhibitor and the platinum-based chemotherapy are administrated concomitantly or sequentially, irrespective of the order.

[0487] Embodiment 165: The PD-1 antagonist for use of any one of embodiments 115 to 164, wherein the human subject has Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1.

[0488] Embodiment 166: The PD-1 antagonist for use of any one of embodiments 115 to 165, wherein the human subject has a tumor that does not have EGFR sensitizing mutation, KRAS mutation, RET mutation, ROS1 mutation, BRAF mutation, NTRK gene infusion, RET rearrangement, ALK gene rearrangement, high-level MET amplification, or METex 14 skipping.

[0489] Embodiment 167: The PD-1 antagonist for use of any one of embodiments 115 to 166, wherein the human subject has not received prior treatment with a 4- IBB (CD 137) targeting agent, such as an anti- 4-1BB (CD137) antibody, with an antitumor vaccine, or with autologous cell immunotherapy.

[0490] Embodiment 168: The PD-1 antagonist for use of any one of embodiments 115 to 167, wherein the human subject has not received prior treatment with a taxane chemotherapeutic agent, such as docetaxel, such as prior treatment for NSCLC with a taxane chemotherapeutic agent, such as docetaxel.

[0491] Embodiment 169: The PD-1 antagonist for use of any one of embodiments 115 to 168, wherein the PD- 1 antagonist is administered prior to, simultaneously with, or after administration of the bispecific antibody.

[0492] Embodiment 170: The PD-1 antagonist for use of embodiment 169, wherein when the administration of the PD-1 antagonist is prior to the administration of the bispecific antibody, the gap between the end of the administration of the PD-1 antagonist and the beginning of the administration of the bispecific antibody is at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes, and / or up to about 14 days (up to about 2 weeks), up to about 13 days, up to about 12 days, up to about 11 days, up to about 10 days, up to about 9 days, up to about 8 days, up to about 7 days (up to about 1 week), up to about 6 days, up to about 5 days, up to about 4 days, up to about 3 days, up to about 2 days, up to about 1 day (up to about 24 hours), up to about 18 hours, up to about 12 hours, up to about 6 hours, up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2.5 hours, or up to about 2 hours.

[0493] Embodiment 171: The PD-1 antagonist for use of embodiment 169, wherein when the administration of the PD-1 antagonist is after the administration of the bispecific antibody, the gap between the end of the administration of the bispecific antibody and the beginning of the administration of the PD-1 antagonist is at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes, and / or up to about 14 days (up to about 2 weeks), up to about 13 days, up to about 12 days, up to about 11 days, up to about 10 days, up to about 9 days, up to about 8 days, up to about 7 days (up to about 1 week), up to about 6 days, up to about 5 days, up to about 4 days, up to about 3 days, up to about 2 days, up to about 1 day (up to about 24 hours), up to about 18 hours, up to about 12 hours, up to about 6 hours, up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2.5 hours, or up to about 2 hours.

[0494] Embodiment 172: A combination for treating cancer in a human subject, wherein the combination comprises a bispecific antibody and a PD-1 antagonist, wherein:

[0495] (a) the bispecific antibody comprises a first binding region binding to CD 137 and a second binding region binding to PD-L1, wherein the first binding region comprises a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, GAS, and SEQ ID NO: 7, respectively, and the second binding region comprises a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 13, DDN, and SEQ ID NO: 14, respectively; and

[0496] (b) the PD-1 antagonist is an anti -PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 33, 34 and 35, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37 and 38, respectively; wherein said cancer is non-small cell lung cancer (NSCLC).

[0497] Embodiment 173: The combination of embodiment 172, wherein the first binding region of the bispecific antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 5; and the second binding region of the bispecific antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 8 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 12.

[0498] Embodiment 174: The combination of either embodiment 172 or embodiment 173, wherein said bispecific antibody comprises a first heavy chain and a first light chain comprising said first binding region binding to CD 137, wherein the first heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 15, and the first light chain comprises the amino acid sequence set forth in SEQ ID NO: 16; and a second heavy chain and a second light chain comprising said second binding region binding to PD-L1, wherein the second heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 17, and the second light chain comprises the amino acid sequence set forth in SEQ ID NO: 18.

[0499] Embodiment 175: The combination of any one of embodiments 172 to 174, wherein said bispecific antibody is acasunlimab or a biosimilar thereof.

[0500] Embodiment 176: The combination of any one of embodiments 172 to 175, wherein the bispecific antibody is in a composition or formulation comprising histidine, sucrose, and Polysorbate-80, and having a pH from 5 to 6, preferably in a composition or formulation comprising about 20 mM histidine, about 250 mM sucrose, about 0.02% Polysorbate-80, and having a pH of about 5.5.

[0501] Embodiment 177: The combination of any one of embodiments 172 to 176, wherein said PD-1 antagonist comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 29, and a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 30.

[0502] Embodiment 178: The combination of any one of embodiments 172 to 177, wherein said PD-1 antagonist comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 31, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 32.

[0503] Embodiment 179: The combination of any one of embodiments 172 to 178, wherein said PD-1 antagonist is pembrolizumab or a biosimilar thereof.

[0504] Embodiment 180: The combination of any one of embodiments 172 to 179, wherein said human subject exhibits median progression-free survival (PFS) of at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least about 20 weeks after administration of the combination. Embodiment 181: The combination of any one of embodiments 172 to 180, wherein said human subject exhibits 6-month PFS of at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, or at least about 40% after administration of the combination.

[0505] Embodiment 182: The combination of any one of embodiments 172 to 181, wherein said human subject exhibits median overall survival (OS) of at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, at least about 26 weeks, at least about 28 weeks, at least about 30 weeks, at least about 32 weeks, at least about 34 weeks, at least about 36 weeks, at least about 38 weeks, at least about 40 weeks, at least about 42 weeks, at least about 44 weeks, at least about 46 weeks, at least about 48 weeks, at least about 50 weeks, at least about 52 weeks, at least about 54 weeks, at least about 56 weeks, at least about 58 weeks, at least about 60 weeks, at least about 62 weeks, at least about 64 weeks, at least about 66 weeks, at least about 68 weeks, at least about 70 weeks, at least about 72 weeks, at least about 74 weeks, at least about 76 weeks, at least about 78 weeks, or at least about 80 weeks after administration of the combination.

[0506] Embodiment 183: The combination of any one of embodiments 172 to 182, wherein said human subject exhibits 12-month overall survival of at least about 40%, at least about 42%, at least about 44%, at least about 46%, at least about 48%, at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, or at least about 70% after administration of the combination.

[0507] Embodiment 184: The combination of any one of embodiments 172 to 183, wherein the objective response rate (ORR) is at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, or at least about 30% after administration of the combination.

[0508] Embodiment 185: The combination of any one of embodiments 172 to 184, wherein the disease control rate (DCR) is at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, at least about 70%, at least about 72%, at least about 74%, at least about 76%, at least about 78%, or at least about 80% after administration of the combination.

[0509] Embodiment 186: The combination of any one of embodiments 172 to 185, wherein said human subject exhibits median duration of response (DOR) of at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, or at least about 18 months after administration of the combination.

[0510] Embodiment 187: The combination of any one of embodiments 172 to 186, wherein the incidence of grade A 3 liver-related adverse events (AEs) for the human subject after administration of the combination is about 16% or lower, about 15% or lower, about 14% or lower, about 13% or lower, about 12% or lower, about 11% or lower, or about 10% or lower.

[0511] Embodiment 188: The combination of any one of embodiments 172 to 187, wherein the human subject exhibits median time to resolution of grade A3 liver-related adverse events (AEs) of about 15 days or less, about 14 days or less, about 13 days or less, about 12 days or less, about 11 days or less, or about 10 days or less.

[0512] Embodiment 189: The combination of any one of embodiments 172 to 188, wherein the bispecific antibody and / or the PD-1 antagonist are administered in at least one treatment cycle, each treatment cycle being three weeks (21 days) or six weeks (42 days).

[0513] Embodiment 190: The combination of any one of embodiments 172 to 189, wherein one dose of the bispecific antibody and / or one dose of the PD-1 antagonist are administered every third week (Q3W).

[0514] Embodiment 191: The combination of any one of embodiments 172 to 189, wherein one dose of the bispecific antibody and / or one dose of the PD-1 antagonist are administered every six weeks (Q6W).

[0515] Embodiment 192: The combination of any one of embodiments 172 to 191, wherein one dose of the bispecific antibody and one dose of the PD-1 antagonist are administered on day 1 of each treatment cycle.

[0516] Embodiment 193: The combination of any one of embodiments 172 to 192, wherein the amount of said bispecific antibody administered in each dose and / or in each treatment cycle is about 100 mg. Embodiment 194: The combination of any one of embodiments 172 to 193, wherein the amount of said PD-1 antagonist administered in each dose and / or in each treatment cycle is about 200 mg.

[0517] Embodiment 195: The combination of any one of embodiments 172 to 193, wherein the amount of said PD-1 antagonist administered in each dose and / or in each treatment cycle is about 400 mg.

[0518] Embodiment 196: The combination of any one of embodiments 172 to 189, wherein an approximate 100 mg dose of the bispecific antibody and an approximate 200 mg dose of the PD-1 antagonist are administered every three weeks (Q3W).

[0519] Embodiment 197: The combination of any one of embodiments 172 to 189, wherein an approximate 100 mg dose of the bispecific antibody and an approximate 400 mg dose of the PD-1 antagonist are administered every six weeks (Q6W).

[0520] Embodiment 198: The combination of any one of embodiments 172 to 189, wherein an approximate 100 mg dose of acasunlimab or a biosimilar thereof and an approximate 200 mg dose of pembrolizumab or a biosimilar thereof are administered every three weeks (Q3W), such as on day 1 of each three-week treatment cycle.

[0521] Embodiment 199: The combination of any one of embodiments 172 to 189, wherein an approximate 100 mg dose of acasunlimab or a biosimilar thereof and an approximate 400 mg dose of pembrolizumab or a biosimilar thereof are administered every six weeks (Q6W), such as on day 1 of every six-week treatment cycle.

[0522] Embodiment 200: The combination of any one of embodiments 172 to 199, wherein the bispecific antibody and / or the PD-1 antagonist are administered systemically, such as by injection or infusion, in particular by intravenous (IV) infusion.

[0523] Embodiment 201 : The combination of any one of embodiments 172 to 200, wherein the PD- 1 antagonist is administered first, followed by the bispecific antibody, preferably wherein the time between infusions is approximately 30 minutes or longer.

[0524] Embodiment 202: The combination of any one of embodiments 172 to 201, wherein said cancer is squamous or non-squamous NSCLC.

[0525] Embodiment 203: The combination of any one of embodiments 172 to 202, wherein the cancer is metastatic, such as metastatic NSCLC (mNSCLC). Embodiment 204: The combination of any one of embodiments 172 to 203, wherein the cancer is a histologically or cytologically confirmed stage 4 NSCLC.

[0526] Embodiment 205: The combination of any one of embodiments 172 to 204, wherein the cancer has relapsed and / or is refractory after prior treatment, such as systemic treatment with a checkpoint inhibitor.

[0527] Embodiment 206: The combination of any one of embodiments 172 to 205, wherein the human subject has demonstrated disease progression (PD), such as PD defined by RECIST vl.l, after prior treatment, such as systemic treatment with a checkpoint inhibitor.

[0528] Embodiment 207: The combination of any one of embodiments 172 to 206, wherein the human subject has received at least 1 prior line of systemic therapy, such as systemic therapy comprising a PD-1 inhibitor and / or a PD-L1 inhibitor, such as an anti-PD-1 antibody and / or an anti-PD-Ll antibody.

[0529] Embodiment 208: The combination of any one of embodiments 172 to 207, wherein the human subject has demonstrated disease progression (PD) after prior treatment with a PD-1 inhibitor or PD-L1 inhibitor, such as an anti-PD-1 antibody or an anti-PD-Ll antibody, the PD-1 inhibitor or PD-L1 inhibitor being administered as monotherapy or as part of a combination therapy.

[0530] Embodiment 209: The combination of any one of embodiments 172 to 208, wherein last prior treatment was with a PD-1 inhibitor or PD-L1 inhibitor, such as an anti-PD-1 antibody or an anti-PD-Ll antibody, the PD-1 inhibitor or PD-L1 inhibitor being administered as monotherapy or as part of a combination therapy, such as a combination therapy with a platinum-based chemotherapy.

[0531] Embodiment 210: The combination of any one of embodiments 172 to 209, wherein the human subject has demonstrated disease progression (PD) during or after platinum doublet chemotherapy following treatment with an anti-PD-1 antibody or an anti-PD-Ll antibody.

[0532] Embodiment 211: The combination of any one of embodiments 172 to 210, wherein the human subject has demonstrated disease progression (PD) during or after prior treatment with an anti-PD-1 antibody or an anti-PD-Ll antibody following platinum doublet chemotherapy.

[0533] Embodiment 212: The combination of any one of embodiments 172 to 211, wherein the human subject has relapsed or refractory mNSCLC after prior treatment with an immune checkpoint inhibitor, such as an anti-PD-1 antibody or an anti-PD-Ll antibody. Embodiment 213: The combination of any one of embodiments 172 to 212, wherein the cancer has relapsed and / or is refractory, or the human subject has progressed during or after prior standard-of-care (SOC) treatment for metastatic NSCLC, such as a combination of a checkpoint inhibitor (CPI), such as a PD-1 inhibitor or PD-L1 inhibitor, and a platinum-based chemotherapy.

[0534] Embodiment 214: The combination of embodiment 213, wherein the PD-1 or PD-L1 inhibitor and the platinum-based chemotherapy are administrated concomitantly, or the PD-1 or PD-L1 inhibitor and the platinum-based chemotherapy are administrated sequentially, irrespective of the order.

[0535] Embodiment 215: The combination of any one of embodiments 172 to 214, wherein the human subject has had at least 6 weeks of prior treatment comprising a PD-1 inhibitor or PD-L1 inhibitor, and preferably said human subject has had clinical benefit, such as defined as documented radiographic stable disease (SD) or better, on said prior treatment comprising a PD-1 inhibitor or PD-L1 inhibitor.

[0536] Embodiment 216: The combination of any one of embodiments 172 to 215, wherein the human subject has a PD-L1 positive tumor, preferably as determined by an FDA-approved test.

[0537] Embodiment 217: The combination of any one of embodiments 172 to 216, wherein the human subject has a tumor with PD-L1 expressed in 1% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (

[0538] Embodiment 218: The combination of any one of embodiments 172 to 217, wherein the human subject has a tumor with PD-L1 expressed in 50% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (

[0539] Embodiment 219: The combination of any one of embodiments 172 to 218, wherein the human subject has a tumor with PD-L1 expressed in A 49% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (TPS) 49%.

[0540] Embodiment 220: The combination of any one of embodiments 172 to 219, wherein the human subject has a PD-L1 positive tumor as determined by an FDA-approved test, such as a tumor with a TPS 1%, and the human subject has progressed during or after prior treatment with a combination of a PD-1 inhibitor or PD-L1 inhibitor and a platinum-based chemotherapy.

[0541] Embodiment 221: The combination of any one of embodiments 172 to 220, wherein the PD-1 inhibitor or PD-L1 inhibitor and the platinum-based chemotherapy are administrated concomitantly or sequentially, irrespective of the order. Embodiment 222: The combination of any one of embodiments 172 to 221, wherein the human subject has Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1.

[0542] Embodiment 223: The combination of any one of embodiments 172 to 222, wherein the human subject has a tumor that does not have EGFR sensitizing mutation, KRAS mutation, RET mutation, ROS1 mutation, BRAF mutation, NTRK gene infusion, RET rearrangement, ALK gene rearrangement, high- level MET amplification, or METex 14 skipping.

[0543] Embodiment 224: The combination of any one of embodiments 172 to 223, wherein the human subject has not received prior treatment with a 4- 1 BB (CD 137) targeting agent, such as an anti-4- IBB (CD 137) antibody, with an antitumor vaccine, or with autologous cell immunotherapy.

[0544] Embodiment 225: The combination of any one of embodiments 172 to 224, wherein the human subject has not received prior treatment with a taxane chemotherapeutic agent, such as docetaxel, such as prior treatment forNSCLC with a taxane chemotherapeutic agent, such as docetaxel.

[0545] Embodiment 226: The combination of any one of embodiments 172 to 225, wherein the bispecific antibody is administered prior to, simultaneously with, or after administration of the PD-1 antagonist.

[0546] Embodiment 227: The combination of embodiment 226, wherein when the administration of the bispecific antibody is prior to the administration of the PD-1 antagonist, the gap between the end of the administration of the bispecific antibody and the beginning of the administration of the PD-1 antagonist is at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes, and / or up to about 14 days (up to about 2 weeks), up to about 13 days, up to about 12 days, up to about 11 days, up to about 10 days, up to about 9 days, up to about 8 days, up to about 7 days (up to about 1 week), up to about 6 days, up to about 5 days, up to about 4 days, up to about 3 days, up to about 2 days, up to about 1 day (up to about 24 hours), up to about 18 hours, up to about 12 hours, up to about 6 hours, up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2.5 hours, or up to about 2 hours.

[0547] Embodiment 228: The combination of embodiment 226, wherein when the administration of the bispecific antibody is after the administration of the PD-1 antagonist, the gap between the end of the administration of the PD-1 antagonist and the beginning of the administration of the bispecific antibody is at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes, and / or up to about 14 days (up to about 2 weeks), up to about 13 days, up to about 12 days, up to about 11 days, up to about 10 days, up to about 9 days, up to about 8 days, up to about 7 days (up to about 1 week), up to about 6 days, up to about 5 days, up to about 4 days, up to about 3 days, up to about 2 days, up to about 1 day (up to about 24 hours), up to about 18 hours, up to about 12 hours, up to about 6 hours, up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2.5 hours, or up to about 2 hours.

[0548] Embodiment 229: Use of a bispecific antibody for the manufacture of a medicament for the treatment of non-small cell lung cancer (NSCLC) in a human subject, wherein said medicament is administered to said subject with a PD-1 antagonist, and wherein:

[0549] (a) the bispecific antibody comprises a first binding region binding to CD 137 and a second binding region binding to PD-L1, wherein the first binding region comprises a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, GAS, and SEQ ID NO: 7, respectively, and the second binding region comprises a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 13, DDN, and SEQ ID NO: 14, respectively; and

[0550] (b) the PD-1 antagonist is an anti -PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 33, 34 and 35, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37 and 38, respectively.

[0551] Embodiment 230: The use of embodiment 229, wherein the first binding region of the bispecific antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 5; and the second binding region of the bispecific antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 8 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 12.

[0552] Embodiment 231: The use of either embodiment 229 or embodiment 230, wherein said bispecific antibody comprises a first heavy chain and a first light chain comprising said first binding region binding to CD137, wherein the first heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 15, and the first light chain comprises the amino acid sequence set forth in SEQ ID NO: 16; and a second heavy chain and a second light chain comprising said second binding region binding to PD-L1, wherein the second heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 17, and the second light chain comprises the amino acid sequence set forth in SEQ ID NO: 18.

[0553] Embodiment 232: The use of any one of embodiments 229 to 231, wherein said bispecific antibody is acasunlimab or a biosimilar thereof.

[0554] Embodiment 233: The use of any one of embodiments 229 to 232, wherein the bispecific antibody is in a composition or formulation comprising histidine, sucrose, and Polysorbate-80, and having a pH from 5 to 6, preferably in a composition or formulation comprising about 20 mM histidine, about 250 mM sucrose, about 0.02% Polysorbate-80, and having a pH of about 5.5.

[0555] Embodiment 234: The use of any one of embodiments 229 to 233, wherein said PD-1 antagonist comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 29, and a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 30.

[0556] Embodiment 235: The use of any one of embodiments 229 to 233, wherein said PD-1 antagonist comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 31, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 32.

[0557] Embodiment 236: The use of any one of embodiments 229 to 235, wherein said PD-1 antagonist is pembrolizumab or a biosimilar thereof.

[0558] Embodiment 237: The use of any one of embodiments 229 to 236, wherein said human subject exhibits median progression-free survival (PFS) of at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least about 20 weeks after administration of said medicament and said PD- 1 antagonist.

[0559] Embodiment 238: The use of any one of embodiments 229 to 237, wherein said human subject exhibits 6-month PFS of at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, or at least about 40% after administration of said medicament and said PD-1 antagonist. Embodiment 239: The use of any one of embodiments 229 to 238, wherein said human subject exhibits median overall survival (OS) of at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, at least about 26 weeks, at least about 28 weeks, at least about 30 weeks, at least about 32 weeks, at least about 34 weeks, at least about 36 weeks, at least about 38 weeks, at least about 40 weeks, at least about 42 weeks, at least about 44 weeks, at least about 46 weeks, at least about 48 weeks, at least about 50 weeks, at least about 52 weeks, at least about 54 weeks, at least about 56 weeks, at least about 58 weeks, at least about 60 weeks, at least about 62 weeks, at least about 64 weeks, at least about 66 weeks, at least about 68 weeks, at least about 70 weeks, at least about 72 weeks, at least about 74 weeks, at least about 76 weeks, at least about 78 weeks, or at least about 80 weeks after administration of said medicament and said PD-1 antagonist.

[0560] Embodiment 240: The use of any one of embodiments 229 to 239, wherein said human subject exhibits 12-month overall survival of at least about 40%, at least about 42%, at least about 44%, at least about 46%, at least about 48%, at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, or at least about 70% after administration of said medicament and said PD-1 antagonist.

[0561] Embodiment 241: The use of any one of embodiments 229 to 240, wherein the objective response rate (ORR) is at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, or at least about 30% after administration of said medicament and said PD-1 antagonist.

[0562] Embodiment 242: The use of any one of embodiments 229 to 241, wherein the disease control rate (DCR) is at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, at least about 70%, at least about 72%, at least about 74%, at least about 76%, at least about 78%, or at least about 80% after administration of said medicament and said PD-1 antagonist.

[0563] Embodiment 243: The use of any one of embodiments 229 to 242, wherein said human subject exhibits median duration of response (DOR) of at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, or at least about 18 months after administration of said medicament and said PD- 1 antagonist.

[0564] Embodiment 244: The use of any one of embodiments 229 to 243, wherein the incidence of grade A3 liver-related adverse events (AEs) for the treated human subject is about 16% or lower, about 15% or lower, about 14% or lower, about 13% or lower, about 12% or lower, about 11% or lower, or about 10% or lower.

[0565] Embodiment 245: The use of any one of embodiments 229 to 244, wherein the human subject exhibits median time to resolution of grade A3 liver-related adverse events (AEs) of about 15 days or less, about 14 days or less, about 13 days or less, about 12 days or less, about 11 days or less, or about 10 days or less.

[0566] Embodiment 246: The use of any one of embodiments 229 to 245, wherein the medicament and / or the PD-1 antagonist are administered in at least one treatment cycle, each treatment cycle being three weeks (21 days) or six weeks (42 days).

[0567] Embodiment 247 : The use of any one of embodiments 229 to 246, wherein one dose of the medicament and / or one dose of the PD-1 antagonist are administered every third week (Q3W).

[0568] Embodiment 248: The use of any one of embodiments 229 to 246, wherein one dose of the medicament and / or one dose of the PD-1 antagonist are administered every six weeks (Q6W).

[0569] Embodiment 249: The use of any one of embodiments 229 to 248, wherein one dose of the medicament and one dose of the PD-1 antagonist are administered on day 1 of each treatment cycle.

[0570] Embodiment 250: The use of any one of embodiments 229 to 249, wherein the amount of said bispecific antibody in the medicament administered in each dose and / or in each treatment cycle is about 100 mg.

[0571] Embodiment 251: The use of any one of embodiments 229 to 250, wherein the amount of said PD-1 antagonist administered in each dose and / or in each treatment cycle is about 200 mg.

[0572] Embodiment 252: The use of any one of embodiments 229 to 250, wherein the amount of said PD-1 antagonist administered in each dose and / or in each treatment cycle is about 400 mg. Embodiment 253: The use of any one of embodiments 229 to 246, wherein an approximate 100 mg dose of the bispecific antibody and an approximate 200 mg dose of the PD-1 antagonist are administered every three weeks (Q3W).

[0573] Embodiment 254: The use of any one of embodiments 229 to 246, wherein an approximate 100 mg dose of the bispecific antibody and an approximate 400 mg dose of the PD-1 antagonist are administered every six weeks (Q6W).

[0574] Embodiment 255: The use of any one of embodiments 229 to 246, wherein an approximate 100 mg dose of acasunlimab or a biosimilar thereof and an approximate 200 mg dose of pembrolizumab or a biosimilar thereof are administered every three weeks (Q3W), such as on day 1 of each three-week treatment cycle.

[0575] Embodiment 256: The use of any one of embodiments 229 to 246, wherein an approximate 100 mg dose of acasunlimab or a biosimilar thereof and an approximate 400 mg dose of pembrolizumab or a biosimilar thereof are administered every six weeks (Q6W), such as on day 1 of every six-week treatment cycle.

[0576] Embodiment 257: The use of any one of embodiments 229 to 256, wherein the medicament and / or the PD-1 antagonist are administered systemically, such as by injection or infusion, in particular by intravenous (IV) infusion.

[0577] Embodiment 258: The use of any one of embodiments 229 to 257, wherein the PD-1 antagonist is administered first, followed by the medicament, preferably wherein the time between infusions is approximately 30 minutes or longer.

[0578] Embodiment 259: The use of any one of embodiments 229 to 258, wherein said cancer is squamous or non-squamous NSCLC.

[0579] Embodiment 260: The use of any one of embodiments 229 to 259, wherein the cancer is metastatic, such as metastatic NSCLC (mNSCLC).

[0580] Embodiment 261 : The use of any one of embodiments 229 to 260, wherein the cancer is a histologically or cytologically confirmed stage 4 NSCLC.

[0581] Embodiment 262: The use of any one of embodiments 229 to 261, wherein the cancer has relapsed and / or is refractory after prior treatment, such as systemic treatment with a checkpoint inhibitor. Embodiment 263: The use of any one of embodiments 229 to 262, wherein the human subject has demonstrated disease progression (PD), such as PD defined by RECIST vl.l, after prior treatment, such as systemic treatment with a checkpoint inhibitor.

[0582] Embodiment 264: The use of any one of embodiments 229 to 263, wherein the human subject has received at least 1 prior line of systemic therapy, such as systemic therapy comprising a PD-1 inhibitor and / or a PD-L1 inhibitor, such as an anti-PD-1 antibody and / or an anti-PD-Ll antibody.

[0583] Embodiment 265: The use of any one of embodiments 229 to 264, wherein the human subject has demonstrated disease progression (PD) after prior treatment with a PD-1 inhibitor or PD-L1 inhibitor, such as an anti-PD-1 antibody or an anti-PD-Ll antibody, the PD-1 inhibitor or PD-L1 inhibitor being administered as monotherapy or as part of a combination therapy.

[0584] Embodiment 266: The use of any one of embodiments 229 to 265, wherein last prior treatment was with a PD-1 inhibitor or PD-L1 inhibitor, such as an anti-PD-1 antibody or an anti-PD-Ll antibody, the PD-1 inhibitor or PD-L1 inhibitor being administered as monotherapy or as part of a combination therapy, such as a combination therapy with a platinum-based chemotherapy.

[0585] Embodiment 267: The use of any one of embodiments 229 to 266, wherein the human subject has demonstrated disease progression (PD) during or after platinum doublet chemotherapy following treatment with an anti-PD-1 antibody or an anti-PD-Ll antibody.

[0586] Embodiment 268: The use of any one of embodiments 229 to 267, where...

Claims

CLAIMS1. A method for treating cancer in a human subject, said method comprising administering to said human subject a bispecific antibody and a PD-1 antagonist, wherein:(a) the bispecific antibody comprises a first binding region binding to CD 137 and a second binding region binding to PD-L1, wherein the first binding region comprises a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, GAS, and SEQ ID NO: 7, respectively, and the second binding region comprises a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 13, DDN, and SEQ ID NO: 14, respectively; and(b) the PD-1 antagonist is an anti -PD-1 monoclonal antibody comprising a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 33, 34 and 35, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37 and 38, respectively; wherein said cancer is non-small cell lung cancer (NSCLC).

2. The method of claim 1, wherein the first binding region of the bispecific antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 5; and the second binding region of the bispecific antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 8 and a light chain variable region (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 12.

3. The method of either claim 1 or claim 2, wherein said bispecific antibody comprises a first heavy chain and a first light chain comprising said first binding region binding to CD 137, wherein the first heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 15, and the first light chain comprises the amino acid sequence set forth in SEQ ID NO: 16; and a second heavy chain and a second light chain comprising said second binding region binding to PD-L1, wherein the second heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 17, and the second light chain comprises the amino acid sequence set forth in SEQ ID NO: 18.

4. The method of any one of the preceding claims, wherein said bispecific antibody is acasunlimab or a biosimilar thereof.

5. The method of any one of the preceding claims, wherein the bispecific antibody is in a composition or formulation comprising histidine, sucrose, and Polysorbate-80, and having a pH from 5 to 6, preferably in a composition or formulation comprising about 20 mM histidine, about 250 mM sucrose, about 0.02% Polysorbate-80, and having a pH of about 5.5.

6. The method of any one of the preceding claims, wherein said PD-1 antagonist comprises a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 29, and a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 30.

7. The method of any one of the preceding claims, wherein said PD-1 antagonist comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 31, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 32.

8. The method of any one of the preceding claims, wherein said PD-1 antagonist is pembrolizumab or a biosimilar thereof.

9. The method of any one of the preceding claims, wherein said human subject exhibits median progression-free survival (PFS) of at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least about 20 weeks after administration of said bispecific antibody and said PD-1 antagonist.

10. The method of any one of the preceding claims, wherein said human subject exhibits 6-month PFS of at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, or at least about 40% after administration of said bispecific antibody and said PD-1 antagonist.

11. The method of any one of the preceding claims, wherein said human subject exhibits median overall survival (OS) of at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, at least about 26 weeks, at least about 28 weeks, at least about 30 weeks, at least about 32 weeks, at least about 34 weeks, at least about 36 weeks, at least about 38 weeks, at least about 40 weeks, at least about 42 weeks, at least about 44 weeks, at least about 46 weeks, at least about 48 weeks, at least about 50 weeks, at least about 52 weeks, at least about 54 weeks, at least about 56 weeks, at least about 58 weeks, at least about 60 weeks, at least about 62 weeks, at least about 64 weeks, at least about 66 weeks, at least about68 weeks, at least about 70 weeks, at least about 72 weeks, at least about 74 weeks, at least about 76 weeks, at least about 78 weeks, or at least about 80 weeks after administration of said bispecific antibody and said PD-1 antagonist.

12. The method of any one of the preceding claims, wherein said human subject exhibits 12-month overall survival of at least about 40%, at least about 42%, at least about 44%, at least about 46%, at least about 48%, at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, or at least about 70% after administration of said bispecific antibody and said PD-1 antagonist.

13. The method of any one of the preceding claims, wherein the objective response rate (ORR) is at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, or at least about 30% after administration of said bispecific antibody and said PD-1 antagonist.

14. The method of any one of the preceding claims, wherein the disease control rate (DCR) is at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, at least about 70%, at least about 72%, at least about 74%, at least about 76%, at least about 78%, or at least about 80% after administration of said bispecific antibody and said PD-1 antagonist.

15. The method of any one of the preceding claims, wherein said human subject exhibits median duration of response (DOR) of at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, or at least about 18 months after administration of said bispecific antibody and said PD-1 antagonist.

16. The method of any one of the preceding claims, wherein the incidence of grade >3 liver-related adverse events (AEs) for the treated human subject is about 16% or lower, about 15% or lower, about 14% or lower, about 13% or lower, about 12% or lower, about 11% or lower, or about 10% or lower.

17. The method of any one of the preceding claims, wherein the human subject exhibits median time to resolution of grade >3 liver-related adverse events (AEs) of about 15 days or less, about 14 days or less, about 13 days or less, about 12 days or less, about 11 days or less, or about 10 days or less.

18. The method of any one of the preceding claims, wherein the bispecific antibody and / or the PD- 1 antagonist are administered in at least one treatment cycle, each treatment cycle being three weeks (21 days) or six weeks (42 days).

19. The method of any one of the preceding claims, wherein one dose of the bispecific antibody and / or one dose of the PD-1 antagonist are administered every third week (Q3W).

20. The method of any one of claims 1 to 18, wherein one dose of the bispecific antibody and / or one dose of the PD-1 antagonist are administered every six weeks (Q6W).

21. The method of any one of the preceding claims, wherein one dose of the bispecific antibody and one dose of the PD-1 antagonist are administered on day 1 of each treatment cycle.

22. The method of any one of the preceding claims, wherein the amount of said bispecific antibody administered in each dose and / or in each treatment cycle is about 100 mg.

23. The method of any one of the preceding claims, wherein the amount of said PD-1 antagonist administered in each dose and / or in each treatment cycle is about 200 mg.

24. The method of any one of claims 1 to 22, wherein the amount of said PD-1 antagonist administered in each dose and / or in each treatment cycle is about 400 mg.

25. The method of any one of claims 1 to 18, wherein an approximate 100 mg dose of the bispecific antibody and an approximate 200 mg dose of the PD-1 antagonist are administered every three weeks (Q3W).

26. The method of any one of claims 1 to 18, wherein an approximate 100 mg dose of the bispecific antibody and an approximate 400 mg dose of the PD- 1 antagonist are administered every six weeks (Q6W).

27. The method of any one of claims 1 to 18, wherein an approximate 100 mg dose of acasunlimab or a biosimilar thereof and an approximate 200 mg dose of pembrolizumab or a biosimilar thereof are administered every three weeks (Q3W), such as on day 1 of each three-week treatment cycle.

28. The method of any one of claims 1 to 18, wherein an approximate 100 mg dose of acasunlimab or a biosimilar thereof and an approximate 400 mg dose of pembrolizumab or a biosimilar thereof are administered every six weeks (Q6W), such as on day 1 of every six-week treatment cycle.

29. The method of any one of the preceding claims, wherein the bispecific antibody and / or the PD- 1 antagonist are administered systemically, such as by injection or infusion, in particular by intravenous (IV) infusion.

30. The method of any one of the preceding claims, wherein the PD-1 antagonist is administered first, followed by the bispecific antibody, preferably wherein the time between infusions is approximately 30 minutes or longer.

31. The method of any one of the preceding claims, wherein said cancer is squamous or non- squamous NSCLC.

32. The method of any one of the preceding claims, wherein the cancer is metastatic, such as metastatic NSCLC (mNSCLC).

33. The method of any one of the preceding claims, wherein the cancer is a histologically or cytologically confirmed stage 4 NSCLC.

34. The method of any one of the preceding claims, wherein the cancer has relapsed and / or is refractory after prior treatment, such as systemic treatment with a checkpoint inhibitor.

35. The method of any one of the preceding claims, wherein the human subject has demonstrated disease progression (PD), such as PD defined by RECIST vl. l, after prior treatment, such as systemic treatment with a checkpoint inhibitor.

36. The method of any one of the preceding claims, wherein the human subject has received at least 1 prior line of systemic therapy, such as systemic therapy comprising a PD-1 inhibitor and / or a PD-L1 inhibitor, such as an anti-PD-1 antibody and / or an anti-PD-Ll antibody.

37. The method of any one of the preceding claims, wherein the human subject has demonstrated disease progression (PD) after prior treatment with a PD-1 inhibitor or PD-L1 inhibitor, such as an anti- PD-1 antibody or an anti-PD-Ll antibody, the PD-1 inhibitor or PD-L1 inhibitor being administered as monotherapy or as part of a combination therapy.

38. The method of any one of the preceding claims, wherein last prior treatment was with a PD-1 inhibitor or PD-L1 inhibitor, such as an anti-PD-1 antibody or an anti-PD-Ll antibody, the PD-1 inhibitor or PD-L1 inhibitor being administered as monotherapy or as part of a combination therapy, such as a combination therapy with a platinum-based chemotherapy.

39. The method of any one of the preceding claims, wherein the human subject has demonstrated disease progression (PD) during or after platinum doublet chemotherapy following treatment with an anti-PD-1 antibody or an anti-PD-Ll antibody.

40. The method of any one of the preceding claims, wherein the human subject has demonstrated disease progression (PD) during or after prior treatment with an anti-PD-1 antibody or an anti-PD-Ll antibody following platinum doublet chemotherapy.

41. The method of any one of the preceding claims, wherein the human subject has relapsed or refractory mNSCLC after prior treatment with an immune checkpoint inhibitor, such as an anti-PD-1 antibody or an anti-PD-Ll antibody.

42. The method of any one of the preceding claims, wherein the cancer has relapsed and / or is refractory, or the human subject has progressed during or after prior standard-of-care (SOC) treatment for metastatic NSCLC, such as a combination of a checkpoint inhibitor (CPI), such as a PD-1 inhibitor or PD-L1 inhibitor, and a platinum-based chemotherapy.

43. The method of claim 42, wherein the PD-1 or PD-L1 inhibitor and the platinum-based chemotherapy are administrated concomitantly, or the PD-1 or PD-L1 inhibitor and the platinum-based chemotherapy are administrated sequentially, irrespective of the order.

44. The method of any one of the preceding claims, wherein the human subject has had at least 6 weeks of prior treatment comprising a PD-1 inhibitor or PD-L1 inhibitor, and preferably said human subject has had clinical benefit, such as defined as documented radiographic stable disease (SD) or better, on said prior treatment comprising a PD-1 inhibitor or PD-L1 inhibitor.

45. The method of any one of the preceding claims, wherein the human subject has a PD-L 1 positive tumor, preferably as determined by an FDA-approved test.

46. The method of any one of the preceding claims, wherein the human subject has a tumor with PD-L1 expressed in > 1% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (TPS) > 1%.

47. The method of any one of the preceding claims, wherein the human subject has a tumor with PD-L1 expressed in > 50% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (TPS) > 50%.

48. The method of any one of the preceding claims, wherein the human subject has a tumor with PD-L1 expressed in > 1% and < 49% of the cancer or tumor cells, such as a tumor with a Tumor Proportion Score (TPS) > 1 and < 49%.

49. The method of any one of the preceding claims, wherein the human subject has a PD-L1 positive tumor as determined by an FDA-approved test, such as a tumor with a TPS > 1%, and the human subject has progressed during or after prior treatment with a combination of a PD-1 inhibitor or PD-L1 inhibitor and a platinum-based chemotherapy.

50. The method of any one of the preceding claims, wherein the PD-1 inhibitor or PD-L1 inhibitor and the platinum-based chemotherapy are administrated concomitantly or sequentially, irrespective of the order.

51. The method of any one of the preceding claims, wherein the human subject has Eastern Cooperative Oncology Group (ECOG) performance status (PS) <1.

52. The method of any one of the preceding claims, wherein the human subject has a tumor that does not have EGFR sensitizing mutation, KRAS mutation, RET mutation, ROS1 mutation, BRAF mutation, NTRK gene infusion, RET rearrangement, ALK gene rearrangement, high-level MET amplification, or METex 14 skipping.

53. The method of any one of the preceding claims, wherein the human subject has not received prior treatment with a 4- IBB (CD 137) targeting agent, such as an anti-4- IBB (CD 137) antibody, with an antitumor vaccine, or with autologous cell immunotherapy.

54. The method of any one of the preceding claims, wherein the human subject has not received prior treatment with a taxane chemotherapeutic agent, such as docetaxel, such as prior treatment for NSCLC with a taxane chemotherapeutic agent, such as docetaxel.

55. The method of any one of the preceding claims, wherein the bispecific antibody is administered prior to, simultaneously with, or after administration of the PD-1 antagonist.

56. The method of claim 55, wherein when the administration of the bispecific antibody is prior to the administration of the PD-1 antagonist, the gap between the end of the administration of the bispecific antibody and the beginning of the administration of the PD-1 antagonist is at least about 10 minutes, such as at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes, and / or up to about 14 days (up to about 2 weeks), such as up to about 13 days, up to about 12 days, up to about 11 days, up to about 10 days, up to about 9 days, up to about 8 days, up to about 7 days (up to about 1 week), up to about 6 days, up to about 5 days, up to about 4 days, up to about 3 days, up to about 2 days, up to about 1 day (up to about 24 hours), up to about 18 hours, up to about 12 hours, up to about 6 hours, up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2.5 hours, or up to about 2 hours.

57. The method of claim 55, wherein when the administration of the bispecific antibody is after the administration of the PD-1 antagonist, the gap between the end of the administration of the PD-1 antagonist and the beginning of the administration of the bispecific antibody is at least about 10 minutes, such as at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes, and / or up to about 14 days (up to about 2 weeks), such as up to about 13 days, up to about 12 days, up to about 11 days, up to about 10 days, up to about 9 days, up to about 8 days, up to about 7 days (up to about 1 week), up to about 6 days, up to about 5 days, up to about 4 days, up to about 3 days, up to about 2 days, up to about 1 day (up to about 24 hours), up to about 18 hours, up to about 12 hours, up to about 6 hours, up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2.5 hours, or up to about 2 hours.

58. A bispecific antibody for use in a method for treating NSCLC, wherein the bispecific antibody and the method are as defined in any one of claims 1 to 57.

59. A PD-1 antagonist for use in a method for treating NSCLC, wherein the PD-1 antagonist and the method are as defined in any one of claims 1 to 57.

60. Use of a bispecific antibody in a method for treating NSCLC, wherein the bispecific antibody and the method are as defined in any one of claims 1 to 57.

61. Use ofa PD-1 antagonist in a method for treating NSCLC, wherein the PD- 1 antagonist and the method are as defined in any one of claims 1 to 57.

62. A kit comprising a bispecific antibody and a PD-1 antagonist as defined in any one of claims 1 to 57.

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