Combination Therapies for the Treatment of Cancer

Abstract

The present invention relates to the field of binding molecules. In particular, the present invention relates to the field of therapeutic binding molecules for the treatment of diseases involving abnormal cells, such as cancer cells. In particular, the present invention relates to multispecific antibodies that bind to the extracellular portion of two or more different membrane-associated proteins, thereby modulating the biological activity expressed by the cells, and the use of such antibodies in combination therapy.

Description

[Technical field]

[0001] The present invention relates to the field of binding molecules. In particular, the present invention relates to the field of therapeutic binding molecules for the treatment of diseases involving abnormal cells, such as cancer cells. In particular, the present invention relates to multispecific antibodies that bind to the extracellular portion of two or more different membrane-associated proteins, thereby modulating the biological activity expressed by the cells, and the use of such antibodies in combination therapy. [Background technology]

[0002] Cancer remains the leading cause of death in the world, despite many advances that have been made in the treatment of the disease and increasing knowledge about the molecular events that lead to cancer.

[0003] Traditionally, most cancer drug discovery has focused on drugs that block essential cellular functions and kill dividing cells. However, in the case of advanced cancer, no matter how aggressively applied, chemotherapy rarely results in a complete cure, even to the point where patients suffer life-threatening side effects from the treatment. In most cases, the tumor in the patient only stops growing or shrinks temporarily (called remission), and then starts growing again, sometimes more rapidly (called relapse), becoming increasingly difficult to treat. More recently, the focus of cancer drug development has shifted from broad-spectrum cytotoxic chemotherapy to targeted cell suppressive therapies with low toxicity. Treatment of advanced cancer has been clinically validated in leukemia and some other cancers. However, in most carcinomas, targeted approaches still prove ineffective enough to completely eradicate cancer in most patients.

[0004] Cancer targeting has been achieved using a variety of different methods including, for example, small molecules directed against signaling proteins that cancers depend on for survival and / or growth, vaccines with tumor-specific proteins, cell therapies including antibodies that target immune cells and cytotoxic molecules to tumors that actively kill tumor cells, disrupting signal transduction and / or (re)directing the host's immune system to tumor cells.

[0005] (Re)direction of the immune system can be achieved in several ways. One way is by activating T cell costimulatory molecules such as the tumor necrosis factor receptor superfamily, including CD137 (4-1BB, TNFRSF9). Activation of CD137 induces increased T cell proliferation, cytokine production, and CD8 + This results in the prolongation of T cell survival. Another way is by blocking the negative signals induced by molecules involved in immune checkpoints, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death (PD-1) expressed on T cells, or its cognate ligand programmed cell death 1 ligand 1 (PD-L1), which may be expressed on tumor cells. Upon binding of PD-L1 to PD-1, signaling leads to attenuation of T cell receptor (TCR) signaling and T cell exhaustion. This is a mechanism used by tumors to evade and / or suppress the immune system.

[0006] This immune suppression can be blocked by immune checkpoint inhibitor therapy (ICI), such as antagonistic antibodies against PD-1 or PD-L1. ICI treatment inhibits activated CD8 + A subset of cancer patients have demonstrated remarkable and durable responses that correlate with T cell infiltration and proliferation. Combinations of ICIs (e.g., anti-PD-1 and anti-CTLA-4) have been shown to further enhance efficacy, but at the cost of toxicity, with the majority of patients experiencing grade 3 or 4 treatment-related adverse events.

[0007] Dual targeting of the PD-1 / PD-L1 axis and CD137 may be beneficial in optimally engaging specific antitumor immunity. Currently, two of the most advanced therapeutic CD137 agonist antibodies in clinical trials are urelumab (IgG4) and utomilumab (IgG2). Development of urelumab has been halted as a result of dose-dependent hepatitis due to systemic activation of the CD137 pathway in patients. Safe administration of urelumab requires dose reduction, and 0.1 mg / kg was selected for combination studies with PD-1 inhibitors. Utomilumab is well tolerated by patients, but has modest antitumor activity as a monotherapy and no clear synergy with PD-1 blockade in combination therapy.

[0008] Thus, there remains a need to provide more and better options to medical practitioners treating cancer, particularly advanced or metastatic solid tumors. Summary of the Invention

[0009] The present disclosure relates to combination therapy using a multispecific antibody comprising an antigen-binding site that binds to the extracellular portion of CD137 and an antigen-binding site that binds to the extracellular portion of a second membrane protein, together with a PD-L1 or PD-1 inhibitor, in a method of treating cancer in a subject in need thereof.

[0010] The present disclosure provides means and methods for the (re)direction of immune system components in the treatment of cancer, in particular advanced or metastatic solid tumors.

[0011] In certain aspects, the present disclosure provides a multispecific antibody comprising an antigen-binding site that binds to an extracellular portion of CD137 and an antigen-binding site that binds to an extracellular portion of a second membrane protein, for use in a method of treating cancer in a subject in need thereof, wherein the treatment further comprises administering a PD-L1 or PD-1 inhibitor.

[0012] In certain aspects, the present disclosure provides a multispecific antibody comprising an antigen-binding site that binds to an extracellular portion of CD137 and an antigen-binding site that binds to an extracellular portion of a second membrane protein, for use in a method of treating cancer in a subject in need thereof, wherein the multispecific antibody is for simultaneous, sequential or separate administration with a PD-1 or PD-L1 inhibitor.

[0013] In certain aspects, the disclosure provides a combination of a multispecific antibody comprising an antigen binding site that binds to the extracellular portion of CD137 and an antigen binding site that binds to the extracellular portion of a second membrane protein, and a PD-L1 or PD-1 inhibitor, for use in a method of treating cancer in a subject in need of such treatment.

[0014] In certain aspects, the disclosure provides methods of treating cancer in a subject in need of such treatment comprising administering to a subject in need of such treatment a multispecific antibody comprising an antigen binding site that binds to an extracellular portion of CD137 and an antigen binding site that binds to an extracellular portion of a second membrane protein, and a PD-1 or PD-L1 inhibitor.

[0015] In certain aspects, the multispecific antibody is administered simultaneously, sequentially, or separately with a PD-1 or PD-L1 inhibitor.

[0016] In certain embodiments, the cancer is an advanced or metastatic solid tumor, such as NSCLC, such as selected from locally advanced or metastatic lung cancer and locally advanced or metastatic melanoma. In certain embodiments, the melanoma is selected from cutaneous melanoma, acral melanoma, or mucosal melanoma. In certain embodiments, the cancer is Merkel cell carcinoma (also called cutaneous neuroendocrine carcinoma or trabecular carcinoma).

[0017] In certain aspects, the cancer has relapsed to PD-1 / PD-L1 therapy and / or is positive for PD-L1 expression.

[0018] In certain aspects, the multispecific antibody is administered prior to the PD-1 or PD-L1 inhibitor.

[0019] In certain aspects, the multispecific antibody is a bispecific antibody.

[0020] In certain embodiments, the antigen-binding site of the multispecific antibody that binds to the extracellular portion of the second membrane protein binds to PD-L1.

[0021] In certain aspects, the present disclosure provides a multispecific antibody for use in a method of treating cancer in a subject in need thereof, the antibody comprising: A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 50, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 51, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 52; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 40, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 41, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 42; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 21, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 22, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 23; or and / or a binding domain that binds to CD137, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 32, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 33, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 34. The antibody, A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:68, a CDR2 having the amino acid sequence set forth in SEQ ID NO:55, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:56; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 93, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 94, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 95; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 93, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 101, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 102; or a binding domain that binds to PD-L1, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 90, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 79, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 91; Each individual SEQ ID NO: has 0, 1, 2, 3, 4, or 5 amino acid insertions, deletions, or substitutions, or a combination thereof; Multispecific antibodies are provided, wherein the multispecific antibodies are for simultaneous, sequential, or separate administration with a PD-1 or PD-L1 inhibitor.

[0022] In certain aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a multispecific antibody comprising: A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 50, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 51, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 52; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 40, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 41, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 42; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 21, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 22, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 23; or and / or a binding domain that binds to CD137, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 32, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 33, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 34. The antibody, A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:68, a CDR2 having the amino acid sequence set forth in SEQ ID NO:55, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:56; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 93, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 94, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 95; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 93, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 101, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 102; or a binding domain that binds to PD-L1, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 90, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 79, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 91; a multispecific antibody, wherein each of the individual SEQ ID NOs has 0, 1, 2, 3, 4, or 5 amino acid insertions, deletions, or substitutions, or a combination thereof; The present invention provides a method for treating cancer comprising administering to a subject in need of treatment a PD-1 or PD-L1 inhibitor.

[0023] In certain aspects, the present disclosure provides a multispecific antibody for use in a method of treating cancer in a subject in need thereof, the antibody comprising: A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 50, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 51, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 52; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 40, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 41, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 42; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 21, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 22, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 23; or and / or a binding domain that binds to CD137, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 32, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 33, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 34. The antibody, A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:68, a CDR2 having the amino acid sequence set forth in SEQ ID NO:55, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:56; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 93, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 94, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 95; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 93, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 101, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 102; or a binding domain that binds to PD-L1, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 90, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 79, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 91; Each individual SEQ ID NO: has 0, 1, 2, 3, 4, or 5 amino acid insertions, deletions, or substitutions, or a combination thereof; the multispecific antibody is for administration simultaneously with, subsequent to, or separately from the PD-1 or PD-L1 inhibitor; The multispecific antibody is provided wherein the cancer is an advanced or metastatic solid tumor.

[0024] In certain aspects, the present disclosure provides a pharmaceutical combination or kit of parts comprising a multispecific antibody comprising an antigen binding site that binds to the extracellular portion of CD137 and an antigen binding site that binds to the extracellular portion of a second membrane protein, and instructions for use of the multispecific antibody in combination with a PD-1 or PD-L1 inhibitor, particularly for the treatment of cancer.

[0025] In certain aspects, the present disclosure provides a combination of a multispecific antibody comprising an antigen-binding site that binds the extracellular portion of CD137 and an antigen-binding site that binds the extracellular portion of PD-L1, and a PD-1 or PD-L1 inhibitor, for use in a method of treating cancer in a subject in need of such treatment.

[0026] In certain aspects, the disclosure provides a PD-1 or PD-L1 inhibitor for the treatment of cancer in a subject in need thereof, where the PD-L1 inhibitor is for simultaneous or sequential administration with a multispecific antibody comprising an antigen-binding site that binds to the extracellular portion of CD137 and an antigen-binding site that binds to the extracellular portion of a second membrane protein.

[0027] In certain aspects, the disclosure provides a multispecific antibody comprising an antigen-binding site that binds to the extracellular portion of CD137 and an antigen-binding site that binds to the extracellular portion of PD-L1 for use in treating cancer in a subject that has been administered, or will be administered, a PD-1 or PD-L1 inhibitor.

[0028] In certain aspects, the disclosure provides a PD-1 or PD-L1 inhibitor for use in the treatment of cancer in a patient who has received, or will receive, a multispecific antibody comprising an antigen-binding site that binds to the extracellular portion of CD137 and an antigen-binding site that binds to the extracellular portion of PD-L1.

[0029] In certain aspects, the multispecific antibody is administered at a dose of 25 to 300 mg, such as 25 to 150 or mg 25 to 100 mg, or such as 25 to 50 mg or 50 to 100 mg.

[0030] In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered at a dose of 200-600 mg, such as 300-500, or about 400 mg.

[0031] In certain aspects, the cancer is an advanced or metastatic solid tumor.

[0032] In certain aspects, the multispecific antibody, PD-L1 or PD-1 inhibitor is an isolated antibody.

[0033] In certain aspects, the subject is a human subject.

[0034] In certain aspects, the subject has not received prior treatment with a CD137 agonist, or prior treatment with CAR T cell therapy, or prior treatment including targeted small molecule therapy or radiation therapy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] In certain aspects, the disclosure provides a multispecific antibody comprising an antigen-binding site that binds the extracellular portion of CD137 and an antigen-binding site that binds the extracellular portion of a second membrane protein for use in a method of treating cancer in a subject in need of such treatment, wherein the multispecific antibody is for simultaneous, sequential, or separate administration with a PD-1 or PD-L1 inhibitor.In certain aspects, the disclosure provides a method of treating cancer in a subject in need of such treatment comprising administering to the subject a multispecific antibody comprising an antigen-binding site that binds the extracellular portion of CD137 and an antigen-binding site that binds the extracellular portion of a second membrane protein and a PD-1 or PD-L1 inhibitor.

[0036] In certain embodiments, the second membrane protein is PD-L1 and the antigen-binding site that binds to the extracellular portion of the second membrane protein binds to PD-L1.

[0037] CD137 can be expressed by activated T cells. CD137 is also found on other cells such as dendritic cells, natural killer cells, granulocytes, and cells of the blood vessel wall at sites of inflammation. This protein is known for its costimulatory activity for T cell activation. CD137 is known by a number of different names, including: TNFRSF9; TNF receptor superfamily member 9; tumor necrosis factor receptor superfamily member 9; T cell antigen 4-1BB homolog; 4-1BB ligand receptor; T cell antigen ILA; CD137 antigen; CDw137; ILA; interleukin-activated receptor, homolog of mouse Ly63; induced by lymphocyte activation (ILA); homolog of mouse 4-1BB; receptor protein 4-1BB; cell antigen ILA; and 4-1BB. The external Ids for CD137 are HGNC:11924, Entrez Gene:3604, Ensembl:ENSG00000049249, OMIM:602250, and UniProtKB:Q07011. CD137 is the most commonly upregulated inducible receptor on activated CD8+ T cells. CD137 signaling enhances T cell function by activating NF-κB [Arch et al,1998]. CD4+ T cells, monocytes, B cells, dendritic cell (DC) subpopulations, and other cellular immune cell types including granulocytes and NK cells can express CD137 at various levels [Shao et al,2011]. In monocytes, CD137 is inducible by activation with lipopolysaccharide (LPS) and IL-1b. In B lymphocytes, CD137 expression is induced by antibodies against cell surface immunoglobulins and transformation by EBV. In DCs, CD137 ligation induces maturation through upregulation of B7 costimulatory molecules (CD80 and CD86) in addition to increasing the production of proinflammatory cytokines (IL-6 and IL-12) and their survival [Makkouk et al., 2015]. A natural function of CD137 ligation on neutrophils is increased phagocytosis of bacterial and parasitic infections.In addition, ligation of CD137 blocks anti-apoptotic signals mediated by IL-3 / IL-5 / GM-CSF receptors in neutrophils and eosinophils in vitro, thereby preventing granulocyte accumulation [Simon, 2001; Vinay et al, 2011]. In non-lymphoid cells such as chondrocytes, endothelial cells, and tumor cells, expression of CD137 is driven by cytokine stimulation such as IL-1b in chondrocytes, the proinflammatory cytokines TNF alpha / IFNγ / IL-1b in endothelial cells, and IFNγ in tumor cells. The ligand that stimulates CD137 (CD137L) is expressed on activated antigen-presenting cells. CD137 exists in the membrane as a monomer and a dimer [Pollok et al, 1993].

[0038] The B7 family includes a number of structurally related cell surface proteins that bind to receptors on lymphocytes that regulate the immune response. Activation of lymphocytes is initiated by engagement of the cell surface, antigen-specific T cell receptors or B cell receptors. Additional signals delivered simultaneously by B7 ligands further determine the immune response of these cells. These so-called "costimulatory" or "co-inhibitory" signals are delivered by B7 family members via the CD28 family of receptors on lymphocytes. Binding of B7 family members to costimulatory receptors enhances the immune response, whereas binding to costimulatory receptors attenuates the immune response. Currently, the following members are considered to be part of this family: B7.1 (CD80), B7.2 (CD86), inducible costimulatory ligand (ICOS-L), programmed death-1 ligand (PD-L1), programmed death-2 ligand (PD-L2), B7-H3 (CD276), B7-H4, B7-H5, B7-H6, and B7-H7. B7 family members are expressed in lymphoid and non-lymphoid tissues. The effect of members on regulating immune response is shown in the development of immunodeficiency and autoimmune disease in mice with mutations in B7 family genes. Manipulation of the signals delivered by B7 ligands shows potential in the treatment of autoimmunity, inflammatory disease, and cancer.

[0039] PD-L1 is a type 1 transmembrane protein that plays a role in suppressing immune responses during certain events such as pregnancy, tissue allografts, autoimmune diseases, and other disease states such as hepatitis. PD-L1 is expressed in various types of cancers, especially NSCLC (Boland et al., 2013; Velcheti et al., 2014), melanoma, renal cell carcinoma, gastric cancer, hepatocellular, and various leukemias and multiple myelomas (Bernstein et al., 2014; Thompson et al., 2005). PD-L1 is present in the cytoplasm and plasma membrane of cancer cells, but not all cells in all cancers or tumors express PD-L1 (Dong et al., 2002). Multiple tumor microenvironment cells contribute to immune suppression by upregulating PD-L1 expression. This effect is called "adaptive immune resistance" because tumors protect themselves by inducing PD-L1 in response to IFN-γ produced by activated T cells (Sharma et al., 2017). PD-L1 can also be regulated by oncogenes, a mechanism known as intrinsic immune resistance (Akbay et al., 2013). Within the tumor microenvironment, PD-L1 is also expressed on myeloid cells and activated T cells (Tumeh et al., 2014). PD-L1 expression is induced by multiple proinflammatory molecules, including type I and type II IFN-γ, TNF-α, LPS, GM-CSF, and VEGF, as well as the cytokines IL-10 and IL-4, with IFN-γ being the most potent inducer (Sznol and Chen, 2013).

[0040] Programmed cell death 1 protein (PD-1) is a cell surface receptor that belongs to the CD28 family of receptors and is expressed on T cells and pro-B cells. PD-1 is currently known to bind two ligands, PD-L1 and PD-L2. Functioning as an immune checkpoint, PD-1 plays a key role in downregulating the immune system by inhibiting T cell activation, thereby reducing autoimmunity and promoting self-tolerance. The inhibitory effect of PD-1 is thought to be achieved through a dual mechanism that promotes apoptosis (programmed cell death) in antigen-specific T cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (suppressor T cells). PD-1 is known by a number of different names, including PDCD1, programmed cell death 1, systemic lupus erythematosus susceptibility 2, protein PD-1, HPD-1, PD1, programmed cell death 1 protein, CD279 antigen, CD279, HPD-L, HSLE1, SLEB2, and PD-1. The external Ids for PD-1 are HGNC:8760, Entrez Gene:5133, Ensembl:ENSG00000188389, OMIM:600244, and UniProtKB:Q15116. PD-1 inhibitors, a new class of drugs that block the activity of PD-1, activate the immune system to attack tumors and thus have been used successfully to treat several types of cancer.

[0041] Binding of PD-L1 to PD-1 or B7.1 (CD80) delivers an inhibitory signal that reduces proliferation of PD-1-expressing T cells. It is believed that PD-1 can control the accumulation of foreign antigen-specific T cells through apoptosis. PD-L1 is expressed by a variety of cancer cells, and its expression is believed to be at least partially responsible for the attenuation of immune responses to cancer cells. PD-L1 is a member of the B7 family of proteins and is known by various other names, such as CD274 molecule, CD274 antigen, B7 homolog 1, PDCD1 ligand 1, PDCD1LG1, PDCD1L1, B7H1, PDL1, programmed cell death 1 ligand 1, programmed death ligand 1, B7-H1, and B7-H. The external Ids for CD274 are HGNC:17635; Entrez Genes:29126, Ensembl:ENSG00000120217, OMIM:605402, UniProtKB:Q9NZQ7.

[0042] PD-L2 is the second ligand of PD-1. Engagement of PD-1 by PD-L2 inhibits T cell receptor (TCR)-mediated proliferation and cytokine production by CD4+ T cells. At low antigen concentrations, PD-L2 / PD-1 binding inhibits B7-CD28 signaling. At high antigen concentrations, PD-L2 / PD-1 binding reduces cytokine production. PD-L expression is upregulated on antigen-presenting cells by interferon-gamma treatment. It is expressed in some normal tissues and a variety of tumors. PD-L1 and PD-L2 are thought to have overlapping functions and regulate T cell responses. The protein is known by several other names, including programmed cell death 1 ligand 2, B7 dendritic cell molecule, programmed death ligand 2, butyrophilin B7-DC, PDCD1 ligand 2, PD-1 ligand 2, PDCD1L2, B7-DC, CD273, B7DC, PDL2, PD-1-ligand 2, CD273 antigen, BA574F11.2, and Btdc. The external Ids for PD-L2 are HGNC:18731, Entrez Gene:80380, Ensembl:ENSG00000197646, OMIM:605723, and UniProtKB:Q9BQ51.

[0043] PD-1 inhibitors are known in the art. They include antibodies that bind and block PD-1. Pembrolizumab is a humanized antibody used in cancer immunotherapy to treat melanoma, lung cancer, head and neck cancer, Hodgkin's lymphoma, gastric cancer, and cervical cancer. It is given by slow injection into a vein. Pembrolizumab is a therapeutic antibody that binds and blocks PD-1 located on lymphocytes. This receptor is a so-called "immune checkpoint" and is therefore generally responsible for preventing the immune system from attacking the body's own tissues. Normally, the PD-1 receptor on activated T cells binds to PD-L1 or PD-L2 ligands present on normal cells in the body, inactivating any potential cell-mediated immune response against these cells. Many cancers make proteins such as PD-L1 that also bind to the PD-1 receptor, thus blocking the body's ability to kill the cancer. Pembrolizumab works by inhibiting the lymphocyte PD-1 receptor, inactivating it and blocking a ligand that would prevent an immune response. This allows the immune system to target and destroy cancer cells, but also blocks an important mechanism that prevents the immune system from attacking the body itself.

[0044] Tumors often have mutations that cause DNA mismatch repair deficiency. This, in turn, often leads to microsatellite instability, causing tumors to produce a large number of mutant proteins that can function as tumor antigens and trigger an immune response against the tumor. By preventing the self-checkpoint system from shutting off T cells,

[14]

[30] pembrolizumab appears to promote the clearance of any such tumors by the immune system.

[0045] Pembrolizumab was approved for medical use in the United States in 2014. In 2017, the US Food and Drug Administration (FDA) approved pembrolizumab for any unresectable or metastatic solid tumor with certain genetic abnormalities (mismatch repair deficiency or microsatellite instability).

[0046] In certain embodiments, a multispecific antibody or method according to the present disclosure binds to a second membrane protein that is not a member of the TNF receptor superfamily. In certain embodiments, the second membrane protein is a member of the B7 family. In certain embodiments, the second membrane protein is PD-L1 or PD-L2, and in certain embodiments, is PD-L1.

[0047] In certain aspects, a multispecific antibody or method according to the present disclosure comprises one antigen-binding site that binds to the PD-1 binding domain of PD-L1.

[0048] In certain aspects, the multispecific antibody or method according to the present disclosure binds to a second membrane protein that is not expressed to a significant extent by T cells.

[0049] In certain aspects, the multispecific antibody or method according to the present disclosure binds to a second membrane protein expressed on an antigen presenting cell, a tumor cell, a virus-infected cell, or a parasite-infected cell.

[0050] In certain embodiments, a multispecific antibody or method according to the present disclosure binds to a second membrane protein that is a membrane protein present in one or more zones on the cell membrane, in certain embodiments, the zone is a cluster, domain, microdomain, or compartment on the cell membrane, in certain embodiments, an immunological synapse.

[0051] In certain embodiments, a multispecific antibody or method according to the present disclosure binds to a second membrane protein that is present on a cell membrane as part of a multimeric membrane protein comprising two or more of said second membrane proteins, hi certain embodiments, the second membrane protein is present on a cell membrane as part of a homodimer or homotrimer.

[0052] In certain aspects, a multispecific antibody or method according to the present disclosure comprises one antigen binding site that binds to the CD137L binding domain of CD137.

[0053] In certain aspects, a multispecific antibody or method according to the present disclosure comprises one antigen binding site that blocks binding of a ligand to CD137 or that binds to an extracellular ligand-blocking binding site of CD137, in certain aspects the CD137L-blocking binding site.

[0054] In certain aspects, a multispecific antibody or method according to the present disclosure comprises a variable domain that binds to the extracellular portion of CD137, defined as a variable domain that, when in a bivalent monospecific antibody format comprising two of said variable domains that bind CD137, does not stimulate the activity of CD137 on a cell, or stimulates it at a reduced level compared to one of said variable domains as part of a multispecific antibody having a second variable domain that binds to a tumor associated antigen, such as a member of the B7 family, or such as PD-L1.

[0055] In certain embodiments, a variable domain that binds to the extracellular portion of CD137 is defined as a variable domain that, when in a bivalent monospecific antibody format (such as IgG, particularly IgG1, or human IgG1) comprising two of said variable domains that bind to CD137, does not stimulate the activity of CD137 on cells or stimulates it at a reduced level compared to one of said variable domains as part of a bispecific antibody (such as IgG, particularly IgG1, or human IgG1) having a second variable domain that binds to a tumor-associated antigen. The skilled artisan will appreciate that, when comparing the CD137 stimulating activity between the bivalent monospecific antibodies and bispecific antibodies mentioned above, the antibodies are of the same format (such as IgG, in particular IgG1 or human IgG1), the difference between the antibodies compared being, on the one hand, monospecific antibodies comprising the presence of identical variable domains binding in bivalent form that bind to CD137, and, on the other hand, the presence of one of the CD137 variable domains and the corresponding nucleotide sequence of the following antibodies: MF5554 (SEQ ID NO: 53), MF5576 (SEQ ID NO: 57), MF5578 (SEQ ID NO: 59), MF9375 (SEQ ID NO: 62), MF9376 (SEQ ID NO: 64), MF7702 (SEQ ID NO: 67), and a variable domain that binds a tumor associated antigen, such as a variable domain comprising the amino acid sequence of the VH of MF5359 (SEQ ID NO:69), MF5377 (SEQ ID NO:73), MF5382 (SEQ ID NO:77), MF5424 (SEQ ID NO:81), MF5426 (SEQ ID NO:85), MF5439 (SEQ ID NO:89), MF5442 (SEQ ID NO:92), MF5553 (SEQ ID NO:96), MF5557 (SEQ ID NO:97), MF5561 (SEQ ID NO:100), MF5576 (SEQ ID NO:103), MF5594 (SEQ ID NO:104), or MF5708 (SEQ ID NO:107). In certain embodiments, the variable domain that binds the extracellular portion of CD137 that is non-stimulatory when in a bivalent monospecific antibody format comprises the CDR sequences of a VH such as MF6754, MF6808, MF6763, MF6785, or MF6797.

[0056] In certain aspects, a multispecific antibody or method according to the present disclosure comprises a variable domain that binds to the extracellular portion of CD137, which, when combined in a multispecific antibody with a second variable domain that binds PD-L1, can stimulate the activity of CD137 on a cell when in the presence of a first cell that expresses CD137 and a second cell that expresses PD-L1.

[0057] In certain aspects, a multispecific antibody or method according to the present disclosure can simultaneously bind CD137 and PD-L1.

[0058] Multispecific antibodies according to the present disclosure that bind to CD137 and the extracellular portion of a second membrane protein, in particular a membrane protein that is a member of the B7 family, offer the advantage that they are particularly well able to promote the desired immune response, since B7 family members deliver "costimulatory" or "co-inhibitory" signals to lymphocytes, thereby enhancing or attenuating the immune response. Thus, by targeting a second transmembrane protein, in particular a transmembrane protein that is a member of the B7 family, it is possible to enhance stimulatory signals and / or inhibit inhibitory signals, thereby inducing or enhancing the desired immune response against abnormal cells, such as, for example, cancer cells. As a result, multispecific antibodies according to the present disclosure are used in the treatment of cancer in subjects in need thereof, where the desired immune response is elicited against abnormal cells found in the cancer.

[0059] In certain embodiments, a multispecific antibody according to the present disclosure has one antigen-binding site capable of binding to the extracellular portion of CD137 and a second antigen-binding site capable of binding to the extracellular portion of a second membrane protein that is not a member of the TNF receptor superfamily, but in certain embodiments is a member of the B7 family or PD-L1. This offers the advantage that cis activation of (immune) cells, such as T cells, expressing several different members of the TNF receptor superfamily is at least partially avoided, thereby reducing potential adverse side effects and toxicity due to non-specific T cell activation. Prior art approaches may result in T cell activation in cis, meaning the absence of a second target, with the risk of an excessive T cell response resulting, for example, in a cytokine storm. As a result, such prior art approaches have an increased likelihood of adverse side effects compared to a binding molecule according to the present disclosure having an antigen-binding site capable of binding to CD137 and an antigen-binding site capable of binding to the extracellular portion of a second membrane protein.

[0060] In certain aspects, the present disclosure relates to multispecific antibodies that target both PD-L1 and CD137, in order to partially avoid cis-activation of (immune) cells such as T cells. In certain aspects, the variable domain that binds to the extracellular portion of CD137 is one that, when in a bivalent monospecific antibody format comprising two of such CD137 binding domains, does not stimulate the activity of CD137 on cells, or stimulates it at a reduced level compared to one of said variable domains as part of a multispecific antibody with a second variable domain that binds to a tumor associated antigen, in certain aspects a member of the B7 family, or PD-L1, etc. Suitable CD137 binding arms are disclosed in WO2018 / 056821.

[0061] In certain aspects, a multispecific antibody or method according to the use of the present disclosure may be an agonistic CD137 antibody, e.g., an antibody that can stimulate the activity of CD137. In certain aspects, a multispecific antibody or method according to the use of the present disclosure may be an antagonistic CD137 antibody, e.g., an antibody that can reduce the activity of CD137.

[0062] In certain aspects, a multispecific antibody or method according to the present disclosure may be an agonistic B7 antibody, e.g., an antibody capable of stimulating the activity of B7. In certain aspects, a multispecific antibody or method according to the present disclosure may be an antagonistic B7 antibody, e.g., an antibody capable of reducing the activity of a B7 family member.

[0063] In certain aspects, a multispecific antibody or method according to the use of the present disclosure may be an agonistic PD-L1 antibody, e.g., an antibody that can stimulate the activity of PD-L1. In certain aspects, a multispecific antibody or method according to the use of the present disclosure may be an antagonistic PD-L1 antibody, e.g., an antibody that can reduce the activity of PD-L1.

[0064] In certain aspects, a multispecific antibody or method according to the present disclosure may stimulate CD137 activity when bound to a B7 family member. In certain aspects, a multispecific antibody stimulates CD137 activity when bound to CD137 and PD-L1. In certain aspects, a multispecific antibody induces or activates CD137 signaling only in the presence of PD-L1 expressing cells.

[0065] In certain aspects, a multispecific antibody or method according to the present disclosure comprises an antigen binding site consisting of one immunoglobulin variable domain that binds to CD137 and one immunoglobulin variable domain that binds to the extracellular portion of a second membrane protein.

[0066] In certain aspects, the variable domain comprised by a multispecific antibody or method according to the present disclosure that binds to the extracellular portion of CD137 and at least partially blocks binding of a CD137 ligand to CD137 is a variable domain comprising the amino acid sequence of the VH of MF6783 (SEQ ID NO: 1), MF6861 (SEQ ID NO: 5), MF6795 (SEQ ID NO: 9), MF6808 (SEQ ID NO: 13), MF6798 (SEQ ID NO: 17), MF6754 (SEQ ID NO: 20), MF6763 (SEQ ID NO: 24), MF6744 (SEQ ID NO: 28), MF6785 (SEQ ID NO: 31), MF6825 (SEQ ID NO: 35), MF6737 (SEQ ID NO: 39), MF6749 (SEQ ID NO: 43), MF6788 (SEQ ID NO: 46), or MF6797 (SEQ ID NO: 49).

[0067] In certain aspects, the variable domain comprised by a multispecific antibody or method according to the present disclosure that binds to the extracellular portion of CD137 and at least partially blocks binding of a CD137 ligand to CD137 is a variable domain comprising the CDR1, CDR2, and CDR3 sequences of the amino acid sequence of the VH of MF6783 (SEQ ID NO: 1), MF6861 (SEQ ID NO: 5), MF6795 (SEQ ID NO: 9), MF6808 (SEQ ID NO: 13), MF6798 (SEQ ID NO: 17), MF6754 (SEQ ID NO: 20), MF6763 (SEQ ID NO: 24), MF6744 (SEQ ID NO: 28), MF6785 (SEQ ID NO: 31), MF6825 (SEQ ID NO: 35), MF6737 (SEQ ID NO: 39), MF6749 (SEQ ID NO: 43), MF6788 (SEQ ID NO: 46), or MF6797 (SEQ ID NO: 49).

[0068] In certain aspects, a multispecific antibody, or a functional part, derivative, and / or analogue thereof, or method according to the present disclosure comprising a variable domain that binds to the extracellular portion of CD137, comprises a heavy chain variable region having a CDR3 region comprising the amino acid sequence of the CDR3 region of the variable heavy chain region of MF6808 (SEQ ID NO: 13), MF6754 (SEQ ID NO: 23), MF6763 (SEQ ID NO: 27), MF6785 (SEQ ID NO: 34), or MF6797 (SEQ ID NO: 52).

[0069] In certain aspects, a multispecific antibody, or functional part, derivative, and / or analogue thereof, or method according to the present disclosure comprising a variable domain that binds to the extracellular portion of CD137, comprises a heavy chain variable region having a CDR2 region comprising the amino acid sequence of the CDR2 region of the variable heavy chain region of MF6808 (SEQ ID NO: 13), MF6754 (SEQ ID NO: 22), MF6763 (SEQ ID NO: 26), MF6785 (SEQ ID NO: 33), or MF6797 (SEQ ID NO: 51).

[0070] In certain aspects, a multispecific antibody, or a functional part, derivative, and / or analogue thereof, or method according to the present disclosure comprising a variable domain that binds to the extracellular portion of CD137, comprises a heavy chain variable region having a CDR1 region comprising the amino acid sequence of the CDR1 region of the variable heavy chain region of MF6808 (SEQ ID NO: 13), MF6754 (SEQ ID NO: 21), MF6763 (SEQ ID NO: 25), MF6785 (SEQ ID NO: 32), or MF6797 (SEQ ID NO: 50).

[0071] In certain aspects, a multispecific antibody, or functional part, derivative and / or analogue thereof, or method according to the present disclosure, comprising a variable domain that binds to the extracellular portion of CD137, comprises a heavy chain variable region having CDR1, CDR2 and CDR3 regions comprising the amino acid sequences of the CDR1, CDR2 and CDR3 of the variable heavy chain region of one of the VHs designated as MF6808, MF6754, MF6763, MF6785 or MF6797. In certain aspects, the CDR1, CDR2 and CDR3 sequences are selected from the same VH region.

[0072] In certain aspects, a multispecific antibody, or functional part, derivative, and / or analogue thereof, or method according to the present disclosure, comprising a variable domain that binds to the extracellular portion of CD137, comprises the amino acid sequence of the variable heavy chain region of MF6808, MF6754, MF6763, MF6785, or MF6797, having up to 15, such as 0, 1, 2, 3, 4, or 5 amino acid insertions, deletions, substitutions, or combinations thereof, relative to the amino acid sequence of the VH of the indicated MF. In certain aspects, the amino acid sequence of the variable heavy chain region has up to 5, such as 0, 1, 2, 3, or 4, such as 0, 1, 2, or 3, such as 0, 1, or 2, or such as 0 or 1 amino acid insertions, deletions, substitutions, or combinations thereof, relative to the amino acid sequence of the VH of the indicated MF. In certain embodiments, amino acid insertions, deletions, substitutions, or combinations thereof, if present, are absent in the amino acid sequences of the CDR regions.

[0073] In certain aspects, the variable domain that binds to the extracellular portion of CD137, or a functional part, derivative, and / or analog thereof, comprised by a multispecific antibody or method according to the use of the present disclosure, comprises a VH region having the amino acid sequence of CDR3, or a VH region having the amino acid sequences of CDR1, CDR2, and CDR3 of one of the VHs of MF6808, MF6754, MF6763, MF6785, or MF6797. In certain aspects, the variable domain that binds the extracellular portion of CD137 comprises a VH region having the amino acid sequence of the VH of MF6808 (SEQ ID NO: 13), MF6754 (SEQ ID NO: 20), MF6763 (SEQ ID NO: 24), MF6785 (SEQ ID NO: 31), or MF6797 (SEQ ID NO: 49), which has up to 15 amino acid insertions, deletions, substitutions, or combinations thereof, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or up to 15, such as 0, 1, 2, 3, 4, or 5, amino acid insertions, deletions, substitutions, or combinations thereof, relative to the amino acid sequence of the VH of the indicated MF. In certain aspects, the amino acid sequence of the variable heavy chain region has up to 5 amino acid insertions, deletions, substitutions, or combinations thereof, such as 0, 1, 2, 3, or 4, such as 0, 1, 2, or 3, such as 0, 1, or 2, or up to 5, such as 0 or 1, amino acid insertions, deletions, substitutions, or combinations thereof, relative to the amino acid sequence of the VH of the indicated MF. In certain embodiments, amino acid insertions, deletions, substitutions, or combinations thereof, if present, are absent in the amino acid sequences of the CDR regions.

[0074] In certain aspects, the variable domains comprised by the multispecific antibodies, or functional parts, derivatives, and / or analogs thereof, or methods according to the use of the present disclosure that bind to the extracellular portion of PD-L1 and block binding of PD-1 to PD-L1 are selected from the group consisting of MF5554 (SEQ ID NO: 53), MF5576 (SEQ ID NO: 57), MF5578 (SEQ ID NO: 59), MF9375 (SEQ ID NO: 62), MF9376 (SEQ ID NO: 64), MF7702 (SEQ ID NO: 67), MF5359 (SEQ ID NO: 68), MF5360 (SEQ ID NO: 69), MF5361 (SEQ ID NO: 70), MF5362 (SEQ ID NO: 71), MF5363 (SEQ ID NO: 72), MF5364 (SEQ ID NO: 73), MF5365 (SEQ ID NO: 74), MF5366 (SEQ ID NO: 75), MF5367 (SEQ ID NO: 76), MF5368 (SEQ ID NO: 77), MF5369 (SEQ ID NO: 78), MF5366 (SEQ ID NO: 79), MF5369 (SEQ ID NO: 80), MF5369 (SEQ ID NO: 81), MF5369 (SEQ ID NO: 82), MF5369 (SEQ ID NO: 83), MF5369 (SEQ ID NO: 84), MF5369 (SEQ ID NO: 85), MF5369 (SEQ ID NO: 86), MF5369 (SEQ ID NO: 87), MF5369 (SEQ ID NO: 89), MF536 MF5576 (SEQ ID NO:103), MF5594 (SEQ ID NO:104), or MF5708 (SEQ ID NO:107). In certain aspects, the CDRs from the MF sequences are determined using the Kabat numbering system, as noted elsewhere herein.

[0075] In certain aspects, the variable domains comprised in a multispecific antibody, or a functional part, derivative, and / or analogue thereof, or a method according to the use of the present disclosure, that bind to the extracellular portion of PD-L1 and block the binding of PD-1 to PD-L1 are selected from the group consisting of MF5554 (SEQ ID NO:53), MF5576 (SEQ ID NO:57), MF5578 (SEQ ID NO:59), MF9375 (SEQ ID NO:62), MF9376 (SEQ ID NO:64), MF7702 (SEQ ID NO:67), MF5359 (SEQ ID NO:69), MF537 MF5382 (SEQ ID NO:77), MF5424 (SEQ ID NO:81), MF5426 (SEQ ID NO:85), MF5439 (SEQ ID NO:89), MF5442 (SEQ ID NO:92), MF5553 (SEQ ID NO:96), MF5557 (SEQ ID NO:97), MF5561 (SEQ ID NO:100), MF5576 (SEQ ID NO:103), MF5594 (SEQ ID NO:104), or MF5708 (SEQ ID NO:107).

[0076] In certain aspects, a multispecific antibody, or functional part, derivative, and / or analogue thereof, or method according to the present disclosure, comprising a variable domain that binds to the extracellular portion of PD-L1, comprises a heavy chain variable region having a CDR3 region comprising the amino acid sequence of the CDR3 region of the variable heavy chain region of MF5554 (SEQ ID NO:56), MF5576 (SEQ ID NO:58), MF5578 (SEQ ID NO:61), MF9375 (SEQ ID NO:56), MF9376 (SEQ ID NO:56), MF7702 (SEQ ID NO:56), MF5424 (SEQ ID NO:84), MF5561 (SEQ ID NO:102), MF5439 (SEQ ID NO:91), MF5553 (SEQ ID NO:56), MF5594 (SEQ ID NO:106), MF5426 (SEQ ID NO:88), or MF5442 (SEQ ID NO:95).

[0077] In certain aspects, a multispecific antibody, or functional part, derivative, and / or analogue thereof, or method according to the present disclosure, comprising a variable domain that binds to the extracellular portion of PD-L1, comprises a heavy chain variable region having a CDR3 region comprising the amino acid sequence of the CDR3 region of the variable heavy chain region of MF7702 (SEQ ID NO:56), MF5424 (SEQ ID NO:84), MF5561 (SEQ ID NO:102), MF5439 (SEQ ID NO:91), MF5553 (SEQ ID NO:56), MF5594 (SEQ ID NO:106), MF5426 (SEQ ID NO:88), or MF5442 (SEQ ID NO:95).

[0078] In certain aspects, a multispecific antibody, or a functional part, derivative, and / or analog thereof, or a method according to the use of the present disclosure, comprises a heavy chain variable region that binds to the extracellular portion of PD-L1 comprising a CDR3 region having the amino acid sequence set forth in SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 84, SEQ ID NO: 88, SEQ ID NO: 91, SEQ ID NO: 95, SEQ ID NO: 102, or SEQ ID NO: 106. In certain aspects, a multispecific antibody, or a functional part, derivative, and / or analog thereof, or a method according to the use of the present disclosure, comprises a heavy chain variable region that binds to the extracellular portion of PD-L1 comprising a CDR3 region having the amino acid sequence set forth in SEQ ID NO: 56, SEQ ID NO: 91, SEQ ID NO: 95, or SEQ ID NO: 102, or a variant thereof.

[0079] In certain aspects, a multispecific antibody, or functional part, derivative, and / or analogue thereof, or method according to the present disclosure comprising a variable domain that binds to the extracellular portion of PD-L1, comprises a heavy chain variable region having a CDR2 region comprising the amino acid sequence of the CDR2 region of the variable heavy chain region of MF5554 (SEQ ID NO:55), MF5576 (SEQ ID NO:55), MF5578 (SEQ ID NO:3), MF9375 (SEQ ID NO:63), MF9376 (SEQ ID NO:66), MF7702 (SEQ ID NO:55), MF5424 (SEQ ID NO:83), MF5561 (SEQ ID NO:101), MF5439 (SEQ ID NO:79), MF5553 (SEQ ID NO:55), MF5594 (SEQ ID NO:105), MF5426 (SEQ ID NO:87), or MF5442 (SEQ ID NO:94).

[0080] In certain aspects, a multispecific antibody, or functional part, derivative, and / or analogue thereof, or method according to the present disclosure, comprising a variable domain that binds to the extracellular portion of PD-L1, comprises a heavy chain variable region having a CDR2 region comprising the amino acid sequence of the CDR2 region of the variable heavy chain region of MF7702 (SEQ ID NO:56), MF5424 (SEQ ID NO:84), MF5561 (SEQ ID NO:102), MF5439 (SEQ ID NO:91), MF5553 (SEQ ID NO:56), MF5594 (SEQ ID NO:106), MF5426 (SEQ ID NO:88), or MF5442 (SEQ ID NO:95).

[0081] In certain aspects, a multispecific antibody, or functional portion, derivative, and / or analogue thereof, or method according to the use of the present disclosure comprises a variable domain that binds to the extracellular portion of PD-L1, and the antibody comprises a heavy chain variable region that binds to the extracellular portion of PD-L1 comprising a CDR2 region having the amino acid sequence set forth in SEQ ID NO:3, SEQ ID NO:55, SEQ ID NO:63, SEQ ID NO:66, SEQ ID NO:79, SEQ ID NO:83, SEQ ID NO:87, SEQ ID NO:94, SEQ ID NO:101, or SEQ ID NO:105, or a variant thereof.

[0082] In certain aspects, a multispecific antibody, or functional part, derivative, and / or analogue thereof, or method according to the present disclosure comprising a variable domain that binds to the extracellular portion of PD-L1, comprises a heavy chain variable region having a CDR1 region comprising the amino acid sequence of the CDR1 region of the variable heavy chain region of MF5554 (SEQ ID NO:54), MF5576 (SEQ ID NO:54), MF5578 (SEQ ID NO:60), MF9375 (SEQ ID NO:60), MF9376 (SEQ ID NO:65), MF7702 (SEQ ID NO:68), MF5424 (SEQ ID NO:82), MF5561 (SEQ ID NO:93), MF5439 (SEQ ID NO:90), MF5553 (SEQ ID NO:68), MF5594 (SEQ ID NO:74), MF5426 (SEQ ID NO:86), or MF5442 (SEQ ID NO:93).

[0083] In certain aspects, a multispecific antibody, or functional part, derivative, and / or analogue thereof, or method according to the present disclosure, comprising a variable domain that binds to the extracellular portion of PD-L1, comprises a heavy chain variable region having a CDR1 region comprising the amino acid sequence of the CDR1 region of the variable heavy chain region of MF7702 (SEQ ID NO:56), MF5424 (SEQ ID NO:84), MF5561 (SEQ ID NO:102), MF5439 (SEQ ID NO:91), MF5553 (SEQ ID NO:56), MF5594 (SEQ ID NO:106), MF5426 (SEQ ID NO:88), or MF5442 (SEQ ID NO:95).

[0084] In certain aspects, a multispecific antibody or method according to the present disclosure comprising a variable domain that binds to the extracellular portion of PD-L1 comprises a heavy chain variable region that binds to the extracellular portion of PD-L1 comprising a CDR1 region having the amino acid sequence set forth in SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:65, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:82, SEQ ID NO:86, SEQ ID NO:90, or SEQ ID NO:93, or a variant thereof.

[0085] In certain aspects, a multispecific antibody, or functional part, derivative, and / or analogue thereof, or method according to the use of the present disclosure comprising a variable domain that binds to the extracellular portion of PD-L1 comprises a heavy chain variable region having CDR1, CDR2, and CDR3 regions that comprise the amino acid sequences of the CDR1, CDR2, and CDR3 of the variable heavy chain region of one of the VHs designated as MF5554, MF5576, MF5578, MF9375, MF9376, MF7702, MF5424, MF5561, MF5439, MF5553, MF5594, MF5426, or MF5442. The CDR1, CDR2, and CDR3 sequences are preferably selected from the same VH region.

[0086] In certain aspects, a multispecific antibody, or functional part, derivative and / or analogue thereof, or method according to the present disclosure comprising a variable domain that binds to the extracellular portion of PD-L1, is selected from the group consisting of MF5554 (SEQ ID NO:53), MF5576 (SEQ ID NO:57), MF5578 (SEQ ID NO:59), MF9375 (SEQ ID NO:62), MF9376 (SEQ ID NO:64), MF7702 (SEQ ID NO:67), MF5424 (SEQ ID NO:81), MF5561 (SEQ ID NO:100), The amino acid sequence of the variable heavy chain region of MF5439 (SEQ ID NO:89), MF5553 (SEQ ID NO:96), MF5594 (SEQ ID NO:104), MF5426 (SEQ ID NO:85), or MF5442 (SEQ ID NO:92) has up to 15 amino acid insertions, deletions, substitutions, or combinations thereof, such as 0, 1, 2, 3, 3, 4, 5, 6, 7, 8, 9, or 10, or up to 15, such as 0, 1, 2, 3, 4, or 5, relative to the amino acid sequence of the VH of the indicated MF. In certain aspects, the amino acid sequence of the variable heavy chain region has up to 5 amino acid insertions, deletions, substitutions, or combinations thereof, such as 0, 1, 2, 3, or 4, such as 0, 1, 2, or 3, such as 0, 1, or 2, or up to 5, such as 0 or 1, relative to the amino acid sequence of the VH of the indicated MF. In certain aspects, the amino acid insertions, deletions, substitutions, or combinations thereof, if present, are not present in the amino acid sequences of the CDR regions.

[0087] In certain aspects, particularly preferred combinations of multispecific antibodies, or functional portions, derivatives, and / or analogs, or methods according to the present disclosure are: MF6797 (SEQ ID NO:49) and MF7702 (SEQ ID NO:67), MF6763 (SEQ ID NO:24) and MF7702 (SEQ ID NO:67), MF6785 (SEQ ID NO:31) and MF7702 (SEQ ID NO:67), MF6797 (SEQ ID NO:49) and MF5553 (SEQ ID NO:96), MF6763 (SEQ ID NO:24) and MF5553 (SEQ ID NO:96), MF6785 (SEQ ID NO:31) and and combinations of variable domains comprising the sequences shown: MF5553 (SEQ ID NO:96), MF6754 (SEQ ID NO:20) and MF5424 (SEQ ID NO:81), MF6763 (SEQ ID NO:24) and MF5561 (SEQ ID NO:100), MF6785 (SEQ ID NO:31) and MF5439 (SEQ ID NO:89), MF6754 (SEQ ID NO:20) and MF5553 (SEQ ID NO:96), MF6744 (SEQ ID NO:28) and MF5594 (SEQ ID NO:104), or MF6783 (SEQ ID NO:1) and MF5594 (SEQ ID NO:104), or variants thereof.

[0088] In certain aspects, the multispecific antibody, or functional part, derivative, and / or analogue thereof, or method of use of the present disclosure comprises: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of CDR3 or the amino acid sequences of CDR1, CDR2 and CDR3 of the VH of MF6797 (SEQ ID NO: 49); - a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of CDR3, or the amino acid sequences of the CDR1, CDR2, and CDR3 of the VH of MF5554 (SEQ ID NO:53), MF5576 (SEQ ID NO:57), MF5578 (SEQ ID NO:59), MF9375 (SEQ ID NO:62), MF9376 (SEQ ID NO:64), MF7702 (SEQ ID NO:67), MF5594 (SEQ ID NO:104), MF5424 (SEQ ID NO:81), MF5426 (SEQ ID NO:85), MF5553 (SEQ ID NO:96), MF5442 (SEQ ID NO:92), MF5561 (SEQ ID NO:100), or MF5439 (SEQ ID NO:89).

[0089] In certain aspects, the multispecific antibody, or functional part, derivative, and / or analogue thereof, or method of use of the present disclosure comprises: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the VH of MF6797 (SEQ ID NO: 49), which has 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or up to 15, such as 0, 1, 2, 3, 4, or 5, amino acid insertions, deletions, substitutions, or a combination thereof, relative to the amino acid sequence of the VH of MF6797 (SEQ ID NO: 49); - a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the VH of MF5554 (SEQ ID NO:53), MF5576 (SEQ ID NO:57), MF5578 (SEQ ID NO:59), MF9375 (SEQ ID NO:62), MF9376 (SEQ ID NO:64), MF7702 (SEQ ID NO:67), MF5594 (SEQ ID NO:104), MF5424 (SEQ ID NO:81), MF5426 (SEQ ID NO:85), MF5553 (SEQ ID NO:96), MF5442 (SEQ ID NO:92), MF5561 (SEQ ID NO:100), or MF5439 (SEQ ID NO:89), with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or up to 15, such as 0, 1, 2, 3, 4, or 5 amino acid insertions, deletions, substitutions, or a combination thereof, relative to the amino acid sequence of the VH of the indicated MF. In certain aspects, the amino acid sequence of the variable heavy region has up to 5, such as 0, 1, 2, 3, or 4, such as 0, 1, 2, or 3, such as 0, 1, or 2, or such as 0 or 1 amino acid insertions, deletions, substitutions, or a combination thereof, relative to the amino acid sequence of the VH of the designated MF.

[0090] Certain aspects relate to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, or a method according to the present disclosure, comprising the steps of: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the CDR3 region of the VH of MF6763 (SEQ ID NO: 27); - a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the CDR3 of the VH of MF5442 (SEQ ID NO: 95), or a functional part, derivative, and / or analogue thereof.

[0091] Certain embodiments are directed to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, comprising: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the CDR1, CDR2 and CDR3 regions of the VH of MF6763 (SEQ ID NO: 24); - a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the CDR1, CDR2, CDR3 regions of the VH of MF5442 (SEQ ID NO: 92), or a functional part, derivative, and / or analogue thereof.

[0092] Certain aspects relate to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, or a method according to the present disclosure, comprising the steps of: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the VH of MF6763 (SEQ ID NO: 24), which has 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or up to 15, such as 0, 1, 2, 3, 4, or 5, amino acid insertions, deletions, substitutions, or a combination thereof, relative to the amino acid sequence of the VH of MF6763; and a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the VH of MF5442 (SEQ ID NO: 92), which has up to 15 amino acid insertions, deletions, substitutions, or a combination thereof, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, such as 0, 1, 2, 3, 4, or 5, relative to the amino acid sequence of the VH of MF5442. In certain aspects, the amino acid sequence of the variable heavy chain region has up to 5 amino acid insertions, deletions, substitutions, or a combination thereof, such as 0, 1, 2, 3, or 4, such as 0, 1, 2, or 3, such as 0, 1, or 2, or such as 0 or 1, relative to the amino acid sequence of the VH of the indicated MF.

[0093] Certain aspects relate to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, or a method according to the present disclosure, comprising the steps of: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the CDR3 region of the VH of MF6797 (SEQ ID NO: 52); - a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the CDR3 of the VH of MF7702 (SEQ ID NO:56), or a functional part, derivative, and / or analogue thereof.

[0094] Certain embodiments are directed to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, comprising: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the CDR1, CDR2 and CDR3 regions of the VH of MF6797 (SEQ ID NO: 49); - a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the CDR1, CDR2, CDR3 regions of the VH of MF7702 (SEQ ID NO: 67), or a functional part, derivative, and / or analogue thereof.

[0095] Certain aspects relate to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, or a method according to the present disclosure, comprising the steps of: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the VH of MF6797 (SEQ ID NO: 49), which has 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or up to 15, such as 0, 1, 2, 3, 4, or 5, amino acid insertions, deletions, substitutions, or a combination thereof, relative to the amino acid sequence of the VH of MF6797; and a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the VH of MF7702 (SEQ ID NO: 67), which has up to 15 amino acid insertions, deletions, substitutions, or a combination thereof, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, such as 0, 1, 2, 3, 4, or 5, relative to the amino acid sequence of the VH of MF7702. In certain aspects, the amino acid sequence of the variable heavy chain region has up to 5 amino acid insertions, deletions, substitutions, or a combination thereof, such as 0, 1, 2, 3, or 4, such as 0, 1, 2, or 3, such as 0, 1, or 2, or such as 0 or 1, relative to the amino acid sequence of the VH of the indicated MF.

[0096] Certain aspects relate to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, or a method according to the present disclosure, comprising the steps of: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the CDR3 region of the VH of MF6754 (SEQ ID NO: 23); - a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the VH CDR3 of MF5561 (SEQ ID NO: 102), or a functional part, derivative, and / or analogue thereof.

[0097] Certain embodiments are directed to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, comprising: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the CDR1, CDR2 and CDR3 regions of the VH of MF6754 (SEQ ID NO: 20); - a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the CDR1, CDR2, CDR3 regions of the VH of MF5561 (SEQ ID NO: 100), or a functional part, derivative, and / or analogue thereof.

[0098] Certain aspects relate to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, or a method according to the present disclosure, comprising the steps of: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the VH of MF6754 (SEQ ID NO: 20), which has 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or up to 15, such as 0, 1, 2, 3, 4, or 5, amino acid insertions, deletions, substitutions, or a combination thereof, relative to the amino acid sequence of the VH of MF6754; and a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the VH of MF5561 (SEQ ID NO: 100), which has up to 15 amino acid insertions, deletions, substitutions, or a combination thereof, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, such as 0, 1, 2, 3, 4, or 5, relative to the amino acid sequence of the VH of MF5561. In certain aspects, the amino acid sequence of the variable heavy chain region has up to 5 amino acid insertions, deletions, substitutions, or a combination thereof, such as 0, 1, 2, 3, or 4, such as 0, 1, 2, or 3, such as 0, 1, or 2, or such as 0 or 1, relative to the amino acid sequence of the VH of the indicated MF.

[0099] Certain aspects relate to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, or a method according to the present disclosure, comprising the steps of: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the CDR3 region of the VH of MF6785 (SEQ ID NO: 34); - a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the CDR3 of the VH of MF5439 (SEQ ID NO: 91), or a functional part, derivative, and / or analogue thereof.

[0100] Also provided is a bispecific antibody, or a functional part, derivative, and / or analogue thereof, comprising: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the CDR1, CDR2 and CDR3 regions of the VH of MF6785 (SEQ ID NO: 31); - a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the CDR1, CDR2, CDR3 regions of the VH of MF5439 (SEQ ID NO: 89), or a functional part, derivative, and / or analogue thereof.

[0101] Certain aspects relate to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, or a method according to the present disclosure, comprising the steps of: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the VH of MF6785 (SEQ ID NO: 31), which has 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or up to 15, such as 0, 1, 2, 3, 4, or 5, amino acid insertions, deletions, substitutions, or a combination thereof, relative to the amino acid sequence of the VH of MF6785; and a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the VH of MF5439 (SEQ ID NO: 89), which has up to 15 amino acid insertions, deletions, substitutions, or a combination thereof, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, such as 0, 1, 2, 3, 4, or 5, relative to the amino acid sequence of the VH of MF5439. In certain aspects, the amino acid sequence of the variable heavy chain region has up to 5 amino acid insertions, deletions, substitutions, or a combination thereof, such as 0, 1, 2, 3, or 4, such as 0, 1, 2, or 3, such as 0, 1, or 2, or such as 0 or 1, relative to the amino acid sequence of the VH of the indicated MF.

[0102] Certain aspects relate to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, or a method according to the present disclosure, comprising the steps of: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the CDR3 region of the VH of MF6785 (SEQ ID NO: 34); - a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the CDR3 of the VH of MF5542 (SEQ ID NO: 95), or a functional part, derivative, and / or analogue thereof.

[0103] Certain embodiments are directed to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, comprising: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the CDR1, CDR2 and CDR3 regions of the VH of MF6785 (SEQ ID NO: 31); - a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the CDR1, CDR2, CDR3 regions of the VH of MF5442 (SEQ ID NO: 92), or a functional part, derivative, and / or analogue thereof.

[0104] Certain aspects relate to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, or a method according to the present disclosure, comprising the steps of: - a CD137-binding variable domain comprising a VH region having the amino acid sequence of the VH of MF6785 (SEQ ID NO: 31), which has 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or up to 15, such as 0, 1, 2, 3, 4, or 5, amino acid insertions, deletions, substitutions, or a combination thereof, relative to the amino acid sequence of the VH of MF6785; and a PD-L1-binding variable domain comprising a VH region having the amino acid sequence of the VH of MF5442 (SEQ ID NO: 92), which has up to 15 amino acid insertions, deletions, substitutions, or a combination thereof, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, such as 0, 1, 2, 3, 4, or 5, relative to the amino acid sequence of the VH of MF5542. In certain aspects, the amino acid sequence of the variable heavy chain region has up to 5 amino acid insertions, deletions, substitutions, or a combination thereof, such as 0, 1, 2, 3, or 4, such as 0, 1, 2, or 3, such as 0, 1, or 2, or such as 0 or 1, relative to the amino acid sequence of the VH of the indicated MF.

[0105] Certain aspects relate to a multispecific antibody, or a functional part, derivative, and / or analogue thereof, or a method according to the present disclosure, comprising the steps of: - a variable domain comprising a CDR1 according to SEQ ID NO: 50, a CDR2 according to SEQ ID NO: 51 and a CDR3 according to SEQ ID NO: 52, wherein each CDR1, CDR2 and / or CDR3 has 0, 1, 2, 3, 4 or 5 amino acid insertions, deletions, substitutions or a combination thereof; or - a variable domain comprising a CDR1 as set forth in SEQ ID NO: 40, a CDR2 as set forth in SEQ ID NO: 41, and a CDR3 as set forth in SEQ ID NO: 42, wherein each CDR1, CDR2, and / or CDR3 has 0, 1, 2, 3, 4, or 5 amino acid insertions, deletions, substitutions, or a combination thereof; or - a variable domain comprising a CDR1 according to SEQ ID NO: 21, a CDR2 according to SEQ ID NO: 22 and a CDR3 according to SEQ ID NO: 23, wherein each CDR1, CDR2 and / or CDR3 has 0, 1, 2, 3, 4 or 5 amino acid insertions, deletions, substitutions or a combination thereof; or a binding domain that binds to CD137, comprising a variable domain comprising a CDR1 according to SEQ ID NO: 32, a CDR2 according to SEQ ID NO: 33, and a CDR3 according to SEQ ID NO: 34, wherein each CDR1, CDR2, and / or CDR3 has 0, 1, 2, 3, 4, or 5 amino acid insertions, deletions, substitutions, or a combination thereof; and / or - a variable domain comprising a CDR1 according to SEQ ID NO: 68, a CDR2 according to SEQ ID NO: 55, and a CDR3 according to SEQ ID NO: 56, wherein each CDR1, CDR2 and / or CDR3 has 0, 1, 2, 3, 4 or 5 amino acid insertions, deletions, substitutions, or a combination thereof; or - a variable domain comprising a CDR1 according to SEQ ID NO: 93, a CDR2 according to SEQ ID NO: 94 and a CDR3 according to SEQ ID NO: 95, wherein each CDR1, CDR2 and / or CDR3 has 0, 1, 2, 3, 4 or 5 amino acid insertions, deletions, substitutions or a combination thereof; or - a variable domain comprising a CDR1 according to SEQ ID NO: 93, a CDR2 according to SEQ ID NO: 101 and a CDR3 according to SEQ ID NO: 102, wherein each CDR1, CDR2 and / or CDR3 has 0, 1, 2, 3, 4 or 5 amino acid insertions, deletions, substitutions or a combination thereof; or - a multispecific antibody, or a functional part, derivative, and / or analogue thereof, comprising a binding domain that binds to PD-L1, comprising a CDR1 according to SEQ ID NO: 90, a CDR2 according to SEQ ID NO: 79, and a CDR3 according to SEQ ID NO: 91, wherein each CDR1, CDR2, and / or CDR3 comprises a variable domain having 0, 1, 2, 3, 4, or 5 amino acid insertions, deletions, substitutions, or a combination thereof. In certain aspects, the amino acid sequences of the CDRs have up to 5 amino acid insertions, deletions, substitutions, or a combination thereof, such as 0, 1, 2, 3, or 4, such as 0, 1, 2, or 3, such as 0, 1, or 2, or such as 0 or 1.

[0106] In certain aspects, a multispecific antibody, or functional portion, derivative, and / or analog thereof, or method of use of the present disclosure comprises a variable domain that binds to the extracellular portion of CD137 and blocks binding of CD137 to a CD137 ligand, and a variable domain that binds to the extracellular portion of PD-L1 and blocks binding of PD-1 to PD-L1. In certain aspects, the variable domain that binds to the extracellular portion of PD-L1 in the antibody, or functional portion, derivative, and / or analog thereof, comprises a VH region having the amino acid sequence of CDR3, or the amino acid sequences of CDR1, CDR2, and CDR3 of one of the VHs of MF5554, MF5576, MF5578, MF9375, MF9376, MF7702, MF5424, MF5561, MF5439, MF5553, MF5594, MF5426, MF5442. In certain aspects, the variable domain that binds to the extracellular portion of PD-L1 comprises a VH region having the amino acid sequence of the VH of MF5554 (SEQ ID NO:53), MF5576 (SEQ ID NO:57), MF5578 (SEQ ID NO:59), MF9375 (SEQ ID NO:62), MF9376 (SEQ ID NO:64), MF7702 (SEQ ID NO:67), MF5424 (SEQ ID NO:81), MF5561 (SEQ ID NO:100), MF5439 (SEQ ID NO:89), MF5553 (SEQ ID NO:96), MF5594 (SEQ ID NO:104), MF5426 (SEQ ID NO:85), MF5442 (SEQ ID NO:92), such as having 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid insertions, deletions, substitutions, or a combination thereof, relative to the amino acid sequence of the VH of the indicated MF. In certain aspects, the amino acid sequence of the variable heavy region has up to 5, such as 0, 1, 2, 3, or 4, such as 0, 1, 2, or 3, such as 0, 1, or 2, or such as 0 or 1 amino acid insertions, deletions, substitutions, or a combination thereof, relative to the amino acid sequence of the VH of the designated MF.

[0107] This is shown in the examples of WO2018 / 056821A1, where binding of the CD137-specific VH of MF6797 (sequence number 49) is associated with the presence of amino acids including Arg66, Gly70, and Phe72 in the CD137 amino acid sequence.

[0108] Thus, in certain aspects, the present disclosure also provides for the use or treatment of an isolated, synthetic or recombinant antibody, or functional portion, derivative and / or analog thereof, capable of binding to CD137, wherein the binding of the antibody, or functional portion, derivative or analog to CD137 is associated with the presence of amino acids including Arg66, Gly70 and Phe72 of the CD137 amino acid sequence (SEQ ID NO: 117). In certain aspects, the binding of the antibody, or functional portion, derivative or analog to CD137 is also associated with amino acids including Val71 of the CD137 amino acid sequence.

[0109] The term "Arg66" refers to an arginine residue at position 66 of the CD137 sequence. The term "Gly70" refers to a glycine residue at position 70 of the CD137 sequence according to SEQ ID NO: 117. The term "Val71" refers to a valine residue at position 71 of the CD137 sequence. The term "Phe72" refers to a phenylalanine residue at position 72 of the CD137 sequence.

[0110] In certain embodiments, multispecific antibodies of the present disclosure comprise binding sites that comprise a common light chain according to SEQ ID NO: 109 with 0-5 amino acid insertions, deletions, substitutions, additions, or a combination thereof. In certain embodiments, each of the binding sites comprises a common light chain according to SEQ ID NO: 109 with 0-5 amino acid insertions, deletions, substitutions, additions, or a combination thereof.

[0111] In certain embodiments, the multispecific antibody of the present disclosure comprises a binding site comprising an LCDR sequence according to IMGT of a common light chain according to SEQ ID NO: 109 with 0-5 amino acid insertions, deletions, substitutions, additions, or a combination thereof. In certain embodiments, each of the binding sites comprises an LCDR sequence according to IMGT of a common light chain according to SEQ ID NO: 109 with 0-5 amino acid insertions, deletions, substitutions, additions, or a combination thereof. In certain embodiments, the substitution is a conservative substitution, where an amino acid is replaced with a conservative amino acid. A person skilled in the art is fully capable of replacing one or more amino acids in a CDR sequence according to the present disclosure. For example, conservative amino acid substitutions are applied. Examples of conservative amino acid substitutions include the substitution of one hydrophobic residue, such as isoleucine, valine, leucine, or methionine, with another hydrophobic residue, and the substitution of one polar residue with another polar residue, such as the substitution of arginine with lysine, the substitution of glutamic acid with aspartic acid, or the substitution of glutamine with asparagine. In certain embodiments, the multispecific antibodies of the present disclosure comprise binding sites comprising the LCDR sequence (according to the IMGT database World Wide Web at imgt.org) of a common light chain according to SEQ ID NO: 109, with one or two amino acid insertions, deletions, substitutions, additions, or combinations thereof. In certain embodiments, each of the binding sites comprises the LCDR sequence according to IMGT of a common light chain according to SEQ ID NO: 109, with one or two amino acid insertions, deletions, substitutions, additions, or combinations thereof.

[0112] In certain aspects, the light chain variable region of one or more binding domains of a multispecific antibody of the disclosure comprises an LCDR1 comprising the amino acid sequence QSISSY, an LCDR2 comprising the amino acid sequence AAS, and an LCDR3 comprising the amino acid sequence QQSYSTPPT (i.e., the CDRs of IGKV1-39 according to IMGT).

[0113] In certain embodiments, one or more binding domains of a multispecific antibody of the present disclosure comprises a light chain variable region comprising an amino acid sequence that is at least 90%, and in certain embodiments at least 95%, and in certain embodiments at least 97%, and in certain embodiments at least 98%, and in certain embodiments at least 99% identical, or in certain embodiments 100% identical to the amino acid sequence of SEQ ID NO: 109.

[0114] In certain embodiments, the multispecific antibodies described herein comprise a common light chain variable domain, such as a common light chain variable region according to SEQ ID NO: 110, having 0, 1, 2, 3, or 4, such as 0, 1, 2, or 3, such as 0, 1, or 2, or such as 0 or 1 amino acid insertions, deletions, substitutions, or combinations thereof, with 0-5 amino acid insertions, deletions, substitutions, or combinations thereof. In certain embodiments, the multispecific antibodies described herein comprise a common light chain constant domain, such as a common light chain constant region according to SEQ ID NO: 111, having 0-5 amino acid insertions, deletions, substitutions, additions, or combinations thereof. The term "common light chain" according to the present invention refers to light chains which may be identical or which may differ in some amino acid sequence, but in which the binding specificity of the full-length antibody is not affected. It is possible, for example, within the definition of common light chain used herein, to prepare or find light chains that are not identical but are still functionally equivalent by introducing and testing conservative amino acid changes, changes in amino acids in regions that do not contribute or only partially contribute to binding specificity when paired with a heavy chain, etc. The terms "common light chain", "common LC", "cLC", "single light chain", with or without the addition of the term "rearranged", are all used interchangeably herein. The terms "common light chain variable region", "common VL", "common LCv", "cLCv", "single VL", with or without the addition of the term "rearranged", are all used interchangeably herein. In certain aspects of the present disclosure, the multispecific antibody has a common light chain (variable region) that can be combined with at least two, or more, etc. heavy chains (variable regions) of different binding specificities to form an antibody with a functional antigen-binding domain (WO2004 / 009618, WO2009 / 157771). In certain aspects, the common light chain (variable region) is a human light chain (variable region). In certain aspects, the common light chain (variable region) has a germline sequence. In certain aspects, the germline sequence is a light chain variable region that is frequently used in the human repertoire and has good thermodynamic stability, yield, and solubility.In certain aspects, the common light chain is a rearranged germline human kappa light chain IgVκ1-39*01 / IGJκ1*01 (SEQ ID NO: 109). In certain aspects, the common light chain variable region is a rearranged germline human kappa light chain IgVκ1-39*01 / IGJκ1*01 variable region. In certain aspects, the common light chain comprises a light chain variable region as set forth in SEQ ID NO: 110 with 0-5 amino acid insertions, deletions, substitutions, additions, or combinations thereof, such as 0, 1, 2, 3, or 4, such as 0, 1, 2, or 3, such as 0, 1, or 2, or such as 0 or 1 amino acid insertions, deletions, substitutions, or combinations thereof. In certain aspects, the common light chain further comprises a light chain constant region, such as a kappa light chain constant region. The nucleic acid encoding the common light chain may be codon optimized for the cell system used to express the common light chain protein. The encoding nucleic acid can deviate from the germline nucleic acid sequence.

[0115] In certain aspects, the multispecific antibody or method according to the present disclosure is a full length antibody or a fragment of an antibody, such as a Fab fragment or a single chain variable fragment (scFv). In certain aspects, the multispecific antibody or method according to the present disclosure is a full length antibody.

[0116] In certain embodiments, the multispecific antibody or method according to the present disclosure is an IgG. In certain embodiments, the multispecific antibody is an IgG1 molecule without Fc effector functions.

[0117] The Fc region mediates antibody effector functions such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). Depending on the application of the therapeutic antibody or Fc fusion protein, it may be desirable to reduce or increase the effector function. Reduced effector function is preferred in the present disclosure. Reduced effector function may be desired when the immune response is activated, enhanced, or stimulated, as in some embodiments of the present disclosure. Antibodies with reduced effector function can be used to target cell surface molecules of immune cells, among others. In certain embodiments, the CH2 region of the multispecific antibody of the present disclosure is engineered to reduce the ADCC and / or CDC activity of the antibody. In certain embodiments, the CH3 region of the multispecific antibody is engineered to promote heterodimerization of the heavy chains.

[0118] An antibody with reduced effector function is, for example, an IgG antibody that preferably comprises a modified CH2 / lower hinge region to reduce Fc receptor interaction or to reduce C1q binding. In certain aspects, an antibody of the present disclosure is an IgG antibody with a mutant CH2 and / or lower hinge domain such that the interaction of the multispecific IgG antibody with the Fc-gamma receptor is reduced. In certain aspects, a CH2 region of the present disclosure comprises the amino acid sequence set forth in SEQ ID NO: 114 with 0-5 amino acid insertions, deletions, substitutions, additions, or a combination thereof. In certain aspects, a hinge region of the present disclosure comprises the amino acid sequence set forth in SEQ ID NO: 113 with 0-5 amino acid insertions, deletions, substitutions, additions, or a combination thereof.

[0119] In certain embodiments, the CH3 region of the multispecific antibody is engineered to promote heterodimerization of the heavy chains. In certain embodiments, these variations are present to produce essentially only multispecific full-length IgG molecules with amino acid substitutions at positions 351 and 366, e.g., L351K and T366K (numbering according to EU numbering) in the first CH3 domain ("KK variant" heavy chain), and amino acid substitutions at positions 351 and 368, e.g., L351D and L368E, in the second CH3 domain ("DE variant" heavy chain), or vice versa. Homodimerization of DE variant heavy chains (DE-DE homodimers) or KK variant heavy chains (KK-KK homodimers) hardly occurs due to the strong repulsion between charged residues at the CH3-CH3 interface between identical heavy chains. In certain aspects, the multispecific antibodies of the present disclosure comprise a CH3 domain according to SEQ ID NOs: 115 and 116, with 0-5 amino acid insertions, deletions, substitutions, additions, or combinations thereof, provided that the DE / KK variant is unchanged.

[0120] In certain aspects, the PD-1 or PD-L1 inhibitor is an antibody or other binding molecule.

[0121] In certain embodiments, the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor. In certain embodiments, the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, pemplimab, retifanlimab, sintilimab, tislelizumab, toripalimab, and dostarimab. In certain embodiments, the PD-1 inhibitor is pembrolizumab. In certain embodiments, the PD-1 or PD-L1 inhibitor is a PD-L1 inhibitor. In certain embodiments, the PD-L1 inhibitor is selected from atezolizumab, avelumab, and durvalumab. The amino acid sequences of nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab are well known in the art.

[0122] In certain embodiments, the PD-1 or PD-L1 inhibitor is administered according to the recommendations established by the FDA.

[0123] In one particular embodiment, the PD-1 inhibitor is nivolumab and is administered in an amount of 3 mg / kg as an intravenous infusion (e.g., over 60 minutes) every two weeks until disease progression or unacceptable toxicity.

[0124] In alternative embodiments, nivolumab is administered at 240 mg every 2 weeks, or 480 mg every 4 weeks, or 1 mg / kg on the same day every 3 weeks, followed by ipilimumab at 3 mg / kg for four doses, then 240 mg every 2 weeks, or 480 mg every 4 weeks.

[0125] In an alternative embodiment, nivolumab is administered at 3 mg / kg every 2 weeks with ipilimumab 1 mg / kg every 6 weeks, or 360 mg every 3 weeks with ipilimumab 1 mg / kg every 6 weeks, and two cycles of platinum-doublet chemotherapy.

[0126] In an alternative embodiment, nivolumab is administered at 360 mg every 3 weeks with ipilimumab 1 mg / kg every 6 weeks.

[0127] In alternative embodiments, nivolumab is administered at 240 mg every 2 weeks, or 480 mg every 4 weeks, or 3 mg / kg every 2 weeks, or 3 mg / kg on the same day every 3 weeks, followed by ipilimumab 1 mg / kg for 4 doses, then 240 mg every 2 weeks, or 480 mg every 4 weeks.

[0128] In one particular embodiment, the PD-1 inhibitor is cemiplimab and is administered in an amount of 350 mg as an intravenous infusion (e.g., over 30 minutes) every three weeks until disease progression or unacceptable toxicity.

[0129] In certain embodiments, the PD-1 inhibitor is dostarimab, administered as an intravenous infusion (e.g., over 30 minutes) at doses 1 through 4 of 500 mg every 3 weeks, followed by the following doses thereafter starting 3 weeks after dose 4 (dose 5 onwards): 1,000 mg every 6 weeks until disease progression or unacceptable toxicity.

[0130] In one particular embodiment, the PD-L1 inhibitor is atezolizumab and is administered in an amount of 1200 mg as an intravenous infusion (e.g., over 60 minutes) every three weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions can be delivered over 30 minutes.

[0131] In one particular embodiment, the PD-L1 inhibitor is avelumab and is administered in an amount of 10 mg / kg as an intravenous infusion (e.g., over 60 minutes) every two weeks until disease progression or unacceptable toxicity.

[0132] In one particular embodiment, the PD-L1 inhibitor is durvalumab and is administered in an amount of 10 mg / kg as an intravenous infusion (e.g., over 60 minutes) every two weeks until disease progression or unacceptable toxicity.

[0133] In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 400 mg as an intravenous infusion or 2 mg / kg as an intravenous infusion every 3 weeks. In certain embodiments, administration is at a flat dose of 400 mg every 6 weeks until disease progression or unacceptable toxicity.

[0134] In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered as an intravenous infusion in an amount of 400 mg every 6 weeks. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered as an intravenous infusion in an amount of 400 mg every 6 weeks as a flat dose. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered as an intravenous infusion in an amount of 200 mg every 3 weeks as a flat dose. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered as an intravenous infusion in an amount of 200 mg every 3 weeks as a flat dose. In certain embodiments, administration is a flat dose of 400 mg every 6 weeks until disease progression or unacceptable toxicity. In certain embodiments, administration is a flat dose of 200 mg every 3 weeks until disease progression or unacceptable toxicity.

[0135] The term "flat dose" herein refers to a dosing regimen in which a subject is administered with a fixed amount of a therapeutic substance over multiple doses, regardless of the subject's body weight. Flat doses are typically abbreviated as qnw, where n is an integer indicating an interval, and w is weeks. For example, a q6w flat dose dosing regimen of 400mg antibody means that a fixed amount of 400mg of antibody is administered each 6 weeks. In certain embodiments, pembrolizumab is administered in a q6w dosing regimen of 400mg. In certain embodiments, pembrolizumab is administered in a q3w dosing regimen of 200mg.

[0136] The flat dose may be pre-medicated, meaning that the drug is administered to the subject prior to administration of the antibody of the disclosure, hi certain aspects, the flat dose of pembrolizumab or a multispecific antibody of the disclosure is pre-medicated with an antihistamine, analgesic, antipyretic, and / or anti-inflammatory drug.

[0137] In certain aspects, the PD-1 or PD-L1 inhibitor is a full length antibody or a fragment of an antibody, such as a Fab fragment or a single chain variable fragment (scFv). In certain aspects, the PD-1 or PD-L1 inhibitor or method of use of the present disclosure is a full length antibody. In certain aspects, the PD-1 or PD-L1 inhibitor is or comprises an antibody selected from nivolumab, pembrolizumab, cemiplimab, dostarimab, atezolizumab, avelumab, and durvalumab, or a functional fragment or variant thereof.

[0138] In certain aspects, the PD-1 or PD-L1 inhibitor comprises or consists of an amino acid sequence that is, or has substantial sequence identity to, the antigen-binding site of one of nivolumab, pembrolizumab, cemiplimab, dostarimab, atezolizumab, avelumab, and durvalumab, in particular pembrolizumab.

[0139] In certain embodiments, the PD-1 or PD-L1 inhibitor is or comprises at least one, such as at least two, even three, CDRs that are identical or substantially identical to the CDRs of one of nivolumab, pembrolizumab, cemiplimab, dostarimab, atezolizumab, avelumab, and durvalumab, particularly pembrolizumab. In certain embodiments, the PD-1 or PD-L1 inhibitor comprises at least one, such as at least two, even three, CDRs that are identical to the CDRs found in pembrolizumab.

[0140] In certain embodiments, the PD-1 or PD-L1 inhibitor has a CDR1 identical to CDR1 from one of nivolumab, pembrolizumab, cemiplimab, dostarimab, atezolizumab, avelumab, and durvalumab, a CDR2 identical to CDR2 from one of nivolumab, pembrolizumab, cemiplimab, dostarimab, atezolizumab, avelumab, and durvalumab, or a CDR3 identical to CDR3 from one of nivolumab, pembrolizumab, cemiplimab, dostarimab, atezolizumab, avelumab, and durvalumab, in certain embodiments, a CDR1 identical to CDR1 from one of nivolumab, pembrolizumab, cemiplimab, dostarimab, atezolizumab, avelumab, and durvalumab. or CDR1 and CDR2 that are identical to CDR1 and CDR2 from one of nivolumab, pembrolizumab, cemiplimab, dostarimab, atezolizumab, avelumab, and durvalumab; or CDR2 and CDR3 that are identical to CDR2 and CDR3 from one of nivolumab, pembrolizumab, cemiplimab, dostarimab, atezolizumab, avelumab, and durvalumab; and further CDR1, CDR2, and CDR3 that are identical to CDR1, CDR2, and CDR3 of nivolumab, pembrolizumab, cemiplimab, dostarimab, atezolizumab, avelumab, and durvalumab. In certain aspects, the PD-1 or PD-L1 inhibitor comprises a CDR1, CDR2, and CDR3 that are identical to the CDR1, CDR2, and CDR3 from pembrolizumab.

[0141] In certain embodiments, the multispecific antibody is administered in a dose of 10 to 300 mg, such as 25 to 75 mg, such as 10 to 150 mg or 25 to 100 mg. In certain embodiments, the multispecific antibody is administered in a dose of 25, 30, 35, 40, 45, or 50 mg. In certain embodiments, the multispecific antibody is administered in a flat dose of 25, 30, 35, 40, 45, or 50 mg.

[0142] In certain embodiments, the multispecific antibody is administered about every 7, 10, 11, 12, 13, 14, 15, 16, 17, or 18 days, or 21 days, particularly about every 10, 14, or 18 days, and more particularly about every 14 days.

[0143] In certain embodiments, the PD-1 or PD-L1 inhibitor is administered at a dose according to its approved dose and schedule approved by the USFDA. In certain embodiments, pembrolizumab is administered in an amount of about 300-500 mg, such as 375-425 mg, such as 350-450 mg. In certain embodiments, the PD-1 or PD-L1 inhibitor is administered at a dose of 325, 350, 375, 400, 425, 450, or 475 mg.

[0144] In some embodiments, the multispecific antibody is administered at a dose of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, or 150 mg.

[0145] In certain aspects, the multispecific antibodies or methods according to the present disclosure are administered in a uniform dose.

[0146] In certain embodiments, a multispecific antibody or method according to the present disclosure is administered in a dose or flat dose of 50-150 mg, such as 75-150 mg, such as 25-125 mg or 100-150 mg. In certain embodiments, a multispecific antibody or method according to the present disclosure is administered in a dose or flat dose of 50-150 mg, or 75-150 mg, or 75-125 mg, or 100-150 mg.

[0147] In certain embodiments, the multispecific antibody or method according to the present disclosure is administered in a dose of 75-125 mg or a flat dose.

[0148] In certain embodiments, the multispecific antibody or method according to the present disclosure is administered in a dose or flat dose of 50-150 mg, such as 75-125 mg, In certain embodiments, the multispecific antibody or method according to the present disclosure is administered in a dose or flat dose of 50-100 mg, or 75-100 mg, or 75-125 mg.

[0149] In certain embodiments, the multispecific antibody or method according to the present disclosure is administered in a dose of 25-75 mg or a flat dose.

[0150] In certain embodiments, the multispecific antibody or method according to the present disclosure is administered in a dose of 10-50 mg, such as 25-50 mg, or in a flat dose. In certain embodiments, the multispecific antibody or method according to the present disclosure is administered in a dose of 10-50 mg, such as 25-50 mg, or in a flat dose.

[0151] In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered once every week, once every two weeks, or once every three weeks. In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered once every two weeks. In certain embodiments, when the multispecific antibody or method according to the use of the present disclosure is administered once every week, the multispecific antibody is administered at a dose of 10-100 mg, such as 15-75 mg. In certain embodiments, when the multispecific antibody or method according to the use of the present disclosure is administered once every week, the multispecific antibody is administered at a dose of 10-100 mg, or 15-75 mg, such as 15-50 mg, or 15-40 mg, or 15-30 mg, or 15-25 mg.

[0152] In certain embodiments, the multispecific antibody or method according to the present disclosure is administered in a flat dose once every two weeks.

[0153] In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered in a dose of 25, 30, 35, 40, 45, or 50 mg or a flat dose once every two weeks. In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered in a dose of 25 mg or a flat dose once every two weeks. In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered in a dose of 40 mg or a flat dose once every two weeks. In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered in a dose of 50 mg or a flat dose once every two weeks.

[0154] In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 200 mg as an intravenous infusion every three weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 10 mg once every two weeks. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 200 mg as an intravenous infusion every three weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 15 mg once every two weeks. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 200 mg as an intravenous infusion every three weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 25 mg once every two weeks. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 200 mg as an intravenous infusion every three weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 40 mg once every two weeks.

[0155] In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 400 mg as an intravenous infusion every six weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 10 mg once every two weeks. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 400 mg as an intravenous infusion every six weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 15 mg once every three weeks. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 400 mg as an intravenous infusion every six weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 25 mg once every two weeks. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 400 mg as an intravenous infusion every six weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 40 mg once every two weeks.

[0156] In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 200 mg as an intravenous infusion every three weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 10 mg once every three weeks. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 200 mg as an intravenous infusion every three weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 15 mg once every three weeks. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 200 mg as an intravenous infusion every three weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 25 mg once every three weeks. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 200 mg as an intravenous infusion every three weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 40 mg once every three weeks.

[0157] In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 400 mg as an intravenous infusion every six weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 10 mg once every three weeks. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 400 mg as an intravenous infusion every six weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 15 mg once every three weeks. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 400 mg as an intravenous infusion every six weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 25 mg once every three weeks. In certain embodiments, the PD-1 inhibitor is pembrolizumab and is administered in an amount of 400 mg as an intravenous infusion every six weeks, and the treatment further comprises administering a multispecific antibody of the present disclosure in an amount of 40 mg once every three weeks.

[0158] In certain aspects, the multispecific antibodies or methods according to the present disclosure are administered intravenously.

[0159] In certain aspects, a multispecific antibody or method according to the present disclosure is administered over a period of 30 minutes to 4 hours, such as 1 to 3 hours, or such as 2 hours.

[0160] In certain aspects, a multispecific antibody or method according to the present disclosure is administered over a period of 30 minutes to 4 hours, such as 1 to 3 hours, or such as 2 hours.

[0161] In certain embodiments, a multispecific antibody or method according to the present disclosure is administered intravenously as a flat dose over a 2 hour period every 14 days in a 28 day cycle.

[0162] In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered intravenously as a 10 mg (flat) dose over a period of 2 hours every 14 days in a 28 day cycle. In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered intravenously as a 15 mg (flat) dose over a period of 2 hours every 14 days in a 28 day cycle. In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered intravenously as a 25 mg (flat) dose over a period of 2 hours every 14 days in a 28 day cycle. In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered intravenously as a 30 mg (flat) dose over a period of 2 hours every 14 days in a 28 day cycle. In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered intravenously as a 40 mg (flat) dose over a period of 2 hours every 14 days in a 28 day cycle. In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered intravenously as a 50 mg (flat) dose over a period of 2 hours every 14 days in a 28 day cycle. In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered intravenously as a 60 mg (flat) dose over a period of 2 hours every 14 days in a 28 day cycle. In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered intravenously as a 70 mg (flat) dose over a period of 2 hours every 14 days in a 28 day cycle. In certain embodiments, the multispecific antibody or method according to the use of the present disclosure is administered intravenously as a 75 mg (flat) dose over a period of 2 hours every 14 days in a 28 day cycle.

[0163] In certain embodiments, the multispecific antibodies or methods according to the present disclosure are formulated as a liquid at a concentration between 1 mg / mL and 100 mg / mL, such as at or near 20 mg / mL. In certain embodiments, the multispecific antibodies or methods according to the present disclosure are formulated as a liquid at a concentration between 1 mg / mL and 100 mg / mL, or at or near 20 mg / mL.

[0164] In certain embodiments, pembrolizumab is administered in a dose or flat dose of 100-500 mg, or 100-300 mg, or 300-500 mg, or 150-250 mg, or 350-450 mg, or 175-225 mg, or 375-425 mg.

[0165] In certain embodiments, the PD-1 or PD-L1 inhibitor is administered at a dose of about or about 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, or 475 mg, or a flat dose of about 175 mg, 200 mg, 225 mg, 375 mg, 400 mg, or 425 mg.

[0166] In certain embodiments, the PD-1 or PD-L1 inhibitor, such as pembrolizumab, is administered once every three weeks. In certain embodiments, the PD-1 or PD-L1 inhibitor, such as pembrolizumab, is administered once every six weeks.

[0167] In certain embodiments, pembrolizumab is administered at a dose or flat dose of 100-300 mg, 150-250 mg, or 175-225 mg once every 3 weeks. In certain embodiments, pembrolizumab is administered at a dose or flat dose of 300-500 mg, 350-450 mg, or 375-425 mg once every 6 weeks.

[0168] In certain embodiments, the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered at a dose of about 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, or a flat dose every 21 days. In certain embodiments, the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered at a dose of about 350 mg, 375 mg, 400 mg, 425 mg, or 450 mg, or a flat dose every 42 days.

[0169] In certain embodiments, the PD inhibitor is first administered about 21 days after the first administration of the multispecific antibody, hi certain embodiments, the PD inhibitor is first administered about 42 days after the first administration of the multispecific antibody.

[0170] In certain embodiments, the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered at a dose of about 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, or a flat dose every 21 days. In certain embodiments, the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered at a dose of about 350 mg, 375 mg, 400 mg, 425 mg, or 450 mg, or a flat dose every 42 days. In certain embodiments, the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered at a dose of about 200 mg, or a flat dose every 21 days. In certain embodiments, the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered at a dose of about 400 mg, or a flat dose every 42 days.

[0171] In certain embodiments, the PD-1 or PD-L1 inhibitor is administered via IV, particularly via IV infusion, which may be administered over, for example, 15, 30, or 45 minutes.

[0172] In certain embodiments, the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered via IV infusion at a dose of about 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, or a flat dose every 21 days. In certain embodiments, the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered via IV infusion at a dose of about 350 mg, 375 mg, 400 mg, 425 mg, or 450 mg, or a flat dose every 42 days.

[0173] In certain embodiments, the multispecific antibody is administered as a dose or flat dose of 10 mg, 25 mg, 30 mg, 40 mg, or 50 mg every 14 days and the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered at a dose or flat dose of about 150 mg, 175 mg, 200 mg, 225 mg, 250 mg every 21 days. In certain embodiments, the multispecific antibody is administered as a dose or flat dose of 10 mg, 25 mg, 30 mg, 40 mg, or 50 mg every 14 days and the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered at a dose or flat dose of about 350 mg, 375 mg, 400 mg, 425 mg, or 450 mg every 42 days.

[0174] In certain embodiments, the multispecific antibody is administered as a flat dose of 10 mg, 15 mg, 25 mg, or 40 mg every 14 days and the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered as a flat dose of about 200 mg every 21 days. In certain embodiments, the multispecific antibody is administered as a flat dose of 10 mg, 15 mg, 25 mg, or 40 mg every 14 days and the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered as a flat dose of about 400 mg every 42 days.

[0175] In certain embodiments, the multispecific antibody is administered as a flat dose of 10 mg, 15 mg, 25 mg, or 40 mg every 21 days and the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered as a flat dose of about 200 mg every 21 days. In certain embodiments, the multispecific antibody is administered as a flat dose of 10 mg, 15 mg, 25 mg, or 40 mg every 21 days and the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered as a flat dose of about 400 mg every 42 days.

[0176] In certain embodiments, the multispecific antibody is administered as a 40 mg dose or flat dose every 14 days, and the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered at a dose of about 200 mg or flat dose every 21 days, or at a dose of about 400 mg or flat dose every 42 days.

[0177] In certain embodiments, the multispecific antibody is administered as a 40 mg dose or flat dose every 21 days and the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered at a dose of about 200 mg or flat dose every 21 days or at a dose of about 400 mg or flat dose every 42 days.

[0178] In certain embodiments, the multispecific antibody is administered as a 25 mg dose or flat dose every 14 days, and the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered at a dose of about 200 mg or flat dose every 21 days, or at a dose of about 400 mg or flat dose every 42 days.

[0179] In certain embodiments, the multispecific antibody is administered as a 30 mg dose or flat dose every 14 days and the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered at a dose of about 200 mg or flat dose every 21 days or at a dose of about 400 mg or flat dose every 42 days.

[0180] In certain embodiments, the multispecific antibody is administered as a 40 mg dose or flat dose every 14 days, and the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered at a dose of about 200 mg or flat dose every 21 days, or at a dose of about 400 mg or flat dose every 42 days.

[0181] In certain embodiments, the multispecific antibody is administered as a 50 mg dose or flat dose every 14 days and the PD-1 or PD-L1 inhibitor is pembrolizumab and is administered at a dose of about 200 mg or flat dose every 21 days or at a dose of about 400 mg or flat dose every 42 days.

[0182] In certain embodiments, the PD-1 or PD-L1 inhibitor is formulated as a liquid at a concentration between 1 mg / mL and 100 mg / mL, or at or near 25 mg / mL.

[0183] In certain aspects, a multispecific antibody or method according to the present disclosure is administered before, simultaneously with, or after an antihistamine, a nonsteroidal anti-inflammatory drug (NSAID), a narcotic, an intravenous fluid, an antipyretic, a bronchodilator, oxygen, a corticosteroid (IV / oral), a vasoconstrictor, or any combination thereof, to reduce an infusion-related reaction. If an infusion-related reaction does occur, the subject may be selected to pre-medicate with the indicated substances to prevent and mitigate its incidence and severity.

[0184] In certain aspects, a multispecific antibody or method according to the present disclosure is administered after the subject has been pre-treated with standard of care therapy, such as chemotherapy, immunotherapy, or targeted therapy, for progressive metastatic disease.

[0185] In certain aspects, a multispecific antibody or method according to the present disclosure is administered to a subject who has not been treated with an anti-PD-L1 agent, such as an anti-PD-L1 antibody or a T cell agonist.

[0186] In certain embodiments, the cancer is an advanced or metastatic solid tumor. In particular, the cancer may be selected from lung cancer, particularly locally advanced or metastatic NSCLC, or melanoma, particularly a cancer that has been previously treated with immune checkpoint therapy and / or is positive for PD-L1. In certain embodiments, the cancer is an advanced or metastatic solid tumor with PD-L1 expression of 1% or more. In certain embodiments, the cancer or the subject comprising the cancer has either previously received an approved anti-PD-1 / PD-L1 immunotherapy and has a cancer with PD-L1 expression of 1% or more, or the cancer or subject is treatment naive and has a cancer with PD-L1 expression of 1% or more.

[0187] In certain aspects, the cancer is an advanced or metastatic solid tumor, such as selected from locally advanced or metastatic lung cancer and locally advanced or metastatic melanoma. In certain aspects, the melanoma is selected from cutaneous melanoma, acral melanoma, or mucosal melanoma. In certain aspects, the cancer is Merkel cell carcinoma. Merkel cell carcinoma, also referred to herein as cutaneous neuroendocrine carcinoma or trabecular carcinoma, is a very rare type of skin cancer that forms when Merkel cells grow uncontrollably and form cancer or tumors.

[0188] PD-L1 expression is determined by a clinician of skill in the art, see the exemplary methods of de Ruiter et al. (2021), incorporated herein in its entirety. High expression as determined by any one of these methods constitutes high expression for purposes of this disclosure. When assessed by tumor proportion score (TPS), a TPS score of 1% or greater is a PD-L1 positive cancer. When assessed by combined positive score (CPS), a score of 1% or greater is a PD-L1 positive cancer. A cancer is PD-L1 high if it has a PD-L1 expression score of 10% or greater, 20% or greater, 30% or greater, 40% or greater, or 50% or greater, as determined using the tumor proportion score (TPS). A cancer is PD-L1 high if it has a PD-L1 expression score of 5% or greater, 15% or greater, or 20% or greater, as determined using the combined positive score (CPS). When assessed by multiple such methods, the criteria of this disclosure are met if any one or more of the methods identify the tumor as PD-L1 positive.

[0189] In certain embodiments, the subject has not been previously treated with an immune checkpoint inhibitor. In certain embodiments, the subject has not been previously treated with an immune checkpoint inhibitor, and the subject's cancer is positive for PD-L1 expression. In certain embodiments, the subject has not been previously treated with an immune checkpoint inhibitor, and has been treated for melanoma, particularly locally advanced or metastatic melanoma. In certain embodiments, the subject has not been previously treated with an immune checkpoint inhibitor, and has been treated for lung cancer, particularly non-small cell lung cancer (NSCLC).

[0190] The NSCLC may be non-squamous or squamous. In some embodiments, the subject may have undergone treatment based on the status of BRAF, ALK, EGFR, and / or ROS1. In certain embodiments, the subject may have progressed or not tolerated such treatment. In certain embodiments, the NSCLC is unresectable.

[0191] In certain embodiments, the melanoma is cutaneous melanoma, acral melanoma, or mucosal melanoma. The melanoma can be confirmed by standard histological or cytological processes. In certain embodiments, the melanoma is not ocular or uveal melanoma. In certain embodiments, the melanoma is stage III or stage IV melanoma (according to standard staging systems such as the American Joint Staging Committee). It may be unresectable and / or may be ineffective against local therapy.

[0192] In certain embodiments, the melanoma may be BRAF positive. In these embodiments, the subject may have undergone BRAF±MEF targeted therapy and may have shown progression.

[0193] In certain embodiments, the subject may have previously undergone standard therapy for progressive or recurrent / metastatic disease, particularly systemic therapy, or may be intolerant to such therapy. Standard therapy may include, for example, chemotherapy, immunotherapy, and targeted regimens. The subject may have undergone, for example, 1, 2, 3, 4, or 5 regimens, but particularly 4 or less regimens.

[0194] In certain embodiments, the subject has previously received immune checkpoint therapy, particularly PD-L1 / PD-1 therapy. In some such embodiments, the subject has previously received no more than one PD-1 therapy for advanced or metastatic cancer. In some such embodiments, the subject may have relapsed after a previous therapy, e.g., the subject's disease has progressed or at best remains stable after at least 6 months of treatment. In certain embodiments, the subject has not received prior treatment with an immune checkpoint inhibitor.

[0195] In some embodiments, the subject may have been on multispecific antibody monotherapy for 1, 2, 3, 4, 5, or 6 months, particularly 1 or 2 months, prior to initiating the combination therapy.

[0196] In certain embodiments, the subject is an adult. In certain embodiments, the subject is a mammal, particularly a human.

[0197] In certain embodiments, the subject does not have one or more conditions selected from Burkitt's lymphoma, lymphoblastic leukemia / lymphoma, lymphoplasmacytic lymphoma, chronic lymphocytic leukemia, CNS metastasis / lymphoma, carcinomatous meningitis, autoimmune disease, active HBV, active HCV, HIV. In certain embodiments, the subject has not received prior treatment including 4-1BB agonist, CAR T cell therapy, or solid organ or allogeneic stem cell transplant. In certain embodiments, the subject does not have a history of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia), drug-induced pneumonia, or idiopathic pneumonia, or interstitial pneumonia.

[0198] In certain aspects, the multispecific antibodies or methods of use of the present disclosure inhibit CD8 + Increases the number of T cells.

[0199] In certain aspects, the multispecific antibodies or methods according to the present disclosure are significantly less toxic than the combination of urelumab and atezolizumab, as determined in the same study, and in particular in immunodeficient mice bearing breast cancer, and more specifically, human MDA-MB-231 tumors.

[0200] In certain aspects, the multispecific antibodies or methods according to the present disclosure do not induce graft-versus-host disease.

[0201] The term "antibody" as used herein means a proteinaceous molecule, such as belonging to the immunoglobulin class of proteins, that contains one or more domains that bind to an epitope on an antigen, such domains being derived from or sharing sequence homology with the variable domains of the antibody. Antibodies for therapeutic use are preferably as close as possible to the natural antibody of the subject to be treated (e.g., human antibodies for human subjects). Antibody binding can be expressed in terms of specificity and affinity. Specificity determines which antigen or its epitope is specifically bound by a binding domain. Affinity is a measure of the strength of binding to a particular antigen or epitope. Antibodies, such as the multispecific antibodies of the present disclosure, typically contain the constant domains (Fc portion) of a natural antibody, which can be engineered as described elsewhere herein, for example, to reduce ADCC and / or CDC activity.

[0202] A "multispecific antibody" refers to an antibody that comprises at least two binding sites with different antigen or epitope specificities. In certain embodiments, one or more of the antigen binding sites comprises an immunoglobulin VH / VL pair. In certain embodiments, each of the antigen binding sites comprises an immunoglobulin VH / VL pair.

[0203] In certain embodiments, a multispecific antibody according to the present disclosure has no more than two antigen-binding sites. This means that the antigen-binding portion of such a multispecific antibody consists of two antigen-binding sites without the presence of an additional antigen-binding site. In certain embodiments, each of the two antigen-binding sites contains an immunoglobulin VH / VL pair.

[0204] In certain embodiments, the VL in each VH / VL pair is similar. In certain embodiments, the VL in each VH / VL pair is identical. In certain embodiments, the multispecific antibody is a full-length antibody having one heavy / light (H / L) chain combination that binds to the extracellular portion of CD137 and one H / L chain combination that binds to the extracellular portion of a member of the B7 family. In certain embodiments, the light chain in the first H / L chain combination is similar to the light chain in the second H / L chain combination. In certain embodiments, the light chains in the first and second H / L chain combinations are identical.

[0205] In certain aspects, the multispecific antibody is a bispecific antibody.

[0206] The term "bispecific antibody" means that one part of an antibody binds to one epitope on an antigen, while a second part binds to either a different epitope on the same antigen, or to a different antigen. The different epitopes are typically present on different antigens. However, the different epitopes can also be present on the same antigen. Depending on the expression levels, (sub)cellular localization, and stoichiometry of the two antigens recognized by the bispecific antibody, both Fab arms of the antibody may or may not simultaneously bind to their epitopes. One arm of the bispecific antibody typically contains the variable domain of one antibody, and the other arm contains the variable domain of another antibody (i.e., one arm of the bispecific antibody is formed by one heavy chain paired with one light chain, and the other arm is formed by a different heavy chain paired with a light chain). In certain aspects, the heavy chain variable regions of the bispecific antibodies of the present disclosure are different from each other, but the light chain variable regions are the same in the bispecific antibodies of the present disclosure. Bispecific antibodies in which different heavy chain variable regions are associated with the same or a common light chain variable region are also referred to as bispecific antibodies with a common light chain variable region (cLcv). In certain embodiments, the light chain constant regions are also the same. Such bispecific antibodies are referred to as having a common light chain (cLc).

[0207] Certain preferred embodiments are immunoglobulins with an IgG format, which offers the advantage that the half-life of the bivalent binding molecules / antibodies / variants according to the present disclosure is typically longer compared to multivalent compounds. Furthermore, the immunogenicity of the bivalent binding molecules according to the present disclosure is typically lower compared to multivalent compounds. The molecules / antibodies / variants according to these aspects preferably maintain the structure of native IgG and therefore maintain all the benefits associated with that structure of native IgG.

[0208] A "variant" of an antibody or multispecific antibody described herein includes a functional portion, derivative, and / or analog of the antibody or multispecific antibody. The variant may be a fragment of the antibody, e.g., a Fab fragment. The variant may be a single chain variable fragment (scFv). The variant maintains the binding specificity of the antibody. The functional portion, derivative, and / or analog maintains the binding specificity of the antibody. The binding specificity is defined by the ability to bind to the extracellular portion of the first membrane protein and the second membrane protein, as described herein. A variant may have amino acid insertions, deletions, substitutions, or combinations thereof relative to a given amino acid sequence (e.g., a SEQ ID NO: of the present disclosure), such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, such as 0, 1, 2, 3, 4, or 5, such as 0, 1, 2, 3, or 4, such as 0, 1, 2, or 3, such as 0, 1, or 2, or up to 15, such as 0 or 1 amino acid insertions, deletions, substitutions, or combinations thereof relative to the amino acid sequence of a given SEQ ID NO.

[0209] As used herein, the term "antigen-binding site" refers to the site of a binding molecule or antibody that specifically binds to an epitope of an antigen. Such antigen-binding sites are preferably derived from or share sequence homology with the variable domains of an antibody, in particular the CDR regions thereof. In some preferred embodiments, the antigen-binding site is an immunoglobulin variable domain formed by an immunoglobulin VH / VL pair. In other embodiments, the antigen-binding site is derived from an antibody mimetic, such as, for example, an affibody molecule, an affilin, an affimer, an affitin, an alphabody, an anticalin, an avimer, a DARPin, a finomer, a Kunitz domain peptide, or a monobody, as described herein above.

[0210] The term "full length" according to the present disclosure is defined to include essentially complete antibodies that do not include one or more artificially added moieties having a size of more than 20 amino acid residues, such as, for example, additional antigen binding sites or additional activation sites, or additional ligands or additional ligand binding sites. However, a full length antibody does not necessarily have all the functions of an intact antibody. For the avoidance of doubt, a full length antibody contains two heavy chains and two light chains. Each chain contains a constant (C) and a variable (V) region, which can be classified into domains designated CH1, CH2, CH3, VH for the heavy chain, and CL, VL for the light chain. The domains of the heavy chain are preferably present in the order of natural antibodies (VHCH1-CH2-CH3; meaning that the VH domain is adjacent to the CH1 domain, followed by the CH2 domain, followed by the CH3 domain). The domains of the light chain are also preferably present in the order of natural antibodies (VL-CL; meaning that the VL domain is adjacent to the CL domain). The antibody binds to the antigen via the variable domain contained in the Fab fragment portion. Antibodies can interact with molecules and cells of the immune system via their constant domains, primarily via the Fc portion.

[0211] In certain aspects, full-length IgG antibodies are preferred due to their typically favorable half-life and because one wants to remain close to fully self (human) molecules for immunogenicity reasons, hi certain aspects, the multispecific antibodies of the present disclosure are full-length IgG1, full-length IgG2, full-length IgG3, or full-length IgG4 antibodies.

[0212] Full length antibodies include antibodies in which there may be mutations that provide desired characteristics or that may simply be replacements for those in the original chain. Such mutations are typically not deletions of substantial portions of any region. However, antibodies in which one or several amino acid residues are inserted, deleted, substituted, or have a combination thereof without essentially changing the antigen binding properties of the resulting antibody are encompassed by the term "full length antibody." For example, an IgG antibody may have 1 to 20 amino acid residue insertions, substitutions, deletions, or a combination thereof in the constant region.

[0213] It should be noted that, unless otherwise stated, herein, the amino acid positions assigned to the CDRs and frameworks in the heavy chain variable region of an antibody or antibody fragment are designated according to the Kabat numbering system (see Sequences of Proteins of Immunological Interest (National Institute of Health, Bethesda, Md., 1987 and 1991)). Amino acids in the constant region are designated according to the EU numbering system.

[0214] In certain aspects, the "percent identity" of nucleic acid or amino acid sequences herein is defined as the percentage of residues in a candidate sequence that are identical to the residues in a selected sequence after aligning the sequences for optimal comparison purposes. To optimize the alignment between these two sequences, gaps can be introduced in either of the two sequences being compared. Such alignment can be performed over the entire length of the sequences being compared. Alternatively, alignment can be performed over a shorter length, for example, about 20, about 50, about 100 or more nucleic acids / bases or amino acids. Alignment can also be performed over individual CDR sequences. The sequence identity is the percentage of perfect matches between these two sequences over the reported aligned region.

[0215] In certain embodiments, the comparison of sequences and the determination of the percentage of sequence identity between two sequences are accomplished using a mathematical algorithm. Those skilled in the art will recognize the fact that several different computer programs are available for aligning two sequences and determining the identity between two sequences (Kruskal, JB (1983) An overview of sequence comparison In D. Sankoff and JB Kruskal, (ed.), Time warps, string edits and macromolecules: the theory and practice of sequence comparison, pp. 1-44 Addison Wesley). The percentage of sequence identity between two amino acid or nucleic acid sequences can be determined using the Needleman and Wunsch algorithm for aligning two sequences (Needleman, SB and Wunsch, CD (1970) J. Mol. Biol. 48, 443-453). The Needleman-Wunsch algorithm is implemented in the computer program NEEDLE. In certain embodiments, the NEEDLE program from the EMBOSS package is used to determine percent identity of amino acid and nucleic acid sequences (version 2.8.0, EMBOSS: The European Molecular Biology Open Software Suite (2000) Rice, P. Longden J. and Bleasby, A. Trends in Genetics 16, (6) pp276- 277, http: / / emboss.bioinformatics.nl / ). In certain embodiments, for protein sequences, EBLOSUM62 is used as the substitution matrix. In certain embodiments, DNAFULL is used for DNA sequences. The parameters used are a gap open penalty of 10 and a gap extension penalty of 0.5.

[0216] After alignment with the program NEEDLE as described above, the percentage of sequence identity between the query sequence and the sequences of the disclosure is calculated as follows: the number of corresponding positions in the alignment represents the number of identical amino acids or identical nucleotides in both sequences divided by the total length of the alignment after subtraction of the total number of gaps in the alignment.

[0217] In certain embodiments, at the start of treatment, at least one, more than one, or all of the following inclusion factors IF1 to IF20 apply to the subject of treatment. By initiation of treatment is meant the first administration of a multispecific antibody of the present disclosure. In certain embodiments, the subject includes or complies with all of IF1 to IF: IF1. Life expectancy of 12 weeks or more. Have an ECOG performance status of IF2.0 or 1. IF3. Have locally advanced tumors that have relapsed to PD-L1 / PD-1 and have positive PD-L1 expression (≥1%) on tumor and / or tumor-associated immune cells (based on local testing after completion of the most recent prior line of therapy) IF4. Have measurable disease according to RECIST v1.1 or Lugano criteria. IF5. Previously received standard therapy for progressive or recurrent / metastatic disease appropriate for tumor type and is intolerant to or has refused standard therapy. IF6. Have received up to 4 prior systemic treatment regimens (including chemotherapy, immunotherapy, and targeted therapy regimens) for progressive or recurrent / metastatic disease unless approved by Medical Monitor. IF7. Received up to 1 prior anti-PD-1 containing immunotherapy regimen in the advanced / metastatic setting, provided anti-PD-1 therapy is permitted in combination with chemotherapy, targeted therapy, or other immunotherapy. Tumor-specific criteria IF8. Subject with histologically or cytologically confirmed melanoma, with histologically or cytologically confirmed cutaneous melanoma, acral melanoma, or mucosal melanoma. IF9. Unresectable stage III or stage IV melanoma according to the American Joint Committee on Cancer staging system, where local therapy has failed. IF10. Have V600 activating BRAF mutation status during screening period if not previously tested, or consent to BRAF testing. IF11.BRAF mutation-positive patients must have received BRAF±MEK targeted therapy with documented progression. IF12. Relapse to PD-L1 / PD-1 therapy (e.g., progression after >6 months of treatment with at least stable disease as the best response) IF13. Relapse to PD-L1 / PD-1 therapy (e.g., progression after >6 months of treatment with at least stable disease as the best response) IF14.Naive to PD-L1 / PD-1 therapy IF15.Subject with documented progression on anti-PD-1 therapy defined by meeting one of the following criteria: IF15a. Primary refractory: Previously treated with anti-PD-1 therapy (alone or as part of a combination) for at least 12 weeks in the progressive or metastatic setting with PD as the best response to treatment. IF15b. Secondary resistance: Previously received anti-PD-1 therapy (alone or as part of a combination) in the advanced or metastatic setting and achieved CR, PR, or SD, but subsequently developed PD while receiving anti-PD-1 therapy (PD was confirmed after at least 4 weeks [≥28 days]). IF16. Subjects with histologically or cytologically confirmed NSCLC, with a diagnosis of histologically or cytologically confirmed NSCLC (either non-squamous or squamous). IF16a. Documentation of test results for EGFR, ALK, BRAF, and ROS1 mutations or gene rearrangements if tumor is of non-squamous histology only, whereas if mutations or gene rearrangements are present, subject has progressed on or is intolerant of targeted therapy. IF17. Unresectable advanced or metastatic NSCLC according to the AJCC staging system, where local therapy has failed. IF18. Subjects who have relapsed to PD-L1 / PD-1 therapy (e.g., progressed after >6 months of treatment with at least stable disease as the best response) IF19. Subjects who are either relapsed to PD-L1 / PD-1 therapy (e.g., progressed after more than 6 months of treatment with at least stable disease as the best response) or are PD-L1 / PD-1 therapy naïve. IF20.Subject with documented progression on anti-PD-1 therapy defined by meeting one of the following criteria: IF20a.If primary refractory, subjects who have previously received anti-PD-1 therapy (alone or as part of a combination) in the progressive or metastatic setting for a minimum of 12 weeks and have PD as their best response to treatment. IF20b. For secondary resistance, subjects in the advanced or metastatic setting who have previously received anti-PD-1 therapy (alone or as part of a combination) and achieved CR, PR, or SD, but subsequently had confirmed PD while receiving anti-PD-1 therapy (PD confirmed after at least 4 weeks [≥ 28 days]).

[0218] In certain embodiments, the subject of treatment complies with any one or more factors selected from the group consisting of IF1-IF20.

[0219] In certain embodiments, at the start of treatment, at least one, two or more, or all of the following exclusion factors EF1-EF23 apply to a patient eligible for treatment: EF1. Have received treatment with an anti-cancer drug or investigational drug within the following intervals prior to administration of the first dose of a multispecific antibody of the disclosure: EF1a: At least 14 days for chemotherapy (6 weeks for mitomycin C and nitrosoureas), targeted small molecule therapy, or radiation therapy, if the subject does not have radiation pneumonitis as a result of treatment and a 1-week washout period is permitted for palliative radiation for non-CNS disease. EF1b: For antibodies previously used in anticancer therapy, at least 14 or 28 days; EF1c: For other drugs with long half-lives (e.g., more than 5 days), administration of the multispecific antibody of the present disclosure before the 5th half-life requires medical monitor approval. EF1d: For radioimmunotherapy, at least 10 weeks, or EF1e: Subjects who have not undergone allogeneic SCT within the past 6 months or autologous SCT within the past 3 months. EF2: Subjects who have not recovered from toxic effects of prior therapy (including prior immunotherapy) and / or complications from prior surgical interventions, to Grade 1 or below or to baseline prior to the first administration of a multispecific antibody of the disclosure, provided that alopecia and stable neuropathy (Grade 2 or below) is expected. EF3. Subjects with Grade 1 or greater liver toxicity from prior anti-PD-1 therapy (± anti-CTLA-4 therapy), provided baseline transaminases and bilirubin are outside normal limits. EF4. Subjects with prior Grade 3 or greater immune-mediated adverse events from anti-PD-1 therapy, provided the following Grade 3 or greater adverse events are tolerated: Grade 3 rash that resolved with topical therapy; immune-mediated adrenal insufficiency, type 1 diabetes mellitus, or other endocrine abnormality resulting from prior immunotherapy who are medically stable and adequately managed with stable doses of replacement therapy; and asymptomatic amylase or lipase elevations not requiring treatment interruption. EF5. History of immune-mediated ocular adverse events of any grade. EF6.Subject has laboratory values ​​at Screening as defined in the table below. [Table 1] EF7. Subjects with clinically significant cardiac disease, including known history of left ventricular ejection fraction less than 50%, unstable angina within 6 months of Cycle Day 1, acute myocardial infarction, New York Heart Association Class III or IV congestive heart failure, or arrhythmia requiring therapy, provided that the subject with arrhythmia is taking antiarrhythmic medication and is in sinus rhythm on screening ECG. EF7. Subject with a history or presence of a clinically significant ECG in the opinion of the Investigator. EF8. Subject with immune-related toxicity during previous checkpoint inhibitor therapy for which permanent discontinuation of treatment was recommended (per product labeling or consensus guidelines) or any immune-related toxicity requiring intensive or prolonged immunosuppression to manage (excluding endocrine disorders adequately controlled with replacement hormones). EF9. Subjects with a history of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonia or idiopathic pneumonia, or evidence of interstitial pneumonia on a screening chest CT scan. EF10. Subjects with a history of uncontrolled asthma or chronic obstructive pulmonary disease, provided that they are permitted to have a history of radiation pneumonitis (fibrosis) in the radiation field. EF11. Subjects with previously treated brain metastases, if EF11a, subject with known active CNS metastases / lymphoma and / or carcinomatous meningitis, subject to be permitted: radiologically stable (i.e., no evidence of progression by repeat imaging for at least 28 days prior to first administration of a multispecific antibody of the disclosure; EF11b: no need for steroid treatment for at least 14 days prior to first administration of a multispecific antibody of the disclosure; or EF11c: clinically stable with return of any neurological signs or symptoms to baseline, subject to the exclusion of carcinomatous meningitis regardless of clinical stability. EF12: Subjects with evidence of cerebral edema or less than 28 days after CNS-directed radiation therapy. EF13: Subjects with vitiligo, resolved childhood asthma / atopy, hypothyroidism stabilized on hormone replacement, controlled asthma, type I diabetes, Graves' disease, or Hashimoto's disease, or an active or inactive autoimmune disease or syndrome (e.g., rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease) that has required systemic treatment within the past 2 years, or subjects receiving systemic therapy (i.e., involving use of disease-modifying agents, corticosteroids, or immunosuppressants) for an autoimmune or inflammatory disease, provided that subjects with medical monitor approval are allowed if they meet all other eligibility criteria. EF14: Subjects using systemic corticosteroids (≥10 mg / day of prednisone or equivalent) within 7 days prior to administration of the first dose of a multispecific antibody of the disclosure, provided that the use of inhaled or topical or systemic corticosteroids for imaging procedures is permitted and the use of physiological corticosteroid replacement therapy may be approved after consultation with a medical monitor. EF15. Administration of a live vaccine within 30 days prior to administration of the first dose of a multispecific antibody of the disclosure or pembrolizumab, including but not limited to, measles, mumps, rubella, chickenpox, yellow fever, rabies, BCG, and typhoid vaccines. EF16.If a live COVID-19 vaccine is available, a medical monitor should be consulted prior to administration. EF17. Injectable seasonal influenza vaccines, which will generally be inactivated virus vaccines, are anticipated, with the exception that an intranasal influenza vaccine that is a live attenuated vaccine is not anticipated. EF18. Active infection requiring systemic therapy. EF19. History of solid organ or allogeneic stem cell transplant. EF20. Active HBV or HCV infection requiring treatment but hepatitis B viral DNA and HCV RNA must be undetectable, provided that subjects who have previously cleared HBV infection (defined as hepatitis B surface antigen negative, hepatitis B surface antibody positive, hepatitis B core antibody positive) and subjects with no previous history of HBV infection who have been vaccinated against HBV and are seropositive for hepatitis B surface antigen as evidenced only by previous exposure, and hepatitis C antibody positive subjects who have undetectable HCV RNA levels and, if acceptable, have undergone and completed hepatitis C treatment intended to eradicate the virus may be enrolled. EF21. Have a known history of HIV (HIV1 / 2 antibodies). EF22. Known hypersensitivity or severe reaction to any component of the multispecific antibody of the disclosure, pembrolizumab, or formulation components. EF23. Be pregnant or breastfeeding, or expect to conceive or father within the planned duration of the study, starting from the screening visit and continuing through 90 days after the last administration of a multispecific antibody of the disclosure.

[0220] In certain embodiments, the subject of treatment complies with any one or more factors selected from the group consisting of EF1-EF23. In certain embodiments, the subject of treatment complies with all of factors EF1-EF23.

[0221] Terms Certain aspects of the present disclosure are as defined in the following clauses. 1. A multispecific antibody comprising an antigen binding site that binds to the extracellular portion of CD137 and an antigen binding site that binds to the extracellular portion of a second membrane protein, for use in a method of treating cancer in a subject in need thereof, wherein the treatment further comprises administering a PD-L1 or PD-1 inhibitor. 2. A method of treating cancer in a subject in need of such treatment, comprising administering to a subject in need of such treatment a multispecific antibody comprising an antigen-binding site that binds to an extracellular portion of CD137 and an antigen-binding site that binds to an extracellular portion of a second membrane protein, and a PD-1 or PD-L1 inhibitor. 3. The multispecific antibody for use according to claim 1 or the method according to claim 2, wherein the multispecific antibody is administered simultaneously, sequentially or separately with a PD-1 or PD-L1 inhibitor. 4. The multispecific antibody or method for use according to any one of the preceding claims, wherein the cancer is an advanced or metastatic solid tumor, such as selected from locally advanced or metastatic lung cancer, and locally advanced or metastatic melanoma. 5. The multispecific antibody or method for use according to any one of the preceding claims, wherein the cancer is NSCLC. 6. The multispecific antibody for use or method according to claim 4, wherein the melanoma is selected from cutaneous melanoma, acral melanoma, or mucosal melanoma. 7. The multispecific antibody for use or method according to any preceding clause, wherein the cancer has relapsed to PD-1 / PD-L1 therapy and / or is positive for PD-L1 expression. 8. The multispecific antibody for use or method according to any preceding clause, wherein the PD-1 or PD-LI inhibitor is an antibody, or a variant or functional fragment thereof. 9. The multispecific antibody for use or method according to any preceding clause, wherein the PD-1 or PD-LI inhibitor is a PD-1 inhibitor. 10. The multispecific antibody for use or method according to clause 9, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, penprimab, retifanlimab, sintilimab, tislelizumab, toripalimab, and dostarimab. 11. The multispecific antibody for use or method according to clause 10, wherein the PD-1 inhibitor is pembrolizumab. 12. The multispecific antibody for use or method according to any preceding clause, wherein the PD-1 or PD-LI inhibitor is a PD-L1 inhibitor. 13. The multispecific antibody for use or method according to clause 12, wherein the PD-L1 inhibitor is selected from atezolizumab, avelumab, and durvalumab. 14. The multispecific antibody or method for use according to any preceding clause, wherein the multispecific antibody is administered in a dose of 10-600mg, 15-600mg, 25-600mg, 10-300mg, 15-300mg, or 25-300mg, such as 10-150mg, 10-100mg, 10-75mg, 15-150mg, 15-100mg, 15-75mg, 25-150mg, 25-100mg, or 25-75mg, or 10mg-1200mg, 15-1200mg, or 25-1200mg, such as 10-50mg, 15-50mg, 25-50mg, or 50-100mg. 15. The multispecific antibody for use or method according to any preceding clause, wherein the multispecific antibody is administered in a dose of about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, or 75 mg. 16. The multispecific antibody for use or method according to any preceding clause, wherein the PD-1 or PD-L1 inhibitor is administered at a dose of about 300 to 500 mg, such as 325 to 475 mg, 350 to 450 mg, or 375 to 425 mg. 17. The multispecific antibody for use or method according to any preceding clause, wherein the multispecific antibody is administered every 14 days. 18. The multispecific antibody for use or method according to any preceding clause, wherein the PD-1 or PD-L1 inhibitor is administered every 4, 5, 6, 7, or 8 weeks. 19. The multispecific antibody for use or method according to clause 18, wherein the PD-1 or PD-L1 inhibitor is administered every 6 weeks. 20. The multispecific antibody for use or method according to any preceding clause, wherein the multispecific antibody and the PD-1 or PD-L1 inhibitor are administered in the dosage combinations shown in the table below: [Table 2-1] [Table 2-2] 21. The multispecific antibody for use or method according to any preceding clause, wherein the multispecific antibody is administered intravenously. 22. The multispecific antibody for use or method according to any preceding clause, wherein the multispecific antibody is administered once every two weeks. 23. The multispecific antibody for use or method according to any preceding clause, wherein said second membrane protein is not a member of the TNF receptor superfamily. 24. The multispecific antibody for use or method according to any preceding clause, wherein the second membrane protein is a member of the B7 family. 25. The multispecific antibody for use or method according to any preceding clause, wherein the second membrane protein is PD-L1 or PD-L2, such as PD-L1. 26. The multispecific antibody for use or method according to any preceding clause, wherein the multispecific antibody comprises one antigen-binding site that binds to the PD-1-binding domain of PD-L1. 27. A multispecific antibody for use or method according to any preceding clause, wherein the multispecific antibody comprises one antigen-binding site that binds to the CD137L-binding domain of CD137. 28. A multispecific antibody for use or method according to any preceding clause, wherein the multispecific antibody comprises one antigen-binding site that blocks binding of a ligand to CD137 or binds to an extracellular ligand-blocking binding site of CD137, such as a CD137L-blocking binding site. 29. A multispecific antibody or method for use according to any preceding clause, wherein a variable domain that binds to the extracellular portion of CD137 is defined as a variable domain which, when in a bivalent, monospecific antibody format comprising two of said variable domains that bind CD137, does not stimulate the activity of CD137 on cells, or stimulates it at a reduced level compared to one of said variable domains as part of a bispecific antibody having a second variable domain that binds to a tumor associated antigen, such as PD-L1, such as a member of the B7 family. 30. A multispecific antibody for use or method according to any preceding clause, wherein when the multispecific antibody is in the presence of a first cell expressing CD137 and a second cell expressing PD-L1, a variable domain that binds to the extracellular portion of CD137, when combined in the multispecific antibody with a second variable domain that binds PD-L1, is capable of stimulating the activity of CD137 on the cell. 31. The multispecific antibody for use or method according to any preceding clause, wherein the multispecific antibody is capable of binding to CD137 and PD-L1, such as simultaneously. 32. The multispecific antibody for use or method according to any preceding clause, wherein the multispecific antibody induces or activates CD137 signalling only in the presence of PD-L1 expressing cells. 33. A multispecific antibody for use or method according to any preceding clause, wherein the antigen-binding site of said multispecific antibody consists of one immunoglobulin variable domain that binds to CD137 and one immunoglobulin variable domain that binds to the extracellular portion of a second membrane protein. 34. The multispecific antibody for use or method according to any preceding clause, wherein the multispecific antibody is a full-length antibody. 35. A multispecific antibody or method for use according to any preceding clause, wherein the multispecific antibody is an IgG1 molecule without Fc effector functions. 36. The multispecific antibody for use or method according to any preceding clause, wherein the second membrane protein is not expressed to a significant extent by T cells. 37. The multispecific antibody for use or method according to any preceding clause, wherein the second membrane protein is present on a cell membrane as part of a multimeric membrane protein comprising two or more of the second membrane proteins. 38. The multispecific antibody for use or method according to any preceding clause, wherein said second membrane protein is present on the cell membrane as part of a homodimer or homotrimer. 39. The multispecific antibody for use or method according to any preceding clause, wherein the antibody comprises a heavy chain variable region that binds to the extracellular portion of CD137 comprising a CDR3 region having the amino acid sequence set forth in SEQ ID NO:23, SEQ ID NO:27, SEQ ID NO:34, or SEQ ID NO:52, or a variant thereof. 40. The multispecific antibody for use or method according to any preceding clause, wherein the antibody comprises a heavy chain variable region that binds to the extracellular portion of CD137 comprising a CDR2 region having the amino acid sequence set forth in SEQ ID NO:22, SEQ ID NO:26, SEQ ID NO:33, or SEQ ID NO:51, or a variant thereof. 41. The multispecific antibody for use or method according to any preceding clause, wherein the antibody comprises a heavy chain variable region that binds to the extracellular portion of CD137 comprising a CDR1 region having the amino acid sequence set forth in SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:32, or SEQ ID NO:50, or a variant thereof. 42. A multispecific antibody for use or method according to any preceding clause, wherein the antibody comprises a heavy chain variable region having the amino acid sequence as set forth in SEQ ID NO:1, SEQ ID NO:5, SEQ ID NO:9, SEQ ID NO:13, SEQ ID NO:17, SEQ ID NO:20, SEQ ID NO:24, SEQ ID NO:28, SEQ ID NO:31, SEQ ID NO:35, SEQ ID NO:39, SEQ ID NO:43, SEQ ID NO:46, or SEQ ID NO:49, or a variant thereof, which binds to the extracellular portion of CD137, such as SEQ ID NO:20, SEQ ID NO:24, SEQ ID NO:31, or SEQ ID NO:49. 43. A multispecific antibody for use or method according to any preceding clause, wherein the antibody comprises a heavy chain variable region comprising a CDR3 region having the amino acid sequence set forth in SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:61, SEQ ID NO:84, SEQ ID NO:88, SEQ ID NO:91, SEQ ID NO:95, SEQ ID NO:102, or SEQ ID NO:106, or a variant thereof, which binds to the extracellular portion of PD-L1, such as SEQ ID NO:56, SEQ ID NO:91, SEQ ID NO:95, or SEQ ID NO:102, which binds to the extracellular portion of PD-L1. 44. The multispecific antibody for use or method according to any preceding clause, wherein the antibody comprises a heavy chain variable region comprising a CDR2 region having the amino acid sequence set forth in SEQ ID NO:3, SEQ ID NO:55, SEQ ID NO:63, SEQ ID NO:66, SEQ ID NO:79, SEQ ID NO:83, SEQ ID NO:87, SEQ ID NO:94, SEQ ID NO:101, or SEQ ID NO:105, or a variant thereof, which binds to the extracellular portion of PD-L1. 45. The multispecific antibody of any preceding clause, wherein the antibody comprises a heavy chain variable region comprising a CDR1 region having an amino acid sequence as set forth in SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:65, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:82, SEQ ID NO:86, SEQ ID NO:90, or SEQ ID NO:93, or a variant thereof, which binds to the extracellular portion of PD-L1. 46. ​​A multispecific antibody for use or method according to any preceding clause, wherein the antibody comprises a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:73, SEQ ID NO:77, SEQ ID NO:81, SEQ ID NO:85, SEQ ID NO:89, SEQ ID NO:92, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:100, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:107, or a variant thereof, which binds to the extracellular portion of PD-L1, such as SEQ ID NO:67, SEQ ID NO:89, SEQ ID NO:92, or SEQ ID NO:100. 47. The multispecific antibody or method for use according to any preceding clause, wherein the multispecific antibody comprises CDR1, 2, and 3 of MF6797 and CDR1, 2, and 3 of MF7702, or variants thereof. 48. The multispecific antibody for use or method according to any preceding clause, wherein the multispecific antibody comprises SEQ ID NO: 49 and SEQ ID NO: 67, or a variant thereof. 49. The multispecific antibody for use or method according to any preceding clause, wherein the cancer is Merkel cell carcinoma. 50. A multispecific antibody for use in a method for treating cancer in a subject in need thereof, comprising: A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 50, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 51, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 52; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 40, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 41, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 42; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 21, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 22, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 23; or and / or a binding domain that binds to CD137, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 32, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 33, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 34. The antibody, A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:68, a CDR2 having the amino acid sequence set forth in SEQ ID NO:55, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:56; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 93, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 94, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 95; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 93, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 101, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 102; or a binding domain that binds to PD-L1, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 90, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 79, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 91; Each individual SEQ ID NO: has 0, 1, 2, 3, 4, or 5 amino acid insertions, deletions, or substitutions, or a combination thereof; A multispecific antibody, wherein the multispecific antibody is for simultaneous, sequential or separate administration with a PD-1 or PD-L1 inhibitor. 51. The multispecific antibody for use according to clause 49, wherein the multispecific antibody is administered in a dose of 10 to 300 mg, such as 50 to 100 mg, such as 25 to 150, or 25 to 100 mg. 52. The multispecific antibody for use according to clause 50 or 51, wherein the cancer is Merkel cell carcinoma. 53. A method of treating cancer in a subject in need thereof, comprising administering to said subject a multispecific antibody, A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 50, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 51, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 52; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 40, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 41, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 42; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 21, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 22, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 23; or and / or a binding domain that binds to CD137, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 32, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 33, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 34. The antibody, A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:68, a CDR2 having the amino acid sequence set forth in SEQ ID NO:55, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:56; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 93, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 94, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 95; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 93, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 101, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 102; or a binding domain that binds to PD-L1, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 90, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 79, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 91; a multispecific antibody, wherein each of the individual SEQ ID NOs has 0, 1, 2, 3, 4, or 5 amino acid insertions, deletions, or substitutions, or a combination thereof; A method comprising administering a PD-1 or PD-L1 inhibitor to a subject in need of treatment for cancer. 54. The method according to clause 53, wherein the multispecific antibody is administered at a dose of 10 to 300 mg, such as 50 to 100 mg, such as 25 to 150 or mg 25 to 100 mg, such as 10 to 300 mg, such as 25 to 300 mg. 55. The multispecific antibody or method for use according to any one of clauses 50 to 54, wherein the cancer is an advanced or metastatic solid tumor. 56. The multispecific antibody for use or method according to clause 55, wherein the progressive or metastatic solid tumor is selected from progressive or metastatic lung cancer, in particular non-small cell lung cancer (NSCLC), and progressive or metastatic melanoma. 57. A multispecific antibody for use in a method for treating cancer in a subject in need thereof, comprising: A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 50, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 51, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 52; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 40, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 41, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 42; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 21, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 22, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 23; or and / or a binding domain that binds to CD137, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 32, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 33, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 34. The antibody, A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:68, a CDR2 having the amino acid sequence set forth in SEQ ID NO:55, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:56; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 93, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 94, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 95; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 93, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 101, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 102; or a binding domain that binds to PD-L1, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 90, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 79, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 91; Each individual SEQ ID NO: has 0, 1, 2, 3, 4, or 5 amino acid insertions, deletions, or substitutions, or a combination thereof; the multispecific antibody is for administration simultaneously with, subsequent to, or separately from the PD-1 or PD-L1 inhibitor; A multispecific antibody, wherein the cancer is an advanced or metastatic solid tumor. 58. The multispecific antibody for use or method according to any one of clauses 50 to 57, wherein the multispecific antibody is administered intravenously. 59. The multispecific antibody or method for use according to any one of clauses 50 to 58, wherein the multispecific antibody is administered once every two weeks. 60. The multispecific antibody or method for use according to any one of clauses 50 to 59, wherein the multispecific antibody comprises CDR1, 2, and 3 of MF6797 and CDR1, 2, and 3 of MF7702, or variants thereof. 61. The multispecific antibody for use or method according to clause 60, wherein the multispecific antibody comprises SEQ ID NO: 49 and SEQ ID NO: 67, or a variant thereof. 62. The multispecific antibody or method for use according to any one of clauses 50 to 59, wherein the multispecific antibody comprises CDR1, 2, and 3 of MF6783 and CDR1, 2, and 3 of MF5542, or variants thereof. 63. The multispecific antibody for use or method according to clause 62, wherein the multispecific antibody comprises SEQ ID NO:1 and SEQ ID NO:92, or a variant thereof. 64. The multispecific antibody or method for use according to any one of clauses 50 to 59, wherein the multispecific antibody comprises CDR1, 2, and 3 of MF6754 and CDR1, 2, and 3 of MF5561, or variants thereof. 65. The multispecific antibody for use or method according to clause 64, wherein the multispecific antibody comprises SEQ ID NO: 20 and SEQ ID NO: 100, or a variant thereof. 66. The multispecific antibody or method for use according to any one of clauses 50 to 59, wherein the multispecific antibody comprises CDR1, 2, and 3 of MF6785 and CDR1, 2, and 3 of MF5439, or variants thereof. 67. The multispecific antibody for use or method according to clause 66, wherein the multispecific antibody comprises SEQ ID NO: 31 and SEQ ID NO: 89, or a variant thereof. 68. The multispecific antibody or method for use according to any one of clauses 50 to 59, wherein the multispecific antibody comprises CDR1, 2, and 3 of MF6795 and CDR1, 2, and 3 of MF5442, or variants thereof. 69. The multispecific antibody for use or method according to clause 68, wherein the multispecific antibody comprises SEQ ID NO: 9 and SEQ ID NO: 92, or a variant thereof. 70. A multispecific antibody or method for use according to any preceding clause, wherein the antibody comprises the CDR1, CDR2 and CDR3 sequences of a common light chain variable domain having the amino acid sequence set forth in SEQ ID NO: 110, or a common light chain having the amino acid sequence set forth in SEQ ID NO: 109, or a variant thereof, and the CDR nomenclature or numbering is according to IMGT. 71. The multispecific antibody or method for use according to any preceding clause, wherein the antibody comprises a common light chain variable domain having the amino acid sequence set forth in SEQ ID NO: 110, or a common light chain having the amino acid sequence set forth in SEQ ID NO: 109, or a variant thereof. 72. The multispecific antibody or method for use according to any preceding clause, wherein the antibody comprises a heavy chain constant domain 1 (CH1) having the amino acid sequence set forth in SEQ ID NO: 112, a heavy chain constant domain 2 (CH2) having the amino acid sequence set forth in SEQ ID NO: 114, a heavy chain constant domain 3 (CH3) having the amino acid sequence set forth in SEQ ID NO: 115, and a heavy chain constant domain 3 (CH3) having the amino acid sequence set forth in SEQ ID NO: 116, or a variant thereof. 73. The multispecific antibody or method according to any of clauses 50 to 72, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor. 74. The multispecific antibody or method according to clause 73, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, penprimab, retifanlimab, sintilimab, tislelizumab, toripalimab, and dostarimab. 75. The multispecific antibody or method according to clause 74, wherein the PD-1 inhibitor is pembrolizumab. 76. The multispecific antibody or method of any of clauses 50 to 72, wherein the PD-1 or PD-L1 inhibitor is a PD-L1 inhibitor. 77. The multispecific antibody or method according to clause 76, wherein the PD-L1 inhibitor is selected from atezolizumab, avelumab, and durvalumab. 75. A kit of parts comprising a multispecific antibody as defined in any one of the preceding clauses and instructions for use of the multispecific antibody in combination with a PD-1 or PD-L1 inhibitor. 79. The kit of parts according to clause 78, further comprising a PD-1 or PD-L1 inhibitor. 80. The kit according to clause 78 or 79, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor. 81. The kit according to clause 80, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, and dostarimab. 82. The kit according to clause 81, wherein the PD-1 inhibitor is pembrolizumab. 83. The kit of clause 78 or 79, wherein the PD-1 or PD-L1 inhibitor is a PD-L1 inhibitor. 84. The kit according to clause 83, wherein the PD-L1 inhibitor is selected from atezolizumab, avelumab, and durvalumab. 85. The kit according to any of the preceding clauses 78 to 84, further comprising instructions for use of the multispecific antibody in a dose of 10-75 mg, or 25-75 mg, or 25-50 mg, or 25-40 mg, or 25-30 mg, or 10 mg, or 25 mg, or 30 mg, or 40 mg, or 50 mg, or 60 mg, or 70 mg, or 75 mg, or a flat dose. 86. The kit according to any of clauses 78 to 85, wherein the kit comprises instructions for use of the multispecific antibody in the treatment of any progressive or metastatic solid tumor. 87. The kit of parts according to clause 86, wherein the progressive or metastatic solid tumor is selected from locally advanced or metastatic lung cancer, in particular non-small cell lung cancer (NSCLC), and locally advanced or metastatic melanoma. 88. A combination of a multispecific antibody comprising an antigen-binding site that binds to the extracellular portion of CD137 and an antigen-binding site that binds to the extracellular portion of a second membrane protein, and a PD-1 or PD-L1 inhibitor, for use in treating cancer in a subject in need of such treatment, wherein the multispecific antibody is as defined in any preceding clause and the inhibitor is as defined in any preceding clause. 89. A PD-1 or PD-L1 inhibitor as defined in any preceding clause for the treatment of cancer in a subject in need thereof, wherein the PD-L1 inhibitor is for simultaneous or sequential administration with a multispecific antibody comprising an antigen-binding site that binds to the extracellular portion of CD137 and an antigen-binding site that binds to the extracellular portion of a second membrane protein. 90. A multispecific antibody comprising an antigen-binding site that binds to the extracellular portion of CD137 and an antigen-binding site that binds to the extracellular portion of a second membrane protein, for use in the treatment of cancer in a subject who has been administered, or will be administered, a PD-1 or PD-L1 inhibitor as defined in any preceding clause. 91. A PD-1 or PD-L1 inhibitor as defined in any provision for use in the treatment of cancer in a patient who has received, or will receive, a multispecific antibody comprising an antigen-binding site that binds to the extracellular part of CD137 and an antigen-binding site that binds to the extracellular part of a second membrane protein. EXAMPLES

[0222] Example 1: A multispecific antibody that binds PD-L1 and CD137. Multispecific antibodies comprising the heavy chain variable regions described in Table 1 were obtained as described in WO2018 / 056821. [Table 3] [Table 4]

[0223] Example 2 - A Phase 1, Open-Label, Dose-Escalation, Safety, Tolerability, and Preliminary Efficacy Study of MCLA-145 in Combination with Pembrolizumab in Participants with Advanced or Metastatic Malignancies Treatment arm and duration: An open-label, non-randomized, Phase 1 study was initiated to determine the safety, tolerability, and preliminary efficacy of a multispecific antibody targeting CD137 and PD-L1 in combination with a PD-1 or PD-L1 inhibitor in adult participants with advanced or metastatic malignancies.

[0224] The following multispecific antibodies are suitable for use in the studies and methods of the disclosure: MF6797×MF7702, such as MF6797×MF7702, MF6763×MF5442, MF6754×MF5561, MF6785×MF5439, and MF6785×MF5442. Each multispecific antibody comprises two VHs designated by MF numbers capable of binding to CD137 and PD-L1, respectively, an Fc region having KK / DE CH3 heterodimerization domains as depicted by SEQ ID NO:115 and SEQ ID NO:116, respectively, a CH2 domain as depicted by SEQ ID NO:114, a CH1 domain as depicted by SEQ ID NO:112, and a common light chain as depicted by SEQ ID NO:109. In particular, a bispecific antibody comprising the heavy chain sequence of MF6797×MF7702 is suitable for use in the studies and methods of the disclosure.

[0225] A dose escalation study was conducted to determine the MTD and / or RDE of a multispecific antibody in combination with a fixed dose of a PD-1 inhibitor in participants with progressive or recurrent / metastatic solid tumors. Participants received escalating doses of one of the exemplary multispecific antibodies described above, further referred to herein as the "study antibody", every 2 weeks until the MTD or RDE was reached. The duration of each treatment cycle with escalating doses was 28 days. Participants also received a fixed dose of pembrolizumab at 400 mg every 6 weeks.

[0226] Overall study design This is an open-label, non-randomized, Phase 1 study to determine the safety, tolerability, and preliminary efficacy of MCLA-145 in adult participants with advanced or metastatic malignancies, and will be conducted in two parts: dose escalation and dose expansion. MCLA-145 in combination with pembrolizumab administered in a flat dose every 6 weeks will be administered intravenously in a flat dose over 2 hours every 14 days in a 28-day cycle.

[0227] Part 1: Dose escalation Part 1 is a dose escalation to determine the maximum tolerated dose (MTD) and / or recommended expansion dose (RDE) of MCLA-145 administered every 14 days in combination with pembrolizumab in participants with advanced or metastatic solid tumors.

[0228] Participants will be treated with a 10 mg dose level of MCLA-145 in combination with a fixed dose of pembrolizumab. At each dose level, 3-6 evaluable patients will be included, and if no dose-limiting toxicities (DLTs) are encountered in the first 28-day cycle, the dose of MCLA-145 will be escalated to the next level. Up to 6 evaluable patients may be included at each dose level until the MTD or RDE is reached, or as determined by the sponsor based on the overall safety of the product.

[0229] Participants first follow the following schema: [Table 5]

[0230] Further doses of the combination may be explored, including 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 100 mg, 125 mg, and 150 mg. Pembrolizumab may also be provided at 200 mg every three weeks.

[0231] Part 2: Dose confirmation / safety expansion Part 2 is a dose expansion to confirm the dose of MCLA-145 in combination with pembrolizumab through further evaluation of safety, tolerability, pharmacokinetics, preliminary antitumor activity, and functional target engagement. Participants with advanced or metastatic tumors will be enrolled as follows:

[0232] Adult males or females with advanced or metastatic solid tumors relapsed against PD1 / PD-L1.Participants with NSCLC and melanoma with PD-L1 >1% relapsed against PD1 / PD-L1 deemed by the site investigator to have benefit from combination with pembrolizumab.

[0233] Any other tumor histology in Part 1 where preliminary efficacy has been observed with MCLA-145 or new data suggest a response may be treated in Part 2, after consent of the Sponsor Medical Monitor. Initial enrollment into the expansion cohorts will be limited to 10 or 20 participants per indication.

[0234] If supported by emerging data, enrollment may be limited to PD-L1 positive tumors, defined as tumor expression ≥1%, as determined on-site by any commercially available assay.

[0235] Selection Criteria A participant is eligible to participate in this study only if all of the following criteria apply to them: Participants with melanoma or NSCLC must meet all criteria listed in the All Participants section below and in the applicable Tumor-Specific Criteria section to confirm eligibility.

[0236] All participants Ability and willingness to sign a written ICF for the study. At least 18 years of age at the time of signing the informed consent. Willingness and ability to meet and comply with all protocol requirements, including all scheduled visits and protocol procedures. Life expectancy of more than 12 weeks. ECOG performance status of 0 or 1. Part 1: Locally advanced or metastatic NSCLC or melanoma recurrent to PD-L1 / PD-1 positive (≥1%) PD-L1 expression on tumor and / or tumor-associated immune cells (based on local testing after completion of the most recent prior line of therapy) Part 2: Locally advanced or metastatic NSCLC or melanoma that is either relapsed to PD-L1 / PD-1 or immunotherapy naïve and has positive PD-L1 expression (≥1%) on tumor and / or tumor-associated immune cells (based on local testing after completion of the most recent prior line of therapy). Measurable disease according to RECIST v1.1 or Lugano criteria. Note: Tumor lesions located in areas that have previously been irradiated or have received other locoregional therapy are considered measurable if clear progression in the lesion has been documented. Previously received standard therapy for progressive or recurrent / metastatic disease appropriate for the tumor type and are intolerant to or have refused standard therapy. Have received up to four prior systemic treatment regimens (including chemotherapy, immunotherapy, and targeted therapy regimens) for progressive or recurrent / metastatic disease unless approved by a medical monitor. Up to 1 prior anti-PD-1 therapy containing an immunotherapy regimen in the advanced / metastatic setting. Anti-PD-1 therapy in combination with chemotherapy, targeted therapy, or other immunotherapy is permitted. Willingness to undergo pre- and intra-treatment tumor biopsies to obtain tumor tissue. NOTE: In participants where tumor tissue cannot be safely obtained, based on discussion with the medical monitor, the participant may still enroll in the study. Part 2 only: Participants with known PD-L1 status or participants undergoing a new tumor biopsy to locally assess PD-L1 expression during screening. Willingness to avoid pregnancy or fatherhood based on the following criteria: Men must agree to take appropriate precautions to avoid fathering (with at least 99% certainty) from screening through 90 days after their last dose of MCLA-145 and must refrain from sperm donation during this period. Permitted methods that are at least 99% effective at preventing pregnancy must be communicated to participants and their understanding confirmed. Women of childbearing potential must have a negative serum pregnancy test at screening and before the first dose on Day 1 and must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through 90 days after the last dose of MCLA-145. Permitted methods that are at least 99% effective to prevent pregnancy should be communicated to participants and their understanding confirmed. Women of childbearing potential should refrain from donating oocytes from 30 days prior to the first dose of MCLA-145 until 90 days after the last dose of MCLA-145. Women of non-childbearing potential (i.e., surgically sterilized by hysterectomy and / or bilateral oophorectomy, or women with 12 months or more of amenorrhea and at least 50 years of age) were eligible for enrollment.

[0237] Combination therapy Patients who have been receiving MCLA145 monotherapy for at least 2 months may participate in the study. These patients must not have reported grade 2 or less liver toxicity during monotherapy with MCLA145.

[0238] Tumor-specific criteria Participants with histologically or cytologically confirmed melanoma: Histologically or cytologically confirmed cutaneous, acral, or mucosal melanoma. NOTE: Participants with ocular or uveal melanoma will be excluded. Unresectable stage III or stage IV melanoma according to the current AJCC staging system that has failed local therapy. Documentation of V600 activating BRAF mutation status or consent to BRAF testing during the screening period, if not previously tested. If BRAF mutation positive, patients must have received BRAF±MEK targeted therapy with documented progression. Combination therapy part 1 participants: relapsed to PD-L1 / PD-1 therapy (e.g., progressed after >6 months of treatment with at least stable disease as best response) Combination Therapy Part 2 Participants: Relapse from PD-L1 / PD-1 therapy to PD-L1 / PD-1 therapy naïve (e.g., progression after >6 months of therapy with at least stable disease as the best response) Monotherapy Only Part 2 Participants: Must have documented progression on anti-PD-1 therapy defined by meeting one of the following criteria: Primary refractory: Participants must have previously been treated with anti-PD-1 therapy (alone or as part of a combination with anti-CTLA-4 therapy) for at least 12 weeks in the progressive or metastatic setting and have PD as their best response to treatment. Participants previously treated with anti-PD-1 therapy for at least 12 weeks in the adjuvant setting and participants who have progressed are also enrolled. Secondary resistance: Previously received anti-PD-1 therapy (alone or as part of a combination) in the progressive or metastatic setting and achieved CR, PR, or SD, but had to have confirmed PD while receiving subsequent anti-PD-1 therapy (PD confirmed after at least 4 weeks [≥ 28 days]).

[0239] Participants with histologically or cytologically confirmed NSCLC: Histologically or cytologically confirmed diagnosis of NSCLC (either non-squamous or squamous). If tumors have exclusively non-squamous histology, documentation of test results for EGFR, ALK, BRAF, and ROS1 mutations or gene rearrangements (molecular testing is not currently part of the diagnostic guidelines for predominantly squamous histology). If mutations or gene rearrangements are present, participants must have progressed on or not tolerated targeted therapy. Unresectable advanced or metastatic NSCLC according to the current AJCC staging system, where local therapy has been ineffective. Combination therapy part 1 participants: relapsed to PD-L1 / PD-1 therapy (e.g., progressed after >6 months of treatment with at least stable disease as best response) Combination Therapy Part 2 Participants: Relapse to PD-L1 / PD-1 therapy (e.g., progression after >6 months of treatment with at least stable disease as the best response) Naïve to PD-L1 / PD-1 therapy Part 2 participants only: Must have documented progression on anti-PD-1 therapy defined by meeting one of the following criteria: Primary refractory: Must have received prior anti-PD-1 therapy (alone or as part of a combination) in the progressive or metastatic setting for at least 12 weeks and have progressive disease (PD) as the best response to treatment. Secondary resistance: Previously received anti-PD-1 therapy (alone or as part of a combination) in the progressive or metastatic setting and achieved CR, PR, or SD, but had to have confirmed PD while receiving subsequent anti-PD-1 therapy (PD confirmed after at least 4 weeks [≥ 28 days]).

[0240] Participants with symptomatic solid tumors with confirmed MSI-H or dMMR status: Must have MSI-H or dMMR solid tumor as determined by local laboratory using IHC or polymerase chain reaction and have tissue available for central diagnostic confirmation. Only Part 2 participants who are deemed primary refractory to anti-PD-1 therapy are considered, defined as follows: have received prior anti-PD-1 therapy (alone or as part of a combination) for at least 12 weeks in the progressive or metastatic setting and have documented PD as their best response to treatment.

[0241] Exclusion criteria Participants will be excluded from the study if any of the following criteria apply: The following B-cell neoplasms: Burkitt lymphoma, lymphoblastic leukemia / lymphoma, lymphoplasmacytic lymphoma, and chronic lymphocytic leukemia. The previous therapy contains a 4-1BB agonist or the previous therapy is with CART cell therapy. Treatment with anticancer or investigational drugs within the following intervals prior to the first dose of MCLA-145: At least 14 days for chemotherapy (6 weeks for mitomycin C and nitrosoureas), targeted small molecule therapy, or radiation therapy. NOTE: Participants must not have radiation pneumonitis as a result of treatment. A 1-week washout period will be allowed for palliative radiation for non-CNS disease, subject to sponsor approval. For previous mAbs used in anticancer therapy, for at least 28 days. NOTE: Participants receiving bisphosphonates and / or denosumab are eligible for enrollment. For other drugs with long half-lives (eg, greater than 5 days), registration prior to the 5th half-life requires approval of the medical monitor. For radioimmunotherapy, at least 10 weeks. Patients must not have undergone allogeneic SCT within the past 6 months or autologous SCT within the past 3 months. Have not recovered to Grade ≤1 or baseline from toxic effects of prior therapy (including prior immunotherapy) and / or complications from prior surgical intervention prior to starting MCLA-145. Note: Alopecia and stable neuropathy (Grade 2 or less) is expected. No prior anti-PD-1 therapy (± anti-CTLA-4 therapy)-related liver toxicity >grade 1. For patients receiving concomitant therapy only: baseline transaminases and bilirubin outside normal limits Grade ≥3 immune-mediated adverse events following prior anti-PD-1 therapy. NOTE: The following grade 3 or higher adverse events are acceptable: grade 3 rash that resolved with topical therapy; immune-mediated adrenal insufficiency, type 1 diabetes, or other endocrine abnormalities resulting from prior immunotherapy who are medically stable and adequately managed with stable doses of replacement therapy; and asymptomatic amylase or lipase elevations not requiring treatment interruption. History of immune-mediated ocular adverse events of any grade. Participants with screening laboratory values ​​as defined in the table below. [Table 6-1] [Table 6-2] Clinically significant cardiac disease, including known history of left ventricular ejection fraction less than 50%, unstable angina within 6 months of Cycle Day 1, acute myocardial infarction, New York Heart Association Class III or IV congestive heart failure, or arrhythmia requiring therapy. NOTE: Participants with arrhythmias may be enrolled if the participant is taking antiarrhythmic medications and is in sinus rhythm on the screening ECG. History or presence of an ECG that, in the opinion of the investigator, is clinically significant. Immune-related toxicity during previous checkpoint inhibitor therapy for which permanent discontinuation of treatment is recommended (per product labeling or consensus guidelines) or any immune-related toxicity requiring intensive or prolonged immunosuppression to manage (excluding endocrine disorders adequately controlled with replacement hormones). History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonia, or idiopathic pneumonia, or evidence of interstitial pneumonia on the screening chest CT scan. Participants with a history of uncontrolled asthma or chronic obstructive pulmonary disease will be excluded. NOTE: A history of radiation pneumonitis (fibrosis) in the radiation field is acceptable. Known active CNS metastases / lymphoma and / or carcinomatous meningitis. NOTE: Participants with previously treated brain metastases may participate provided that they are 1) radiologically stable (i.e., no evidence of progression for at least 28 days by repeat imaging prior to the first dose of MCLA-145 [repeat imaging may be performed during the screening period with medical monitor approval]), 2) not requiring steroid treatment for at least 14 days prior to the first dose of MCLA-145, and 3) clinically stable with any neurological signs or symptoms returning to baseline. This exclusion does not include carcinomatous meningitis, which is excluded regardless of clinical stability. NOTE: Participants with evidence of cerebral edema or who are less than 28 days removed from CNS-directed radiation therapy will be excluded from the study. Participants with an active or inactive autoimmune disease or syndrome that required systemic treatment within the past 2 years (e.g., rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease) or participants receiving systemic therapy for an autoimmune or inflammatory disease (i.e., using disease-modifying agents, corticosteroids, or immunosuppressants). NOTE: Participants with vitiligo, resolved childhood asthma / atopy, hypothyroidism stable on hormone replacement, controlled asthma, type I diabetes, Graves' disease, or Hashimoto's thyroiditis, or with medical monitor approval, are eligible to participate if they meet all other eligibility criteria. Use of systemic corticosteroids (≥10 mg / day prednisone or equivalent) within 7 days prior to the first dose of MCLA-145. NOTE: Use of inhaled, topical or systemic corticosteroids for imaging procedures is permitted. NOTE: The use of physiologic corticosteroid replacement therapy may be approved after consulting with the medical monitor. Administration of a live vaccine within 30 days of the first dose of MCLA-145 or pembrolizumab. NOTE: Examples of live vaccines include, but are not limited to, measles, mumps, rubella, chickenpox, yellow fever, rabies, BCG, and typhoid vaccines. If a live COVID-19 vaccine is available, a medical monitor should be consulted prior to administration. Injectable seasonal influenza vaccines are generally inactivated virus vaccines and are expected, however, intranasal influenza vaccines are live attenuated vaccines and are not expected. Active infection requiring systemic therapy. History of solid organ or allogeneic stem cell transplant. Active HBV or HCV infection requiring treatment. Hepatitis B viral DNA and HCV RNA must be undetectable. Participants who have cleared previous HBV infection (defined as hepatitis B surface antigen negative, hepatitis B surface antibody positive, hepatitis B core antibody positive) are eligible to participate in the study. NOTE: For participants who have previously been cleared of HBV infection, HBV prophylaxis should be considered according to the investigator's discretion. Monitor for HBV reactivation every 3 cycles by performing HBV viral load and Hepatitis B surface antigen serology tests. Additional viral serology tests can be performed at the investigator's discretion. NOTE: Participants who have been vaccinated against HBV and have no previous history of HBV infection with seropositivity for Hepatitis B surface antigen as evidenced only by previous exposure may participate in the study. NOTE: Hepatitis C antibody positive participants who have undergone and completed hepatitis C treatment intended to eradicate the virus may participate if their HCV RNA levels are undetectable. Known history of HIV (HIV1 / 2 antibodies). HIV testing is not required unless mandated by local health authorities or regulations. Known hypersensitivity or severe reaction to any component of MCLA-145 or pembrolizumab, or to any formulation component. Beginning from the screening visit through 90 days after the last dose of MCLA-145, are pregnant or breastfeeding, or expect to become pregnant or father within the planned duration of the study. Any condition that, in the judgment of the investigator, prevents full participation in the study, including administration of MCLA-145 or pembrolizumab, poses significant risk to the participant, or interferes with the interpretation of the study data.

[0242] Example 3 An 80-year-old male patient was diagnosed with Merkel cell carcinoma with a PD-L1 score of 1-10%. The patient was pretreated with radiation therapy, surgery, and systemic therapy. Treatment with avelumab resulted in progressive disease. Carboplatin and etoposide treatment resulted in a partial response.

[0243] The patient was then administered a multispecific antibody having two VHs designated by MF numbers MF6797 and MF7702, an Fc region with KK / DE CH3 heterodimerization domains as shown by SEQ ID NO: 115 and SEQ ID NO: 116, respectively, a CH2 domain as shown by SEQ ID NO: 114, a CH1 domain as shown by SEQ ID NO: 112, and a common light chain as shown by SEQ ID NO: 109 at a dose of 25 mg every 3 weeks (25 mg, q3w) and pembrolizumab at a dose of 200 mg every 3 weeks (200 mg, q3w). The disease site was a skin nodule on the foot. Tumor assessment included the sum of the target lesion diameters. After the first dose, the patient experienced a clinically significant reduction in lesion diameter.

[0244] Example 4 A dose of 40 mg is administered every 3 weeks (40 mg, q3w) or every 2 weeks (40 mg, q2w) to a subject with cancer, using a bispecific antibody having two VHs designated by MF numbers MF6797 and MF7702, an Fc region having KK / DE CH3 heterodimerization domains as shown by SEQ ID NO: 115 and SEQ ID NO: 116, a CH2 domain as shown by SEQ ID NO: 114, a CH1 domain as shown by SEQ ID NO: 112, and a common light chain as shown by SEQ ID NO: 109, along with administration of 200 mg (200 mg, q3w) of pembrolizumab every 3 weeks according to Example 2, followed by tumor assessment, including the sum of target lesion diameters. After the first administration, the patient is allowed to develop a clinically significant reduction in lesion diameter.

[0245] array SEQ ID NO:1: Heavy chain variable region QVQLVQSGSELKKPGASVKVSCKASGYTFTNFAMNWVRRAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSLDTSVNTAYLQISSLKAEDTAVYYCARDWGVIGGHYMDVWGKGTTVTVSS SEQ ID NO:2: HCDR1 according to Kabat from SEQ ID NO:1 NFAMN SEQ ID NO:3: HCDR2 according to Kabat from SEQ ID NO:1 WINTNTGNPTYAQGFTG SEQ ID NO: 4: HCDR3 according to Kabat from SEQ ID NO: 1 DWGVIGGHYMDV SEQ ID NO:5 Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDSDGYGPKAFDYWGQGTLVTVSS SEQ ID NO: 6: HCDR1 according to Kabat SYGIS SEQ ID NO: 7: HCDR2 according to Kabat WISAYNGNTNYAQKLQG SEQ ID NO: 8: HCDR3 according to Kabat DSDGYGPKAFDY SEQ ID NO:9 Heavy chain variable region EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPDDSDTRYSPSFQGQVTISADKSSSTAYLQWSSLKASDTAMYYCASFYTGIVGATGAFDVWGQGTTVTVSS SEQ ID NO: 10: HCDR1 according to Kabat SYWIG SEQ ID NO: 11: HCDR2 according to Kabat IIYPDDSDTRYSPSFQG SEQ ID NO: 12: HCDR3 according to Kabat FYTGIVGATGAFDV SEQ ID NO:13 Heavy chain variable region QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSDAISWVRQAPGQGLEWMGGMIPILGTANYAQKFQGRVTITADRSSTSTAYMELSSLRSEDTAVYYCVRGATYYYGSGTYYSINWFDPWGQGTLVTVSS SEQ ID NO: 14: HCDR1 according to Kabat SDAIS SEQ ID NO: 15: HCDR2 according to Kabat GMIPILGTANYAQKFQG SEQ ID NO: 16: HCDR3 according to Kabat GATYYYGSGTYYSINWFDP SEQ ID NO:17 Heavy chain variable region QVQLVQSGSELKKPGASVKVSCRASGYTFTNFAMTWVRQAPGQGPEYMGWINTNTGNPTYAQGFTGRFVFSLDTSVNTAYLQISSLKAEDTAVYYCARDWASVMVRGDLDYWGQGTLVTVSS SEQ ID NO: 18: HCDR1 according to Kabat NFAMT SEQ ID NO: 19: HCDR3 according to Kabat DWASVMVRGDLDY SEQ ID NO:20 Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKVSGYTLSELSIHWVRQAPGKGVEWMGGFYPEDVEPIYARKFQGRVTMTEDTSTDTAYMELNSLRSEDTAVYYCAAEGFDNYGSGIRGNWFDPWGQGTLVTVSS SEQ ID NO: 21: HCDR1 according to Kabat ELSIH SEQ ID NO: 22: HCDR2 according to Kabat GFYPEDVEPIYARKFQG SEQ ID NO: 23: HCDR3 according to Kabat EGFDNYGSGIRGNNWFDP SEQ ID NO:24 Heavy chain variable region EVQLVQSGAEVKKPGASVKVSCKVSGYTLTELSMHWVRQSPGKGLEWMGSFYPEDGETIYAQKFQGRITMTEDTSADTAYMELSSLRSEDTAVYYCATEGVGVIRGNWFDPWGQGTLVTVSS SEQ ID NO: 25: HCDR1 according to Kabat ELSMH SEQ ID NO: 26: HCDR2 according to Kabat SFYPEDGETIYAQKFQG SEQ ID NO: 27: HCDR3 according to Kabat EGVGVIRGNWFDP SEQ ID NO:28 Heavy chain variable region EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIFPDDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKPSDTAMYYCVRLGGYSGYAEDFVDFWGQGTLVTVSS SEQ ID NO: 29: HCDR2 according to Kabat IIFPDDSDTRYSPSFQG SEQ ID NO: 30: HCDR3 according to Kabat LGGYSGYAEDFVDF SEQ ID NO:31 Heavy chain variable region EVQLVQSGAEVKKPGASVKVSCKVSGYTLTKLSMHWVRQAPGKGLEWMGGFEPEDGETINAQKFQGRVTMTEDTSTDTAYMELSSLRSEDTAVYYCATDLRLGASYYYSYMDVWGRGTMVTVSS SEQ ID NO: 32: HCDR1 according to Kabat KLSMH SEQ ID NO: 33: HCDR2 according to Kabat GFEPEDGETINAQKFQG SEQ ID NO: 34: HCDR3 according to Kabat DLRLGASYYYSYMDV SEQ ID NO:35 Heavy chain variable region QITLKESGPTLVKPTQTLTLSCTFSGFSLSTSGMSVGWIRQPPGKALEWLALIYWNDDKYFSPSLKSRLTITKDTSKNQVVLTLTNMDPVDTATYYCAHTLWGSDDVFDVWGQGTMVTVSS SEQ ID NO: 36: HCDR1 according to Kabat TSGMSVG SEQ ID NO: 37: HCDR2 according to Kabat LIYWNDDKYFSPSLKS SEQ ID NO: 38: HCDR3 according to Kabat TLWGSDDVFDV SEQ ID NO:39 Heavy chain variable region EVQLVQSGAEVKKPGESLKISCKVSGYSFTNYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWHTLKASDTAMYYCARHQGYSFSGSHIDDYWGQGTLVTVSS SEQ ID NO: 40: HCDR1 according to Kabat NYWIG SEQ ID NO: 41: HCDR2 according to Kabat IIYPGDSDTRYSPSFQG SEQ ID NO: 42: HCDR3 according to Kabat HQGYSFSGSHIDDY SEQ ID NO:43 Heavy chain variable region EVQLVQSGAEVRKPGESLKISCKGSGYSFTTYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISADKSISTVYLQWSSLKASDTAMYYCARHAGFIITSQNIDDYWGQGTLVTVSS SEQ ID NO: 44: HCDR1 according to Kabat TYWIG SEQ ID NO: 41: HCDR2 according to Kabat IIYPGDSDTRYSPSFQG SEQ ID NO: 45: HCDR3 according to Kabat HAGFIITSQNIDDY SEQ ID NO:46 Heavy chain variable region EVQLVQSGSELKKPGASVKVSCKASGYTFTNFAMNWVRQAPGQGLEWMGWINTNTGNPTYAQDFTGRFVFSLDTSGNTAYLQISSLKAEDTAVYYCARDWGLVAIGYFDYWGQGTLVTVSS SEQ ID NO: 47: HCDR2 according to Kabat WINTNTGNPTYAQDFTG SEQ ID NO: 48: HCDR3 according to Kabat DWGLVAIGYFDY SEQ ID NO:49 Heavy chain variable region QITLKESGPTLVKPTQTLTLTCTFSGFSLSTTGVGVNWIRQPPGEALEWLALIYWNDDTYYSPSLKSRLTITKDTSKNQVVLTMTNMPDPVDTATYYCAHEGIIGFLGGNWFDPWGQGTLVTVSS SEQ ID NO: 50: HCDR1 according to Kabat TTGVGVN SEQ ID NO: 51: HCDR2 according to Kabat LIYWNDDTYYSPSLKS SEQ ID NO: 52: HCDR3 according to Kabat EGIIGFLGGNWFDP SEQ ID NO:53 Heavy chain variable region QVQLVQSGSELKKPGASVKVSCKASGYTFTSHAMNWVRQAPGQGLEWMGWINPNTGNPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARDRKYVTNWVFAEDFQHWGQGTLVTVSS SEQ ID NO: 54: HCDR1 according to Kabat SHAMN SEQ ID NO: 55: HCDR2 according to Kabat WINPNTGNPTYAQGFTG SEQ ID NO: 56: HCDR3 according to Kabat DRKYVTNWVFAEDFQH SEQ ID NO:57 Heavy chain variable region QVQLVQSGSELKKPGASVKVSCKASGYTFTSHAMNWVRQAPGQGLEWMGWINPNTGNPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCAIDRGYMSNWVFAEYFPHWGQGTLVTVSS SEQ ID NO: 58: HCDR3 according to Kabat DRGYMSNWVFAEYFPH SEQ ID NO:59 Heavy Chain Variable Region QVQLVQSGSELKKPGASVKVSCKASGYTFTSYAMNWVRQAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCATDRGYISSWVFAEDFQHWGQGTLVTVSS SEQ ID NO: 60: HCDR1 according to Kabat SYAMN SEQ ID NO: 61: HCDR3 according to Kabat DRGYISSWVFAEDFQH SEQ ID NO:62 Heavy chain variable region QVQLVQSGSELKKPGASVKVSCTASGYTFTSYAMNWVRQAPGQRLEWMACVNPNTGSPTYAQGSTGRFVVSLDTSVSTAYLQISSLKAEDTAVYYCARDRKYVTNWVFAEDFQHWGHGTLVTVSS SEQ ID NO: 63: HCDR2 according to Kabat CVNPNTGSPTYAQGSTG SEQ ID NO: 64 Heavy chain variable region QVQLVQSGSELKKPGASVKVSCKASGYTFTNYAMNWVRQAPGQGLEWMGWMNPNTGNPTYAQGSTGRFVVSLDTSVSTAYLQISSLKAEDTAVYYCARDRKYVTNWVFAEDFQHWGRGTLVTVSS SEQ ID NO: 65: HCDR1 according to Kabat NYAMN SEQ ID NO: 66: HCDR2 according to Kabat WMNPNTGNPTYAQGSTG SEQ ID NO:67 Heavy chain variable region QVQLVQSGSELKKPGASVKVSCKASGYTFTNYAINWVRQAPGQGLEWMGWINPNTGNPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARDRKYVTNWVFAEDFQHWGRGTLVTVSS SEQ ID NO: 68: HCDR1 according to Kabat NYAIN SEQ ID NO:69 Heavy Chain Variable Region EVQLVQSGAEVKKPGSSVKVSCKASGDTFNTYSITWVRQAPGQGLEWMGSIVPIFGTINNAQKFQGRVTITADKSANTAYMELSSLRSEDTAVYYCARDNTMVRGVDYYYMDVWGKGTMVTVSS SEQ ID NO: 70: HCDR1 according to Kabat TYSIT SEQ ID NO: 71: HCDR2 according to Kabat SIVPIFGTINNAQKFQG SEQ ID NO: 72: HCDR3 according to Kabat DNTMVRGVDYYYMDV SEQ ID NO:73 Heavy chain variable region EVQLVQSGAEVKKPGSSVKVSCKASGGIFSTYAISWVRQAPGQGLEWMGGIIPIFDTPNYAQKFQGRVTITADKSTSTAYMDLSSLRSEDTAVYYCAKNVRGYSAYDLDYWGQGTLVTVSS SEQ ID NO: 74: HCDR1 according to Kabat TYAIS SEQ ID NO: 75: HCDR2 according to Kabat GIIPIFDTPNYAQKFQG SEQ ID NO: 76: HCDR3 according to Kabat NVRGYSAYDLDY SEQ ID NO:77 Heavy chain variable region EVQLVQSGAEVKNPGSSVKVSCKATGGTFNTYGTNWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTTTAYMEVSSLRSEDTAVYYCARGGADMGTLDYWGQGTLVTVSS SEQ ID NO: 78: HCDR1 according to Kabat TYGTN SEQ ID NO: 79: HCDR2 according to Kabat GIIPIFGTANYAQKFQG SEQ ID NO: 80: HCDR3 according to Kabat GGADMGTLDY SEQ ID NO:81 Heavy chain variable region EVQLVQSGAEVMRPGSSVKVSCKASGGIFTYTIIWVRQAPGQGLEWMGGIIPIFDTPNFAQKFQGRLTITADKSTNTAYMELTSLRSEDTAVYYCAREGCNHGVCYPYWGQGTLVTVSS SEQ ID NO: 82: HCDR1 according to Kabat TYTII SEQ ID NO: 83: HCDR2 according to Kabat GIIPIFDTPNFAQKFQG SEQ ID NO: 84: HCDR3 according to Kabat EGCNHGVCYPY SEQ ID NO:85 Heavy Chain Variable Region QVQLVQSGAEVKKPGSSVKVSCKASGDTFRSYGITWVRQAPGQGLEWMGGIIPIFGTTNYAQKFQGRVTITADKSTSTVYMELSSLRSEDTAVYYCARRRGYSNPHWLDPWGQGTLVTVSS SEQ ID NO: 86: HCDR1 according to Kabat SYGIT SEQ ID NO: 87: HCDR2 according to Kabat GIIPIFGTTNYAQKFQG SEQ ID NO: 88: HCDR3 according to Kabat RRGYSNPHWLDP SEQ ID NO:89 Heavy Chain Variable Region QVQLVQSGAEVKKPGSSVKVSCKASGGTFSTYGILWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADISTSTAYMELSSLRSEDTAVYYCARGGGNYYEFVYWGQGTLVTVSS SEQ ID NO: 90 according to Kabat HCDR1 TYGIL SEQ ID NO: 91: HCDR3 according to Kabat GGGNYYEFVY SEQ ID NO:92 Heavy chain variable region EVQLVQSGAEVKKPGSSVRVSCKASGGTFNTYAINWVRQAPGQGLEWVGRIIPIFDTANYAQKFQGRVTISADKSTTTAYMELSSLRSEDTAVFYCAKDETGYSSSNFQHWGQGTLVTVSS SEQ ID NO: 93 according to Kabat HCDR1 TYAIN SEQ ID NO: 94 HCDR2 according to Kabat RIIPIFDTANYAQKFQG SEQ ID NO: 95 HCDR3 according to Kabat DETGYSSSNFQH SEQ ID NO:96 Heavy Chain Variable Region QVQLVQSGSELKKPGASVKVSCKASGYTFTNYAINWVRQAPGQGLEWMGWINPNTGNPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARDRKYVTNWVFAEDFQHWGQGTLVTVSS SEQ ID NO:97 Heavy Chain Variable Region QVQLVQSGAEVKRPGSSVKVSCKASGGTFNTYSITWVRQAPGQGLEWMGIIPVFGTSKYAQKFQDRVTITADKSTNTAYMELSSLRSEDTAVYYCARDPSFSSSSGWFDPWGQGTLVTVSS SEQ ID NO: 98 HCDR2 according to Kabat GIIPVFGTSKYAQKFQD SEQ ID NO: 99: HCDR3 according to Kabat DPSFSSSSGWFDP SEQ ID NO:100 Heavy chain variable region QVQLVQSGAEVKKPGSSVKVSCKASGGTFNTYAINWVRQAPGQGLEWMGGIIPIFDTANYAQRFQGRVTITADKSTSTAYMELSSLRSEDTAVYFCAKDQTGYSSTLFDYWGQGTLVTVSS SEQ ID NO: 101 HCDR2 according to Kabat GIIPIFDTANYAQRFQG SEQ ID NO: 102 HCDR3 according to Kabat DQTGYSSTLFDY SEQ ID NO:103 Heavy chain variable region QVQLVQSGSELKKPGASVKVSCKASGYTFTSHAMNWVRQAPGQGLEWMGWINPNTGNPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCAIDRGYMSNWVFAEYFPHWGQGTLVTVSS SEQ ID NO: 104 Heavy chain variable region EVQLVQSGAEVKKPGSSVKVSCKASGGTFSTYAISWVRQAPGQGLEWMGWIIPIFDTGNYAQKIQGRVTITADKSTSTAYMELTSLRSEDTAVYYCARHDYTNTVDAFDIWGQGTMVTVSS SEQ ID NO: 105 HCDR2 according to Kabat WIIPIFDTGNYAQKIQG SEQ ID NO: 106 HCDR3 according to Kabat HDYTNTVDAFDI SEQ ID NO: 107 Heavy chain variable region QVQLVQSGAEVKKPGSSVKVSCKASGDTFRSYGITWVRQAPGQGLEWMGGIIPVFGTTNYAQKFQGRVTITADKSTSTVFMELNSLRSEDTAVYYCARRRGYSNPHWLDPWGQGTLVTVSS SEQ ID NO: 108 HCDR2 according to Kabat GIIPVFGTTNYAQKFQG SEQ ID NO: 109 Amino acid sequence of human common light chain IGKV1-39 / jk1 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 110 Amino acid sequence of the common light chain variable domain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK SEQ ID NO:111 Amino acid sequence of the common light chain constant domain RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 112 Amino acid sequence of CH1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRV SEQ ID NO: 113 Amino acid sequence of hinge EPKSCDKTHTCPPCP SEQ ID NO:114 Amino acid sequence of CH2 APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK SEQ ID NO: 115 Amino acid sequence of CH3 with KK mutation GQPREPQVYTKPPSREEMTKNQVSLKCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 116 Amino acid sequence of CH3 with DE mutation GQPREPQVYTDPPSREEMTKNQVSLTCEVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 117: Amino acid sequence of CD137 according to HGNC:11924 MGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPPNSFS SAGGQRTCDICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCK QGQELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCG PSPADLSPGASSVTPPAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRFSVVKR GRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL SEQ ID NO: 118 Amino acid sequence of pembrolizumab heavy chain QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 119 Amino acid sequence of pembrolizumab light chain EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGGTKVE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Claims

1. 1. A multispecific antibody comprising an antigen-binding site that binds to an extracellular portion of CD137 and an antigen-binding site that binds to an extracellular portion of a second membrane protein, for use in a method of treating cancer in a subject in need thereof, wherein said treatment further comprises administering a PD-L1 or PD-1 inhibitor.

2. 1. A method of treating cancer in a subject in need of such treatment, comprising administering to said subject in need of such treatment a multispecific antibody comprising an antigen binding site that binds to an extracellular portion of CD137 and an antigen binding site that binds to an extracellular portion of a second membrane protein, and a PD-1 or PD-L1 inhibitor.

3. 3. The multispecific antibody for use according to claim 1 or the method according to claim 2, wherein said multispecific antibody is administered simultaneously, sequentially or separately with said PD-1 or PD-L1 inhibitor.

4. 13. The multispecific antibody or method for use according to any one of the preceding claims, wherein said cancer is an advanced or metastatic solid tumour such as selected from locally advanced or metastatic lung cancer, and locally advanced or metastatic melanoma.

5. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said cancer is NSCLC.

6. 5. The multispecific antibody or method for use according to claim 4, wherein the melanoma is selected from cutaneous melanoma, acral melanoma, or mucosal melanoma.

7. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said cancer is Merkel Cell Carcinoma (MCC).

8. 13. The multispecific antibody for use or method according to any one of the preceding claims, wherein the cancer has relapsed to PD-1 / PD-L1 therapy and / or is positive for PD-L1 expression.

9. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said PD-1 or PD-LI inhibitor is an antibody, or a variant or functional fragment thereof.

10. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said PD-1 or PD-LI inhibitor is a PD-1 inhibitor.

11. The multispecific antibody or method for use according to claim 10, wherein said PD-1 inhibitor is pembrolizumab.

12. 13. The multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody is administered in a dose of 10 mg to 1200 mg, 15 to 1200 mg, or 25 to 1200 mg.

13. 13. The multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody is administered in a dose of about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, or 75 mg.

14. 13. The multispecific antibody or method for use according to any one of the preceding claims, wherein said PD-1 inhibitor is pembrolizumab and is administered at a dose of about 300 to 500 mg.

15. 13. The multispecific antibody or method for use according to any one of the preceding claims, wherein said PD-1 inhibitor is pembrolizumab and is administered at a dose of about 100 to 300 mg.

16. 13. The multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody is administered every 14 days.

17. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody is administered every 21 days.

18. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said PD-1 or PD-L1 inhibitor is administered every 2, 3, 4, 5, 6, 7, or 8 weeks.

19. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody is administered intravenously.

20. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody is administered once every two weeks.

21. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody is administered once every three weeks.

22. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said second membrane protein is not a member of the TNF receptor superfamily.

23. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said second membrane protein is a member of the B7 family.

24. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said second membrane protein is PD-L1 or PD-L2, such as PD-L1.

25. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody comprises one antigen-binding site that binds to the PD-1 binding domain of PD-L1.

26. 2. A multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody comprises one antigen binding site that binds to the CD137L binding domain of CD137.

27. 10. A multispecific antibody or method for use according to any one of the preceding claims, wherein the multispecific antibody comprises one antigen binding site that blocks the binding of a ligand to CD137 or binds to an extracellular ligand-blocking binding site of CD137, such as a CD137L-blocking binding site.

28. 10. The multispecific antibody or method for use according to any one of the preceding claims, wherein a variable domain which binds to the extracellular portion of CD137 is defined as a variable domain which, when in a bivalent, monospecific antibody format comprising two of said variable domains which bind to CD137, does not stimulate the activity of CD137 on cells or stimulates it at a reduced level compared to one of said variable domains as part of a bispecific antibody having a second variable domain which binds to a tumor associated antigen, such as PD-L1, such as a member of the B7 family.

29. 13. The multispecific antibody or method for use according to any one of the preceding claims, wherein said variable domain that binds to the extracellular portion of CD137, when combined in a multispecific antibody with a second variable domain that binds to PD-L1, is capable of stimulating the activity of CD137 on the cell when said multispecific antibody is in the presence of a first cell expressing CD137 and a second cell expressing PD-L1.

30. 13. The multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody is capable of binding to CD137 and PD-L1, such as simultaneously.

31. 13. The multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody induces or activates CD137 signalling only in the presence of PD-L1 expressing cells.

32. 10. A multispecific antibody or method for use according to any one of the preceding claims, wherein the antigen binding site of said multispecific antibody consists of one immunoglobulin variable domain that binds to CD137 and one immunoglobulin variable domain that binds to the extracellular part of a second membrane protein.

33. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody is a full-length antibody.

34. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody is an IgG1 molecule without Fc effector functions.

35. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein said second membrane protein is not expressed to a significant extent by T cells.

36. 13. The multispecific antibody or method for use according to any one of the preceding claims, wherein the second membrane protein is present on the cell membrane as part of a multimeric membrane protein comprising two or more of the second membrane proteins.

37. 2. The multispecific antibody or method for use according to any one of the preceding claims, wherein the second membrane protein is present on the cell membrane as part of a homodimer or homotrimer.

38. 2. A multispecific antibody or method for use according to any one of the preceding claims, wherein said antibody comprises a heavy chain variable region comprising a CDR3 region having the amino acid sequence as set forth in SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 34, or SEQ ID NO: 52, or a variant thereof, which binds to the extracellular portion of CD137.

39. 2. A multispecific antibody or method for use according to any one of the preceding claims, wherein said antibody comprises a heavy chain variable region comprising a CDR2 region having the amino acid sequence as set forth in SEQ ID NO: 22, SEQ ID NO: 26, SEQ ID NO: 33, or SEQ ID NO: 51, or a variant thereof, which binds to the extracellular portion of CD137.

40. 10. A multispecific antibody or method for use according to any one of the preceding claims, wherein said antibody comprises a heavy chain variable region comprising a CDR1 region having the amino acid sequence as set forth in SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 32, or SEQ ID NO: 50, or a variant thereof, which binds to the extracellular portion of CD137.

41. 10. A multispecific antibody or method for use according to any one of the preceding claims, wherein said antibody comprises a heavy chain variable region having the amino acid sequence as set forth in SEQ ID NO:1, SEQ ID NO:5, SEQ ID NO:9, SEQ ID NO:13, SEQ ID NO:17, SEQ ID NO:20, SEQ ID NO:24, SEQ ID NO:28, SEQ ID NO:31, SEQ ID NO:35, SEQ ID NO:39, SEQ ID NO:43, SEQ ID NO:46, or SEQ ID NO:49, or a variant thereof, that binds to the extracellular portion of CD137, such as SEQ ID NO:20, SEQ ID NO:24, SEQ ID NO:31, or SEQ ID NO:

49.

42. 10. The multispecific antibody or method for use according to any one of the preceding claims, wherein said antibody comprises a heavy chain variable region comprising a CDR3 region having the amino acid sequence as set forth in SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:61, SEQ ID NO:84, SEQ ID NO:88, SEQ ID NO:91, SEQ ID NO:95, SEQ ID NO:102 or SEQ ID NO:106, or a variant thereof, such as SEQ ID NO:56, SEQ ID NO:91, SEQ ID NO:95 or SEQ ID NO:102 that binds to the extracellular portion of PD-L1.

43. 10. The multispecific antibody or method for use according to any one of the preceding claims, wherein said antibody comprises a heavy chain variable region comprising a CDR2 region having the amino acid sequence as set forth in SEQ ID NO:3, SEQ ID NO:55, SEQ ID NO:63, SEQ ID NO:66, SEQ ID NO:79, SEQ ID NO:83, SEQ ID NO:87, SEQ ID NO:94, SEQ ID NO:101, or SEQ ID NO:105, or a variant thereof, which binds to the extracellular portion of PD-L1.

44. 10. The multispecific antibody according to any one of the preceding claims, wherein said antibody comprises a heavy chain variable region comprising a CDR1 region having the amino acid sequence as set forth in SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:65, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:82, SEQ ID NO:86, SEQ ID NO:90, or SEQ ID NO:93, or a variant thereof, which binds to the extracellular portion of PD-L1.

45. 10. A multispecific antibody or method for use according to any one of the preceding claims, wherein the antibody comprises a heavy chain variable region having the amino acid sequence as set forth in SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:73, SEQ ID NO:77, SEQ ID NO:81, SEQ ID NO:85, SEQ ID NO:89, SEQ ID NO:92, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:100, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:107, or a variant thereof, such as SEQ ID NO:67, SEQ ID NO:89, SEQ ID NO:92, or SEQ ID NO:100 that binds to the extracellular portion of PD-L1.

46. 10. The multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody comprises CDR1, 2 and 3 of MF6797 and CDR1, 2 and 3 of MF7702, or variants thereof.

47. 13. The multispecific antibody or method for use according to any one of the preceding claims, wherein said multispecific antibody comprises SEQ ID NO: 49 and SEQ ID NO: 67, or variants thereof.

48. 1. A multispecific antibody for use in a method for treating cancer in a subject in need thereof, the antibody comprising: A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:50, a CDR2 having the amino acid sequence set forth in SEQ ID NO:51, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:52; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 40, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 41, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 42; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:21, a CDR2 having the amino acid sequence set forth in SEQ ID NO:22, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:23; or and / or a binding domain that binds to CD137, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 32, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 33, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:

34. The antibody, A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:68, a CDR2 having the amino acid sequence set forth in SEQ ID NO:55, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:56; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:93, a CDR2 having the amino acid sequence set forth in SEQ ID NO:94, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:95; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:93, a CDR2 having the amino acid sequence set forth in SEQ ID NO:101, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:102; or a binding domain that binds to PD-L1, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 90, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 79, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 91; Each individual SEQ ID NO: has 0, 1, 2, 3, 4, or 5 amino acid insertions, deletions, or substitutions, or a combination thereof; The multispecific antibody, wherein the multispecific antibody is administered simultaneously, sequentially, or separately with a PD-1 or PD-L1 inhibitor.

49. 1. A method of treating cancer in a subject in need thereof, comprising: A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:50, a CDR2 having the amino acid sequence set forth in SEQ ID NO:51, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:52; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 40, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 41, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 42; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:21, a CDR2 having the amino acid sequence set forth in SEQ ID NO:22, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:23; or and / or a binding domain that binds to CD137, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 32, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 33, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:

34. The antibody, A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:68, a CDR2 having the amino acid sequence set forth in SEQ ID NO:55, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:56; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:93, a CDR2 having the amino acid sequence set forth in SEQ ID NO:94, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:95; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:93, a CDR2 having the amino acid sequence set forth in SEQ ID NO:101, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:102; or a binding domain that binds to PD-L1, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 90, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 79, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 91; a multispecific antibody, wherein each of the individual SEQ ID NOs has 0, 1, 2, 3, 4, or 5 amino acid insertions, deletions, or substitutions, or a combination thereof; A method comprising administering to a subject in need of treatment for cancer a PD-1 or PD-L1 inhibitor.

50. 1. A multispecific antibody for use in a method for treating cancer in a subject in need thereof, the antibody comprising: A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:50, a CDR2 having the amino acid sequence set forth in SEQ ID NO:51, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:52; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 40, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 41, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 42; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:21, a CDR2 having the amino acid sequence set forth in SEQ ID NO:22, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:23; or and / or a binding domain that binds to CD137, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 32, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 33, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:

34. The antibody, A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:68, a CDR2 having the amino acid sequence set forth in SEQ ID NO:55, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:56; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:93, a CDR2 having the amino acid sequence set forth in SEQ ID NO:94, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:95; or A variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:93, a CDR2 having the amino acid sequence set forth in SEQ ID NO:101, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:102; or a binding domain that binds to PD-L1, comprising a variable domain comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO: 90, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 79, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 91; Each individual SEQ ID NO: has 0, 1, 2, 3, 4, or 5 amino acid insertions, deletions, or substitutions, or a combination thereof; the multispecific antibody is administered simultaneously, sequentially, or separately with a PD-1 or PD-L1 inhibitor; The multispecific antibody, wherein the cancer is selected from advanced or metastatic solid tumors.

51. 51. The multispecific antibody or method for use according to any one of claims 48 to 50, wherein said multispecific antibody comprises CDR1, 2 and 3 of MF6797 and CDR1, 2 and 3 of MF7702, or variants thereof.

52. 50. The multispecific antibody or method for use according to claim 49, wherein said multispecific antibody comprises SEQ ID NO: 51 and SEQ ID NO: 67, or variants thereof.

53. 51. The multispecific antibody or method for use according to any one of claims 48 to 50, wherein said multispecific antibody comprises CDR1, 2 and 3 of MF6783 and CDR1, 2 and 3 of MF5542, or variants thereof.

54. 54. The multispecific antibody or method for use according to claim 53, wherein said multispecific antibody comprises SEQ ID NO: 1 and SEQ ID NO: 92, or a variant thereof.

55. 51. The multispecific antibody or method for use according to any one of claims 48 to 50, wherein said multispecific antibody comprises CDR1, 2 and 3 of MF6754 and CDR1, 2 and 3 of MF5561, or variants thereof.

56. 56. The multispecific antibody or method for use according to claim 55, wherein said multispecific antibody comprises SEQ ID NO: 20 and SEQ ID NO: 100, or variants thereof.

57. 51. The multispecific antibody or method for use according to any one of claims 48 to 50, wherein said multispecific antibody comprises CDR1, 2 and 3 of MF6785 and CDR1, 2 and 3 of MF5439, or variants thereof.

58. 58. The multispecific antibody or method for use according to claim 57, wherein said multispecific antibody comprises SEQ ID NO: 31 and SEQ ID NO: 89, or variants thereof.

59. 51. The multispecific antibody or method for use according to any one of claims 48 to 50, wherein said multispecific antibody comprises CDR1, 2 and 3 of MF6795 and CDR1, 2 and 3 of MF5442, or variants thereof.

60. 60. The multispecific antibody or method for use according to claim 59, wherein said multispecific antibody comprises SEQ ID NO: 9 and SEQ ID NO: 92, or variants thereof.

61. 10. The multispecific antibody or method for use according to any one of the preceding claims, wherein said antibody comprises a common light chain variable domain having the amino acid sequence given in SEQ ID NO: 110, or a common light chain having the amino acid sequence given in SEQ ID NO: 109, or a variant thereof.

62. 10. A multispecific antibody or method for use according to any one of the preceding claims, wherein the antibody comprises a heavy chain constant domain 1 (CH1) having the amino acid sequence given in SEQ ID NO: 112, a heavy chain constant domain 2 (CH2) having the amino acid sequence given in SEQ ID NO: 114, a heavy chain constant domain 3 (CH3) having the amino acid sequence given in SEQ ID NO: 115, and a heavy chain constant domain 3 (CH3) having the amino acid sequence given in SEQ ID NO: 116, or a variant thereof.

63. 1. A pharmaceutical combination comprising a multispecific antibody comprising an antigen-binding site that binds to an extracellular portion of CD137 and an antigen-binding site that binds to an extracellular portion of a second membrane protein, and instructions for use of said multispecific antibody in combination with a PD-1 or PD-L1 inhibitor.

64. 62. The pharmaceutical combination of claim 61, further comprising instructions for use.

65. 63. The pharmaceutical combination of claim 62, wherein said instructions for use include instructions for intravenous administration and / or dosage.

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