Novel combinations of antibodies and uses thereof

Abstract

The present disclosure relates generally to antibody combinations and uses thereof.

Description

[Technical field]

[0001] The present invention generally relates to a combination comprising a first antibody molecule that specifically binds to FcyRllb via its Fab region and lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, a second antibody molecule that specifically binds to PD-1 or PD-L1, and a third antibody molecule that specifically binds to CTLA-4 and binds to at least one Fcγ receptor via its Fc region. The present invention also relates to a combination comprising a first antibody molecule that specifically binds to FcyRllb via its Fab region and lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, and a second antibody molecule that specifically binds to CTLA-4 and binds to at least one Fcγ receptor via its Fc region, where the second antibody molecule can be used at a lower dose than the tolerated therapeutic dose. [Background technology]

[0002] Immunotherapy with therapeutic antibodies has increased survival rates in patients with hematological and solid cancers. Clinically successful antibodies exert their antitumor activity by directly targeting tumor cells [1–4] or by targeting and activating immune cells that seek out and kill cancer cells in the tumor microenvironment (so-called "immune checkpoint antibodies") [5–13]. Both types of antibodies have the potential to cure cancer and are highly potent, but a significant proportion of patients do not respond or acquire resistance during therapy [14–17].

[0003] It has long been known that FcγRs have an important role in controlling the therapeutic activity of tumor-targeting antibodies. However, the role of FcγRs in controlling the efficacy and resistance of immunomodulatory antibodies (e.g., those targeting the immunosuppressive checkpoints CTLA-4 and PD-1 / PD-L1) is less predictable. Antibodies targeting CTLA-4, PD-1, and PD-L1 have been developed based on their ability to block inhibitory signaling in effector T cells, i.e., to "release the brakes" on the immune system, and as such have typically eradicated cancer cells that do not express CTLA-4, PD-1 / PD-L1, or FcγR.

[0004] Thus, surprisingly, we recently reported a role for FcγRs underlying the therapeutic activity of ipilimumab, a CTLA-4-specific antibody

[18] . Melanoma patients expressing a high-affinity single nucleotide polymorphism (SNP) that activates FcγRIIIA showed improved survival in response to ipilimumab therapy, even though their melanoma tumors were negative for CTLA-4. Conversely, independent studies of antibodies directed against PD-1 have shown a detrimental role for FcγRs in antitumor activity, with the proposed underlying mechanisms and roles of activating and inhibiting FcγRs being contradictory [19, 20]. Thus, the effect of FcγR blockade on the therapeutic efficacy of anti-CTLA-4 and anti-PD-1 / PD-L1 antibodies is unpredictable.

[0005] Given that background, the inventors have used FcγR-specific antibodies to evaluate the effect of FcγR blockade on the therapeutic activity of anti-CTLA-4 and PD-1 antibodies in vivo. Surprisingly, it has been found that FcγR blockade using engineered antibodies to silence Fc:FcγR-engagement enhances therapeutic activity when anti-CTLA-4 and anti-PD1 / PD-L1 antibodies are used in combination. This has implications for the treatment of patients who are resistant to anti-CTLA-4 and anti-PD1 / PD-L1 antibody treatment. Furthermore, the inventors have also found that FcγR blockade using engineered antibodies to silence Fc:FcγR binding unexpectedly allows for the use of lower therapeutic doses of anti-CTLA-4 antibodies, thereby reducing the potential for undesirable side effects and toxicity. Summary of the Invention

[0006] As discussed above, the present invention generally relates to a combination comprising a first antibody molecule, a second antibody molecule, and a third antibody molecule. In this regard, first to seventh aspects of the present invention are described below.

[0007] In a first aspect, the present invention provides a combination for use in the treatment of cancer in a patient comprising: - a first antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to PD-1 or PD-L1; and a third antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, The cancer is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4.

[0008] In a second aspect, the present invention provides a method for the manufacture of a medicament for treating cancer in a patient, comprising: - a first antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to PD-1 or PD-L1; and a third antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, The cancer is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4.

[0009] In a third aspect, the present invention provides a method for treating cancer in a patient, the method comprising administering to the patient: - a first antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to PD-1 or PD-L1; and - a third antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor; The cancer is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4.

[0010] In a fourth aspect, the present invention provides a first antibody molecule for treating cancer in a patient, the first antibody molecule specifically binds FcyRllb via its Fab region and lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, a second antibody molecule that specifically binds to PD-1 or PD-L1, and - for use in combination with a third antibody molecule, which specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, A first antibody molecule is provided, wherein the cancer is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4.

[0011] In a fifth aspect, the present invention provides a first antibody molecule for use in treating cancer in a patient, characterised in that the first antibody molecule specifically binds FcyRllb via its Fab region and lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, and wherein the first antibody molecule reduces and / or prevents resistance in the cancer to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4.

[0012] In a sixth aspect, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: - a first antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to PD-1 or PD-L1; and - a third antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor.

[0013] In a seventh aspect, the present invention provides a method for producing a composition comprising the steps of: - a first antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to PD-1 or PD-L1; and - a third antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor.

[0014] The first antibody molecule described herein specifically binds to FcyRllb via its Fab region and lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region. Fc receptors are well known in the art as membrane proteins found on the cell surface of immune effector cells such as macrophages. The name is derived from their binding specificity to the Fc region of the antibody, which is the usual way that antibodies bind to receptors. However, certain antibodies can also bind to Fc receptors via the CDR sequences of the antibody, when the antibody specifically binds to one or more Fc receptors.

[0015] A subgroup of Fc receptors includes Fcγ receptors (Fc-gamma receptors, Fc gamma R), which are specific for IgG antibodies. There are two types of Fcγ receptors: activating Fcγ receptors (also referred to as activatory Fcγ receptors) and inhibitory Fcγ receptors. Activating and inhibitory receptors transmit their signals via immunoreceptor tyrosine-based activation motifs (ITAMs) or immunoreceptor tyrosine-based inhibitory motifs (ITIMs), respectively. In humans, FcγRIIb (CD32b) is an inhibitory Fcγ receptor, while FcγRI (CD64), FcγRIIa (CD32a), FcγRIIc (CD32c), FcγRIIIa (CD16a), and FcγRIV are activating Fcγ receptors. FcγγRIIIb is a GPI-linked receptor expressed on neutrophils that lacks ITAM motifs but is also considered activating due to its ability to cross-link lipid rafts and associate with other receptors. In mice, the activating receptors are FcγRI, FcγRIII, and FcγRIV.

[0016] It is well known that antibodies regulate immune cell activity through interaction with Fcγ receptors. Specifically, how antibody immune complexes regulate immune cell activation is determined by the relative engagement of activating and inhibitory Fcγ receptors. Different antibody isotypes bind to activating and inhibitory Fcγ receptors with different affinities, resulting in different A:I ratios (activation:inhibition ratios) (Nimmerjahn et al; Science. 2005 Dec 2; 310(5753):1510-2).

[0017] By binding to inhibitory Fcγ receptors, antibodies can inhibit, block, and / or downregulate effector cell function.

[0018] Antibodies can activate effector cell function by binding to activating Fcγ receptors, thereby inducing mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), cytokine release, and / or antibody-dependent endocytosis, and in the case of neutrophils, NETosis (i.e., activation and release of NETs (neutrophil extracellular traps)). Antibodies that bind to activating Fcγ receptors can also lead to an increase in certain activation markers, such as CD40, MHCII, CD38, CD80, and / or CD86.

[0019] The first antibody molecule according to the invention that specifically binds to FcγRIIb binds to or interacts with this Fcγ receptor via the Fab region of the antibody, i.e., via the antigen-binding region on the antibody that binds to the antigen, which is composed of one constant domain and one variable domain of each of the heavy and light chains. In particular, it binds to FcγRIIb present on immune effector cells (in particular, FcγRIIb present on the surface of immune effector cells). If this antibody had a normal or ordinary Fc region, the antibody could also bind to an activating Fcγ receptor through the normal interaction between the Fc region and the Fc receptor. However, according to the present invention, an antibody molecule that specifically binds to FcγRIIb either completely lacks an Fc region or has reduced binding to Fcγ receptors, which means that an antibody molecule that specifically binds to or interacts with FcγRIIb via the Fab region does not bind well to Fcγ receptors or cannot bind to or interact with Fcγ receptors at all. This is believed to have at least two important therapeutic consequences: 1) The lack of Fc-mediated binding to activating FcγRs leaves more activating Fc gamma receptors available for binding to the Fc of (other) therapeutic anti-cancer antibodies, e.g., second and / or third antibody molecules as defined herein. This is important because the clustering of an ever-increasing number of activating FcγRs (versus inhibitory FcγRs; Nimmerjahn et al; Science. 2005 Dec 2; 310(5753):1510-2) is known to increase effector cell-mediated target cell deletion, a mechanism that underlies the activity of checkpoint inhibitors as well as immune agonists and other immunomodulatory antibodies such as anti-IL-2R. 2) Absence or reduction of Fc-mediated binding to inhibitory FcγRs has been shown to reduce inhibitory signaling in FcγR-expressing immune effector cells. Thus, absence or reduction of Fc-mediated binding of FcγRIIB-targeted antibodies to FcγRs likely improves therapeutic efficacy through at least two mechanisms, including both enhancement of activating FcγRs and reduction of inhibitory Fcγ signaling in immune effector cells responding to a second immunomodulatory anti-cancer antibody.

[0020] In the case of the above first to seventh aspects of the invention, this is advantageous because it allows antibodies that specifically bind to CTLA-4 (and / or in some embodiments PD-1 / PD-L1) to bind both of their target molecules on immune effector cells, which upregulates the immune response against cancer cells, and also allows these antibodies to specifically bind to activating FcγRs, further upregulating the immune response. This effect can surprisingly restore the therapeutic effect of antibodies that specifically bind to CTLA-4 / PD-1 / PD-L1 in patients that are resistant to such therapies.

[0021] "Lack of Fc region" includes any antibody or antibody fragment thereof that does not have an Fc region, thus preventing Fc-mediated binding of the antibody or antibody fragment to an Fcγ receptor. Such antibodies retain specific binding to FcyRllb via the Fab region. Examples of antibody fragments that lack an Fc region and are compatible with this embodiment of the invention include, but are not limited to, Fab, Fab', F(ab)2, Fv, scFv, dsFv, VH, VL, or PEGylated versions thereof.

[0022] "Reduced binding to Fcγ receptors" (also referred to as "reduced affinity binding") includes that the antibody molecule has reduced Fc-mediated binding to Fcγ receptors, in other words, the Fc region of an antibody molecule that specifically binds to FcγRIIb binds to activating Fcγ receptors with lower affinity than the Fc region of normal human IgG1. Reduced binding can be assessed using techniques such as surface plasmon resonance. In this context, "normal IgG1" means a conventionally produced IgG1 with a non-mutated Fc region that has not been produced to alter its glycosylation. As a reference for this "normal IgG1", rituximab produced in CHO cells can be used without any modification (Tipton et al, Blood 2015 125:1901-1909; rituximab is described, for example, in EP0605442). Human IgG2 and human IgG4 are examples of antibody isotypes that bind with reduced affinity to Fcγ receptors compared to human IgG1. Thus, human IgG2 and IgG4 based antibodies have "reduced binding to Fcγ receptors" within the meaning of this term.

[0023] "Reduced binding" can mean that binding of the Fc region of an antibody molecule that specifically binds FcγRIIb to activating Fcγ receptors is reduced by at least 10-fold at all Fc receptors compared to the binding of the Fc region of normal human IgG1 to the same receptors. In some embodiments, binding is reduced by at least 20-fold. In some embodiments, binding is reduced by at least 30-fold. In some embodiments, binding is reduced by at least 40-fold. In some embodiments, binding is reduced by at least 50-fold. In some embodiments, binding is reduced by at least 60-fold. In some embodiments, binding is reduced by at least 70-fold.

[0024] In some embodiments, the antibody molecule that specifically binds to FcγRIIb may be a llama antibody, in particular a llama hcIgG. Like all mammals, camelids produce conventional antibodies with two heavy chains and two light chains linked in a Y-shape by disulfide bonds (IgG1). However, they also produce two unique subclasses of immunoglobulin G, IgG2 and IgG3, also known as heavy chain IgG (hcIgG). These antibodies are composed of only two heavy chains that lack the CH1 region, but contain a V at their N-terminus. H They retain the antigen-binding domain, called H. Conventional Ig requires the combination of variable regions from both heavy and light chains to allow a high degree of diversity in antigen-antibody interactions. Isolated heavy and light chains still exhibit this ability, but compared to heavy and light chain pairs, they exhibit extremely low affinity. 4 A unique feature of hcIgGs is the ability of their monomeric antigen-binding domain to bind antigens without the need for pairing with another domain and with specificity, affinity, and especially diversity comparable to conventional antibodies.

[0025] In some embodiments, reduced binding means that the antibody has a 20-fold reduced affinity for binding to FcγRI.

[0026] To obtain IgG antibodies (e.g. IgG1 or IgG2 antibodies) with reduced binding to Fc receptors, it is possible to modify the Fc region of an IgG antibody by aglycosylation. For example, such aglycosylation of an IgG1 antibody can be achieved, for example, by amino acid substitution of an asparagine at position 297 (N297X) of the antibody chain. The substitution may be with glutamine (N297Q), or alanine (N297A), or glycine (N297G), or asparagine (N297D), or with serine (N297S). In some preferred embodiments, the substitution is with glutamine (N297Q).

[0027] The Fc region may be modified by further substitutions, for example as described in Jacobsen FW et al., JBC 2017, 292, 1865-1875 (see, for example, Table 1). Such further substitutions include L242C, V259C, A287C, R292C, V302C, L306C, V323C, I332C, and / or K334C. Such modifications also include combinations of the following substitutions in IgG1: L242C, N297G, K334C, A287C, N297G, L306C, R292C, N297G, V302C, N297G, V323C, I332C, and V259C, N297G, L306C.

[0028] Alternatively, the carbohydrate in the Fc region can be enzymatically cleaved, and / or the cells used to produce the antibody can be grown in a medium that impairs the addition of carbohydrate, and / or cells engineered to lack the ability to add glycosyl can be used for antibody production, or by production of the antibody in a host cell that does not glycosylate, or does not functionally glycosylate, e.g., a prokaryote including E. coli, as described above.

[0029] Reduction of affinity for Fc gamma receptors can further be achieved through manipulation of amino acids in the Fc region of the antibody (such modifications have been previously described, for example, by Xencor, Macrogenics, and Genentech), or by production of the antibody in a host cell that does not glycosylate or does not functionally glycosylate the antibody, such as a prokaryote, including E. coli.

[0030] In addition to having reduced binding to Fcγ receptors via the Fc region, in some embodiments, it is preferred that an antibody molecule that specifically binds to FcγRIIb does not cause phosphorylation of FcγRIIb upon target binding, which is an inhibitory phenomenon that blocks immune cell activity.

[0031] Immune effector cells expressing Fc gamma receptors herein primarily refer to innate effector cells, specifically including macrophages, neutrophils, monocytes, natural killer (NK) cells, basophils, eosinophils, mast cells, and platelets. Cytotoxic T cells and memory T cells do not normally express FcγR, but may do so in certain circumstances. In some embodiments, the immune effector cells are innate immune effector cells. In some embodiments, the immune effector cells are macrophages.

[0032] In some embodiments, an antibody molecule that specifically binds to FcγRIIb is a human antibody.

[0033] In some embodiments, antibody molecules that specifically bind to FcγRIIb are human-derived antibodies, i.e., originally human antibodies that have been modified as described herein.

[0034] In some embodiments, an antibody molecule that specifically binds to FcγRIIb is a humanized antibody, i.e., an originally non-human antibody that has been modified to increase similarity to a human antibody. A humanized antibody can be, for example, a mouse antibody or a llama antibody.

[0035] As discussed above, the first antibody can be a monoclonal antibody or an antibody molecule of monoclonal origin.

[0036] In some embodiments, an antibody molecule that specifically binds to FcγRIIb comprises the following constant regions (CH and CL): IgG1-CH [SEQ ID NO: 1] [ka] IgG1-CL [SEQ ID NO: 2] [ka] These constant regions (SEQ ID NO: 1 and SEQ ID NO: 2) are of human origin. The Fc region is further modified to reduce binding to Fcγ receptors via the Fc region. As mentioned herein, in some embodiments, it is preferred that SEQ ID NO: 1 is aglycosylated with a N297Q substitution, and then the IgG1-CH has the following CH sequence [SEQ ID NO: 195], with the 297Q residue marked in bold. [ka] In some embodiments and / or examples, mouse antibody molecules are used. These can also be used as surrogate antibodies. They contain the following constant regions (CH and CL): CH[SEQ ID NO:196] [ka] CL [SEQ ID NO: 197] [ka] Thus, these constant regions (SEQ ID NO: 196 and SEQ ID NO: 197) are of mouse origin. SEQ ID NO: 196 contains the N297A mutation (residue 297A is shown in bold in the sequence above). This N297A mutation in the mouse sequence corresponds to the N297Q mutation in the human sequence.

[0037] In some embodiments, an antibody molecule that specifically binds to FcγRIIb comprises the sequence of one or more of the following clones:

[0038] Antibody clone: ​​1A01 1A01-VH [SEQ ID NO: 3] [ka] 1A01-VL [SEQ ID NO: 27] [ka] CDR area CDRH1: DYYMN [SEQ ID NO:51] CDRH2: LIGWDGGSTYYADSVKG [SEQ ID NO:52] CDRH3: AYSGYELDY [SEQ ID NO:53] CDRL1: SGSSSNIGNNAVN [SEQ ID NO:54] CDRL2: DNNNRPS [SEQ ID NO:55] CDRL3: AAWDDSLNASI [SEQ ID NO:56]

[0039] Antibody clone: ​​1B07 1B07-VH [SEQ ID NO: 4] [ka] 1B07-VL [SEQ ID NO: 28] [ka] CDR area CDRH1: SYGMH [SEQ ID NO:57] CDRH2: FTRYDGSNKYYADSVRG [SEQ ID NO:58] CDRH3: ENIDAFDV [SEQ ID NO:59] CDRL1: SGSSSNIGNNAVN [SEQ ID NO: 60] CDRL2: DNQQRPS [SEQ ID NO:61] CDRL3: WDDRLFGPV [SEQ ID NO:62]

[0040] Antibody clone: ​​1C04 1C04-VH[SEQ ID NO:5] [ka] 1C04-VL [SEQ ID NO: 29] [ka] CDR area CDRH1: SYAMS [SEQ ID NO: 63] CDRH2: SISDSGAGRYYADSVEG [SEQ ID NO: 64] CDRH3: THDSGELLDAFDI [SEQ ID NO: 65] CDRL1: SGSSSNIGSNHVL [SEQ ID NO: 66] CDRL2: GNSNRPS [SEQ ID NO:67] CDRL3: AAWDDSLNGWV [SEQ ID NO: 68]

[0041] Antibody clone: ​​1E05 1E05-VH [SEQ ID NO: 6] [ka] 1E05-VL [SEQ ID NO: 30] [ka] CDR area CDRH1: TYAMN [SEQ ID NO:69] CDRH2: VISYDGSNKNYVDSVKG [SEQ ID NO: 70] CDRH3: NFDNSGYAIPDAFDI [SEQ ID NO: 71] CDRL1: TGSSSNIGAGYDVH [SEQ ID NO: 72] CDRL2: DNNSRPS [SEQ ID NO:73] CDRL3: AAWDDSLGGPV [SEQ ID NO:74]

[0042] Antibody clone: ​​2A09 2A09-VH[SEQ ID NO:7] [ka] 2A09-VL [SEQ ID NO: 31] [ka] CDR area CDRH1: NAWMS [SEQ ID NO: 75] CDRH2: YISRDADITHYPASVKG [SEQ ID NO: 76] CDRH3: GFDYAGDDAFDI [SEQ ID NO:77] CDRL1: SGSSSNIGSNAVN [SEQ ID NO:78] CDRL2: GNSDRPS [SEQ ID NO:79] CDRL3: AAWDDSLNGRWV [SEQ ID NO:80]

[0043] Antibody clone: ​​2B08 2B08-VH [SEQ ID NO: 8] [ka] 2B08-VL [SEQ ID NO: 32] [ka] CDR area CDRH1: DYYMS [SEQ ID NO:81] CDRH2: LIGHDGNNKYYLDSLEG [SEQ ID NO: 82] CDRH3: ATDSGYDLLY [SEQ ID NO: 83] CDRL1: SGSSSNIGNNAVN [SEQ ID NO: 84] CDRL2: YDDLLPS [SEQ ID NO:85] CDRL3: TTWDDSLSGVV [SEQ ID NO:86]

[0044] Antibody clone: ​​2E8-VH 2E8-VH [SEQ ID NO: 9] [ka] 2E8-VL [SEQ ID NO: 33] [ka] CDR area CDRH1: DYYMS [SEQ ID NO:87] CDRH2: AIGFSDDNTYYADSVKG [SEQ ID NO: 88] CDRH3: GDGSGWSF [SEQ ID NO:89] CDRL1: SGSSSNIGNNAVN [SEQ ID NO: 90] CDRL2: DNNKRPS [SEQ ID NO:91] CDRL3: ATWDDSLRGWV [SEQ ID NO:92]

[0045] Antibody clone: ​​5C04 5C04-VH [SEQ ID NO: 10] [ka] 5C04-VL [SEQ ID NO: 34] [ka] CDR area CDRH1: NYGMH [SEQ ID NO: 93] CDRH2: VISYDGSNKYYADSVKG [SEQ ID NO: 94] CDRH3: WRDAFDI [SEQ ID NO: 95] CDRL1: TGSSSNIGAGYDVH [SEQ ID NO: 96] CDRL2: SDNQRPS [SEQ ID NO:97] CDRL3: AAWDDSLSGSWV [SEQ ID NO:98]

[0046] Antibody clone: ​​5C05 5C05-VH [SEQ ID NO: 11] [ka] 5C05-VL [SEQ ID NO: 35] [ka] CDR area CDRH1: TYGMH [SEQ ID NO: 99] CDRH2: VISYDGSNKYYADSVKG [SEQ ID NO: 100] CDRH3: ENFDAFDV [SEQ ID NO: 101] CDRL1: TGSSSNIGAGYDVH [SEQ ID NO: 102] CDRL2: SNSQRPS [SEQ ID NO: 103] CDRL3: AAWDDSLNGQVV [SEQ ID NO: 104]

[0047] Antibody clone: ​​5D07 5D07-VH [SEQ ID NO: 12] [ka] 5D07-VL [SEQ ID NO: 36] [ka] CDR area CDRH1: TYGMH [SEQ ID NO: 105] CDRH2: VIAYDGSKKDYADSVKG [SEQ ID NO: 106] CDRH3: EYRDAFDI [SEQ ID NO: 107] CDRL1: TGSSSNIGAGYDVH [SEQ ID NO: 108] CDRL2: GNSNRPS [SEQ ID NO: 109] CDRL3: AAWDDSVSGWM [SEQ ID NO: 110]

[0048] Antibody clone: ​​5E12 5E12-VH [SEQ ID NO: 13] [ka] 5E12-VL [SEQ ID NO: 37] [ka] CDR area CDRH1: SYGMH [SEQ ID NO: 111] CDRH2: VISYDGINKDYADSMKG [SEQ ID NO: 112] CDRH3: ERKDAFDI [SEQ ID NO: 113] CDRL1: TGSSSNIGAGYDVH [SEQ ID NO: 114] CDRL2: SNNQRPS [SEQ ID NO: 115] CDRL3: ATWDDSLNGLV [SEQ ID NO: 116]

[0049] Antibody clone: ​​5G08 5G08-VH [SEQ ID NO: 14] [ka] 5G08-VL [SEQ ID NO: 38] [ka] CDR area CDRH1: NYGMH [SEQ ID NO: 117] CDRH2: VISYDGSNRYYADSVKG [SEQ ID NO: 118] CDRH3: DRWNGMDV [SEQ ID NO: 119] CDRL1: SGSSSNIGAGYDVH [SEQ ID NO: 120] CDRL2: ANNQRPS [SEQ ID NO: 121] CDRL3: AAWDDSLNGPWV [SEQ ID NO: 122]

[0050] Antibody clone: ​​5H06 5H06-VH [SEQ ID NO: 15] [ka] 5H06-VL [SEQ ID NO: 39] [ka] CDR area CDRH1: SYGMH [SEQ ID NO: 123] CDRH2: VISYDGSDTAYADSVKG [SEQ ID NO: 124] CDRH3: DHSVIGAFDI [SEQ ID NO: 125] CDRL1: SGSSSNIGSNTVN [SEQ ID NO: 126] CDRL2: DNNKRPS [SEQ ID NO: 127] CDRL3: SSYAGSNNVV [SEQ ID NO: 128]

[0051] Antibody clone: ​​6A09 6A09-VH[SEQ ID NO: 16] [ka] 6A09-VL [SEQ ID NO: 40] [ka] CDR area CDRH1: SYGMH [SEQ ID NO: 129] CDRH2: VTSYDGNTKYYANSVKG [SEQ ID NO: 130] CDRH3: EDCGGDCFDY [SEQ ID NO: 131] CDRL1: TGSSSNIGAGYDVH [SEQ ID NO: 132] CDRL2: GNSNRPS [SEQ ID NO: 133] CDRL3: AAWDDSLNEGV [SEQ ID NO: 134]

[0052] Antibody clone: ​​6B01 6B01-VH [SEQ ID NO: 17] [ka] 6B01-VL [SEQ ID NO: 41] [ka] CDR area CDRH1: NYGMH [SEQ ID NO: 135] CDRH2: VISYDGSNKYYADSVKG [SEQ ID NO: 136] CDRH3: DQLGEAFDI [SEQ ID NO: 137] CDRL1: TGSSSNIGAGYDVH [SEQ ID NO: 138] CDRL2: DNNKRPS [SEQ ID NO: 139] CDRL3: ATWDDSLSGPV [SEQ ID NO: 140]

[0053] Antibody clone: ​​6C11 6C11-VH [SEQ ID NO: 18] [ka] 6C11-VL [SEQ ID NO: 42] [ka] CDR area CDRH1: DYGMS [SEQ ID NO: 141] CDRH2: AISGSGSSTYYADSVKG [SEQ ID NO: 142] CDRH3: GDIDYFDY [SEQ ID NO: 143] CDRL1: TGSSSNFGAGYDVH [SEQ ID NO: 144] CDRL2: ENNKRPS [SEQ ID NO: 145] CDRL3: AAWDDSLNGPV [SEQ ID NO: 146]

[0054] Antibody clone: ​​6C12 6C12-VH [SEQ ID NO: 19] [ka] 6C12-VL [SEQ ID NO: 43] [ka] CDR area CDRH1: SYGMH [SEQ ID NO: 147] CDRH2: VISYDGSNKYYADSVKG [SEQ ID NO: 148] CDRH3: ERRDAFDI [SEQ ID NO: 149] CDRL1: TGSSSNIGAGYDVH [SEQ ID NO: 150] CDRL2: SDNQRPS [SEQ ID NO: 151] CDRL3: ATWDSDTPV [SEQ ID NO: 152]

[0055] Antibody clone: ​​6D01 6D01-VH [SEQ ID NO: 20] [ka] 6D01-VL [SEQ ID NO: 44] [ka] CDR area CDRH1: SYGMH [SEQ ID NO: 153] CDRH2: VISYDGSNKYYADSVKG [SEQ ID NO: 154] CDRH3: DHSAAGYFDY [SEQ ID NO: 155] CDRL1: SGSSSNIGSNTVN [SEQ ID NO: 156] CDRL2: GNSIRPS [SEQ ID NO: 157] CDRL3: ASWDDSLSSPV [SEQ ID NO: 158]

[0056] Antibody clone: ​​6G03 6G03-VH [SEQ ID NO: 21] [ka] 6G03-VL [SEQ ID NO: 45] [ka] CDR area CDRH1: SYGMH [SEQ ID NO: 159] CDRH2: GISWDSAIIDYAGSVKG [SEQ ID NO: 160] CDRH3: DEAAAGAFDI [SEQ ID NO: 161] CDRL1: TGSSSNIGAGYDVH [SEQ ID NO: 162] CDRL2: GNTDRPS [SEQ ID NO: 163] CDRL3: AAWDDSLSGPVV [SEQ ID NO: 164]

[0057] Antibody clone: ​​6G08 6G08-VH [SEQ ID NO: 22] [ka] 6G08-VL [SEQ ID NO: 46] [ka] CDR area CDRH1: SYGIS [SEQ ID NO: 165] CDRH2: GISGSGGNTYYADSVKG [SEQ ID NO: 166] CDRH3: SVGAYANDAFDI [SEQ ID NO: 167] CDRL1: TGSSSNIGAGYDVH [SEQ ID NO: 168] CDRL2: GDTNRPS [SEQ ID NO: 169] CDRL3: AAWDDSLNGPV [SEQ ID NO: 170]

[0058] Antibody clone: ​​6G11 6G11-VH [SEQ ID NO: 23] [ka] 6G11-VL [SEQ ID NO: 47] [ka] CDR area CDRH1: SYGMH [SEQ ID NO: 171] CDRH2: VISYDGSNKYYADSVKG [SEQ ID NO: 172] CDRH3: ELYDAFDI [SEQ ID NO: 173] CDRL1: TGSSSNIGAGYDVH [SEQ ID NO: 174] CDRL2: ADDHRPS [SEQ ID NO: 175] CDRL3: ASWDDSQRAVI [SEQ ID NO: 176]

[0059] Antibody clone: ​​6H08 6H08-VH [SEQ ID NO: 24] [ka] 6H08-VL [SEQ ID NO: 48] [ka] CDR area CDRH1: NYGMH [SEQ ID NO: 177] CDRH2: VISYDGSNKYYAD SVKG [SEQ ID NO: 178] CDRH3: EYKDAFDI [SEQ ID NO: 179] CDRL1: TGSSSNIGSNTVN [SEQ ID NO: 180] CDRL2: DNNKRPS [SEQ ID NO: 181] CDRL3: QAWGTGIRV [SEQ ID NO: 182]

[0060] Antibody clone: ​​7C07 7C07-VH[SEQ ID NO:25] [ka] 7C07-VL [SEQ ID NO: 49] [ka] CDR area CDRH1: SYGMH [SEQ ID NO: 183] CDRH2: VISYDGSNKYYADSVKG [SEQ ID NO: 184] CDRH3: EFGYIILDY [SEQ ID NO: 185] CDRL1: SGSSSNIGSNTVN [SEQ ID NO: 186] CDRL2: RDYERPS [SEQ ID NO: 187] CDRL3: MAWDDSLSGVV [SEQ ID NO: 188]

[0061] Antibody clone: ​​4B02 4B02-VH [SEQ ID NO: 26] [ka] 4B02-VL [SEQ ID NO: 50] [ka] CDR area CDRH1: NHGMH [SEQ ID NO: 189] CDRH2: VISYDGTNKYYADSVRG [SEQ ID NO: 190] CDRH3: ETWDAFDV [SEQ ID NO: 191] CDRL1: SGSSSNIGSNNAN [SEQ ID NO: 192] CDRL2: DNNKRPS [SEQ ID NO: 193] CDRL3: QAWDSSTVV [SEQ ID NO: 194]

[0062] Thus, in some embodiments, the first antibody molecule may comprise a variable heavy chain (VH) comprising the following CDRs: (i) SEQ ID NO: 51 and SEQ ID NO: 52 and SEQ ID NO: 53, or (ii) SEQ ID NO: 57 and SEQ ID NO: 58 and SEQ ID NO: 59, or (iii) SEQ ID NO: 63, SEQ ID NO: 64, and SEQ ID NO: 65, or (iv) SEQ ID NO: 69 and SEQ ID NO: 70 and SEQ ID NO: 71, or (v) SEQ ID NO: 75 and SEQ ID NO: 76 and SEQ ID NO: 77, or (vi) SEQ ID NO: 81 and SEQ ID NO: 82 and SEQ ID NO: 83, or (vii) SEQ ID NO: 87, SEQ ID NO: 88, and SEQ ID NO: 89, or (viii) SEQ ID NO: 93 and SEQ ID NO: 94 and SEQ ID NO: 95, or (ix) SEQ ID NO: 99 and SEQ ID NO: 100 and SEQ ID NO: 101, or (x) SEQ ID NO: 105 and SEQ ID NO: 106 and SEQ ID NO: 107, or (xi) SEQ ID NO: 111 and SEQ ID NO: 112 and SEQ ID NO: 113, or (xii) SEQ ID NO: 117 and SEQ ID NO: 118 and SEQ ID NO: 119, or (xiii) SEQ ID NO: 123 and SEQ ID NO: 124 and SEQ ID NO: 125, or (xiv) SEQ ID NO: 129 and SEQ ID NO: 130 and SEQ ID NO: 131, or (xv) SEQ ID NO: 135 and SEQ ID NO: 136 and SEQ ID NO: 137, or (xvi) SEQ ID NO: 141 and SEQ ID NO: 142 and SEQ ID NO: 143, or (xvii) SEQ ID NO: 147 and SEQ ID NO: 148 and SEQ ID NO: 149, or (xviii) SEQ ID NO: 153 and SEQ ID NO: 154 and SEQ ID NO: 155, or (xix) SEQ ID NO: 159 and SEQ ID NO: 160 and SEQ ID NO: 161, or (xx) SEQ ID NO: 165 and SEQ ID NO: 166 and SEQ ID NO: 167, or (xxi) SEQ ID NO: 171 and SEQ ID NO: 172 and SEQ ID NO: 173, or (xxii) SEQ ID NO: 177 and SEQ ID NO: 178 and SEQ ID NO: 179, or (xxiii) SEQ ID NO: 183 and SEQ ID NO: 184 and SEQ ID NO: 185, or (xxiv) SEQ ID NO: 189, SEQ ID NO: 190, and SEQ ID NO: 191.

[0063] In some further or alternative embodiments, the first antibody molecule comprises a variable light chain (VL) that comprises the following CDRs: (i) SEQ ID NO: 54 and SEQ ID NO: 55 and SEQ ID NO: 56, or (ii) SEQ ID NO: 60 and SEQ ID NO: 61 and SEQ ID NO: 62, or (iii) SEQ ID NO: 66, SEQ ID NO: 67, and SEQ ID NO: 68, or (iv) SEQ ID NO: 72 and SEQ ID NO: 73 and SEQ ID NO: 74, or (v) SEQ ID NO: 78 and SEQ ID NO: 79 and SEQ ID NO: 80, or (vi) SEQ ID NO: 84 and SEQ ID NO: 85 and SEQ ID NO: 86, or (vii) SEQ ID NO: 90 and SEQ ID NO: 91 and SEQ ID NO: 92, or (viii) SEQ ID NO: 96 and SEQ ID NO: 97 and SEQ ID NO: 98, or (ix) SEQ ID NO: 102 and SEQ ID NO: 103 and SEQ ID NO: 104, or (x) SEQ ID NO: 108 and SEQ ID NO: 109 and SEQ ID NO: 110, or (xi) SEQ ID NO: 114 and SEQ ID NO: 115 and SEQ ID NO: 116, or (xii) SEQ ID NO: 120 and SEQ ID NO: 121 and SEQ ID NO: 122, or (xiii) SEQ ID NO: 126 and SEQ ID NO: 127 and SEQ ID NO: 128, or (xiv) SEQ ID NO: 132 and SEQ ID NO: 133 and SEQ ID NO: 134, or (xv) SEQ ID NO: 138 and SEQ ID NO: 139 and SEQ ID NO: 140, or (xvi) SEQ ID NO: 144 and SEQ ID NO: 145 and SEQ ID NO: 146, or (xvii) SEQ ID NO: 150 and SEQ ID NO: 151 and SEQ ID NO: 152, or (xviii) SEQ ID NO: 156 and SEQ ID NO: 157 and SEQ ID NO: 158, or (xix) SEQ ID NO: 162 and SEQ ID NO: 163 and SEQ ID NO: 164, or (xx) SEQ ID NO: 168 and SEQ ID NO: 169 and SEQ ID NO: 170, or (xxi) SEQ ID NO: 174 and SEQ ID NO: 175 and SEQ ID NO: 176, or (xxii) SEQ ID NO: 180 and SEQ ID NO: 181 and SEQ ID NO: 182, or (xxiii) SEQ ID NO: 186 and SEQ ID NO: 187 and SEQ ID NO: 188, or (xxiv) SEQ ID NO: 192, SEQ ID NO: 193, and SEQ ID NO: 194.

[0064] In some further or alternative embodiments, the first antibody molecule comprises a variable heavy chain (VH) amino acid sequence selected from the group consisting of: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26.

[0065] In some further or alternative embodiments, the first antibody molecule comprises a variable light chain (VL) amino acid sequence selected from the group consisting of: SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, and SEQ ID NO:50.

[0066] In some further or alternative embodiments, the first antibody molecule comprises the following CDR amino acid sequences: (i) SEQ ID NO: 51 and SEQ ID NO: 52 and SEQ ID NO: 53 and SEQ ID NO: 54 and SEQ ID NO: 55 and SEQ ID NO: 56, or (ii) SEQ ID NO:57 and SEQ ID NO:58 and SEQ ID NO:59 and SEQ ID NO:60 and SEQ ID NO:61 and SEQ ID NO:62, or (iii) SEQ ID NO: 63 and SEQ ID NO: 64 and SEQ ID NO: 65 and SEQ ID NO: 66 and SEQ ID NO: 67 and SEQ ID NO: 68, or (iv) SEQ ID NO: 69 and SEQ ID NO: 70 and SEQ ID NO: 71 and SEQ ID NO: 72 and SEQ ID NO: 73 and SEQ ID NO: 74, or (v) SEQ ID NO: 75 and SEQ ID NO: 76 and SEQ ID NO: 77 and SEQ ID NO: 78 and SEQ ID NO: 79 and SEQ ID NO: 80, or (vi) SEQ ID NO: 81 and SEQ ID NO: 82 and SEQ ID NO: 83 and SEQ ID NO: 84 and SEQ ID NO: 85 and SEQ ID NO: 86, or (vii) SEQ ID NO: 87 and SEQ ID NO: 88 and SEQ ID NO: 89 and SEQ ID NO: 90 and SEQ ID NO: 91 and SEQ ID NO: 92, or (viii) SEQ ID NO: 93 and SEQ ID NO: 94 and SEQ ID NO: 95 and SEQ ID NO: 96 and SEQ ID NO: 97 and SEQ ID NO: 98, or (ix) SEQ ID NO: 99 and SEQ ID NO: 100 and SEQ ID NO: 101 and SEQ ID NO: 102 and SEQ ID NO: 103 and SEQ ID NO: 104, or (x) SEQ ID NO: 105 and SEQ ID NO: 106 and SEQ ID NO: 107 and SEQ ID NO: 108 and SEQ ID NO: 109 and SEQ ID NO: 110, or (xi) SEQ ID NO:111 and SEQ ID NO:112 and SEQ ID NO:113 and SEQ ID NO:114 and SEQ ID NO:115 and SEQ ID NO:116, or (xii) SEQ ID NO: 117 and SEQ ID NO: 118 and SEQ ID NO: 119 and SEQ ID NO: 120 and SEQ ID NO: 121 and SEQ ID NO: 122, or (xiii) SEQ ID NO: 123 and SEQ ID NO: 124 and SEQ ID NO: 125 and SEQ ID NO: 126 and SEQ ID NO: 127 and SEQ ID NO: 128, or (xiv) SEQ ID NO: 129 and SEQ ID NO: 130 and SEQ ID NO: 131 and SEQ ID NO: 132 and SEQ ID NO: 133 and SEQ ID NO: 134, or (xv) SEQ ID NO: 135 and SEQ ID NO: 136 and SEQ ID NO: 137 and SEQ ID NO: 138 and SEQ ID NO: 139 and SEQ ID NO: 140, or (xvi) SEQ ID NO: 141 and SEQ ID NO: 142 and SEQ ID NO: 143 and SEQ ID NO: 144 and SEQ ID NO: 145 and SEQ ID NO: 146, or (xvii) SEQ ID NO: 147 and SEQ ID NO: 148 and SEQ ID NO: 149 and SEQ ID NO: 150 and SEQ ID NO: 151 and SEQ ID NO: 152, or (xviii) SEQ ID NO: 153 and SEQ ID NO: 154 and SEQ ID NO: 155 and SEQ ID NO: 156 and SEQ ID NO: 157 and SEQ ID NO: 158, or (xix) SEQ ID NO: 159 and SEQ ID NO: 160 and SEQ ID NO: 161 and SEQ ID NO: 162 and SEQ ID NO: 163 and SEQ ID NO: 164, or (xx) SEQ ID NO: 165 and SEQ ID NO: 166 and SEQ ID NO: 167 and SEQ ID NO: 168 and SEQ ID NO: 169 and SEQ ID NO: 170, or (xxi) SEQ ID NO: 171 and SEQ ID NO: 172 and SEQ ID NO: 173 and SEQ ID NO: 174 and SEQ ID NO: 175 and SEQ ID NO: 176, or (xxii) SEQ ID NO: 177 and SEQ ID NO: 178 and SEQ ID NO: 179 and SEQ ID NO: 180 and SEQ ID NO: 181 and SEQ ID NO: 182, or (xxiii) SEQ ID NO: 183 and SEQ ID NO: 184 and SEQ ID NO: 185 and SEQ ID NO: 186 and SEQ ID NO: 187 and SEQ ID NO: 188, or (xxiv) SEQ ID NO: 189 and SEQ ID NO: 190 and SEQ ID NO: 191 and SEQ ID NO: 192 and SEQ ID NO: 193 and SEQ ID NO: 194.

[0067] In some further or alternative embodiments, the first antibody molecule comprises the following amino acid sequence: (i) SEQ ID NO: 3 and SEQ ID NO: 27, or (ii) SEQ ID NO: 4 and SEQ ID NO: 28, or (iii) SEQ ID NO: 5 and SEQ ID NO: 29, or (iv) SEQ ID NO: 6 and SEQ ID NO: 30, or (v) SEQ ID NO: 7 and SEQ ID NO: 31, or (vi) SEQ ID NO: 8 and SEQ ID NO: 32, or (vii) SEQ ID NO: 9 and SEQ ID NO: 33, or (viii) SEQ ID NO: 10 and SEQ ID NO: 34, or (ix) SEQ ID NO: 11 and SEQ ID NO: 35, or (x) SEQ ID NO: 12 and SEQ ID NO: 36, or (xi) SEQ ID NO: 13 and SEQ ID NO: 37, or (xii) SEQ ID NO: 14 and SEQ ID NO: 38, or (xiii) SEQ ID NO: 15 and SEQ ID NO: 39, or (xiv) SEQ ID NO: 16 and SEQ ID NO: 40, or (xv) SEQ ID NO: 17 and SEQ ID NO: 41, or (xvi) SEQ ID NO: 18 and SEQ ID NO: 42, or (xvii) SEQ ID NO: 19 and SEQ ID NO: 43, or (xviii) SEQ ID NO: 20 and SEQ ID NO: 44, or (xix) SEQ ID NO: 21 and SEQ ID NO: 45, or (xx) SEQ ID NO: 22 and SEQ ID NO: 46, or (xxi) SEQ ID NO: 23 and SEQ ID NO: 47, or (xxii) SEQ ID NO: 24 and SEQ ID NO: 48, or (xxiii) SEQ ID NO: 25 and SEQ ID NO: 49, or (xxiv) SEQ ID NO: 26 and SEQ ID NO: 50.

[0068] In some embodiments, sometimes preferred embodiments, an antibody molecule that specifically binds to FcγRIIb comprises the following CDR regions: SEQ ID NO: 171 (CDRH1), SEQ ID NO: 172 (CDRH2), SEQ ID NO: 173 (CDRH3), SEQ ID NO: 174 (CDRL1), SEQ ID NO: 175 (CDRL2), and SEQ ID NO: 176 (CDRL3), i.e., the CDR regions of clone 6G11.

[0069] In some embodiments, sometimes preferred embodiments, an antibody molecule that specifically binds to FcγRIIb comprises the following constant regions: SEQ ID NO:1 (CH) and SEQ ID NO:2 (CL), and the following variable regions: SEQ ID NO:23 (VL) and SEQ ID NO:47 (VH), i.e., the constant and variable regions of clone 6G11, which are further modified to reduce binding to Fcγ receptors via their Fc region. In some embodiments, sometimes preferred embodiments, an antibody molecule that specifically binds to FcγRIIb comprises the following constant regions: SEQ ID NO:195 (CH) and SEQ ID NO:2 (CL), and the following variable regions: SEQ ID NO:23 (VL) and SEQ ID NO:47 (VH), i.e., the constant and variable regions of clone 6G11 containing the N297Q mutation.

[0070] In the first to seventh aspects, as defined herein, the second antibody molecule specifically binds PD-1 or PD-L1. The third antibody molecule as defined herein specifically binds CTLA-4 and binds to at least one Fcγ receptor via its Fc region. In some embodiments, the antibody molecule that specifically binds PD-1 also binds to at least one Fcγ receptor via its Fc region. In some embodiments, the antibody molecule that specifically binds PD-L1 also binds to at least one Fcγ receptor via its Fc region.

[0071] The second antibody molecule can specifically bind to Programmed Death-Ligand 1 (PD-L1), also known as CD274 or B7 Homolog 1 (B7-H1).

[0072] In some embodiments, an antibody molecule that specifically binds to PD-L1 is selected from one or more of the following non-limiting examples of anti-PD-L1 antibodies: Atezolizumab (currently approved for use), Durvalumab (currently approved for use), Avelumab (currently approved for use), CS1001 (currently in clinical development), KN035 (embafolimab), a PD-L1 antibody with a subcutaneous formulation currently undergoing clinical evaluation in the United States, China, and Japan; CK-301 (currently in clinical development by Checkpoint Therapeutics)

[0073] In preferred embodiments, the antibody that specifically binds to PD-L1 is atezolizumab, durvalumab, or avelumab, hi some embodiments, the antibody that specifically binds to PD-L1 is a combination of two or more of these antibodies.

[0074] In alternative or additional embodiments, the second antibody molecule is capable of specifically binding to programmed cell death protein 1 (PD1), also known as CD279.

[0075] In some embodiments, an antibody molecule that specifically binds to PD-1 is selected from one or more of the following non-limiting examples of anti-PD-1 antibodies: Pembrolizumab (currently approved for use), Nivolumab (currently approved for use), Cemiplimab (currently approved for use), Camrelizumab (currently approved for use), Spartalizumab (currently in clinical development), Dostarlimab (currently in clinical development), -Tislelizumab (currently in clinical development), JTX-4014 (currently in clinical development), Sintilimab (IBI308) (currently in clinical development), Toripalimab (JS001) (currently in clinical development), AMP-224 (currently in clinical development), ·AMP-514 (MEDI0680) (currently in clinical development).

[0076] In preferred embodiments, the antibody that specifically binds to PD-1 is pembrolizumab, nivolumab, cemiplimab, or camrelizumab. In some embodiments, the antibody that specifically binds to PD-1 is a combination of two or more of these antibodies. In preferred embodiments, the antibody that specifically binds to PD-1 is pembrolizumab.

[0077] The third antibody molecule specifically binds to CTLA-4. CTLA-4, an abbreviation for cytotoxic T-lymphocyte-associated protein 4, is also known as CD152. It is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA4 is constitutively expressed in regulatory T cells, but is only upregulated in normal T cells after activation - a notable phenomenon, especially in cancer. In some embodiments, the third antibody molecule is ipilimumab (such as Yervoy® from Bristol-Myers Squibb). In some embodiments, the third antibody molecule is tremelimumab (CP-675,206, formerly known as ticilimumab), a fully human monoclonal antibody against CTLA-4, previously under development by Pfizer and currently in clinical development by MedImmune. In a preferred embodiment, the antibody that specifically binds to CTLA-4 is ipilimumab.

[0078] The checkpoint inhibitory receptors CTLA-4 and PD-1 / PD-L1 function to limit T cell activation and proliferation and are therefore important in controlling immune homeostasis and preventing reactions against self. At the same time, tumors can evade immune attacks by releasing soluble factors or through cognate interactions to upregulate and / or engage these inhibitory immune receptors that limit T cell activation and proliferation. For example, tumors in response to interferon-gamma exposure can upregulate PD-L1, which upon ligation of the PD-1 molecule (on effector T cells) reduces effector T cell activation, proliferation, and ultimately effector T cell-mediated antitumor immunity. The release of other factors from tumors (e.g., cytokines or chemokines), along with upregulation of immunosuppressive receptors, may promote the maturation of, for example, tumor-associated macrophages, myeloid-derived suppressor cells, or T regulatory cells, and upon ligation of CTLA-4 or PD-1 to effector T cells, may limit T cell proliferation and activation and reduce T cell-mediated antitumor immunity. Thus, one mechanism by which antibodies against CTLA-4, PD-1, and PD-L1 may increase antitumor activity is by blocking the interaction of CTLA-4 and / or PD-1 with their natural ligands and the associated inhibitory signaling in effector T cells, which may be CD8+ or CD4+.

[0079] In contrast, FcγRs regulate the therapeutic activity of antibodies against CTLA-4, PD-1, and PD-L1 in different ways: the therapeutic activity of anti-CTLA-4 antibodies is enhanced by their engagement of FcγRs [18, 21], whereas the activity of anti-PD-1 antibodies is hindered by FcγR engagement [19, 20] and published patent application WO2021 / 009358. Context-dependent enhancement of the therapeutic activity of anti-PD-L1 antibodies by FcγRs in the tumor microenvironment has been described

[19]

[22] .

[0080] Although the mechanisms governing FcγR modulation, particularly for anti-PD-1 and anti-PD-L1 antibodies, have not been fully characterized, available data suggest that FcγR engagement is beneficial for antibodies with targets that are expressed sufficiently highly on immune suppressor cells but not on immune effector cells to trigger FcγR-mediated target cell depletion. For example, CTLA-4 is highly expressed and more highly expressed on intratumoral Tregs compared to effector T cells. Thus, in FcγR-humanized mice, FcγR-engaged anti-CTLA-4 antibodies (e.g., of human IgG1 isotype) efficiently depleted Tregs but not CD8+ effector cells

[18] . Further consistent with a positive role for FcγRs in the therapeutic activity of anti-CTLA-4 antibodies, melanoma patients harboring a high-affinity SNP in FcγRIIIa showed improved survival compared with patients expressing the low-affinity SNP when treated with ipilimumab, a human FcγR-engaging IgG1 anti-CTLA-4 antibody.

[0081] Conversely, PD-1 is highly expressed on effector CD8+ T cells

[19] , including human intratumoral CD8+ T cells (see, e.g., published patent application WO2021 / 009358), and may be more highly expressed on effector compared to (immunosuppressive) Treg cells

[19] . FcγRs have been shown to reduce the efficacy of anti-PD-1 antibodies in vivo, whether by the mechanism of FcγR-dependent depletion of PD-1 expressing antibody-coated CD8+ T cells

[19] , or FcγR-dependent transfer of anti-PD-1 antibodies from CD8+ T cells to tumor-associated macrophages

[20] . Relevance to the human clinical setting is provided by in vitro mechanistic studies with the clinically relevant nivolumab and pembrolizumab anti-PD-1 antibodies, human FcγR-expressing macrophages, and human T cells expressing PD-1 at levels relevant to the human tumor environment ([ 20 ] and published patent application WO2021 / 009358 ).

[0082] The second antibody molecule is also capable of binding to at least one Fcγ receptor via its Fc region. The third antibody molecule binds to at least one Fcγ receptor via its Fc region.

[0083] As discussed above, Fcγ receptors are present on immune effector cells. At least one Fcγ receptor may be present on the same immune effector cell as the FcγRIIb to which the first antibody molecule binds, and / or it may be an Fcγ receptor present on a different immune effector cell.

[0084] Immune effector cells may include, but are not limited to, macrophages, neutrophils, monocytes, natural killer (NK) cells, basophils, eosinophils, mast cells, platelets, cytotoxic T cells, and memory T cells. In some preferred embodiments, the immune effector cells are macrophages.

[0085] In some embodiments, the second antibody molecule and / or the third antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin.

[0086] In some further or alternative embodiments, the second antibody molecule and / or the third antibody molecule are monoclonal or monoclonal-derived antibody molecules.

[0087] In some further or alternative embodiments, the second antibody molecule and / or the third antibody molecule is selected from the group consisting of a full size antibody, a chimeric antibody, a single chain antibody, and an antigen-binding fragment thereof that retains the ability to bind to an Fcγ receptor via its Fc region.

[0088] In some further or alternative embodiments, the second antibody molecule and / or the third antibody molecule is a human IgG antibody, a humanized IgG antibody molecule, or an IgG antibody molecule of human origin.

[0089] The Fcγ receptor specifically bound by the Fc region of the third antibody molecule (and in some embodiments the second antibody molecule) can in some preferred embodiments be an activating Fcγ receptor as described herein, which can activate the function of effector cells, thereby inducing mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), cytokine release, and / or antibody-dependent endocytosis, and in the case of neutrophils, NETosis (i.e., activation and release of NETs (neutrophil extracellular traps)). Antibodies that bind to activating Fcγ receptors can also lead to an increase in certain activation markers, such as CD40, MHCII, CD38, CD80, and / or CD86.

[0090] In some embodiments, the second antibody molecule and / or the third antibody molecule are engineered to improve binding to activating Fc gamma receptors. For example, to enable binding to activating Fc gamma receptors, the Fc region of the second antibody molecule and / or the third antibody may be glycosylated at position 297 in some embodiments. Carbohydrate residues at this position are useful for binding to Fc gamma receptors. In some embodiments, these residues are preferably biantennary carbohydrates including GlnNAc, mannose, with terminal galactose residues and sialic acid. They should include the CH2 portion of the Fc molecule. In a preferred embodiment, the second antibody molecule is engineered to specifically bind PD-L1 and improve binding to activating Fc gamma receptors.

[0091] In other embodiments, the second antibody may be engineered to reduce binding to FcγR, such as the anti-PD-1 antibody tislelizumab (Beigene; IgG4 S228P, E233P, F234V, L235A, D265A, R409K) and / or the anti-PD-L1 antibody atezolizumab (Roche / Genentech; IgG1 N297A).

[0092] The combination of the first, second, and third antibody molecules described herein can be used in the treatment of cancer in a patient.

[0093] It will be understood that the pharmaceutical compositions and kits comprising the first, second, and third antibody molecules disclosed herein are also suitable for use in the treatment of cancer in a patient, and the following embodiments apply to such uses of the pharmaceutical compositions and kits disclosed herein.

[0094] The term "patient" (or "subject"), as used herein, refers to an animal, including a human, diagnosed with cancer or identified as likely to have cancer and / or exhibiting symptoms of cancer. Cancer includes FcγRIIb-negative cancer or cancer considered likely to be FcγRIIb-negative cancer. Cancer also includes FcγRIIb-positive cancer or cancer considered likely to be FcγRIIb-positive cancer.

[0095] The patient may be a mammal or a non-mammal. Preferably, the patient is a human or a mammal such as a horse, cow, sheep, pig, camel, dog, or cat. Most preferably, the mammalian patient is a human.

[0096] "Exhibiting" includes that the subject exhibits cancer symptoms and / or cancer diagnostic markers and / or that the cancer symptoms and / or cancer diagnostic markers can be measured and / or assessed and / or quantified.

[0097] It will be readily apparent to one skilled in the art of medicine what cancer symptoms and cancer diagnostic markers are, and how to measure and / or assess and / or quantify whether there is a reduction or increase in the severity of a cancer symptom, or whether there is a reduction or increase in a cancer diagnostic marker, and how the cancer symptoms and / or cancer diagnostic markers can be used to form a prognosis for cancer.

[0098] Cancer treatments are often administered as a course of treatment, i.e., the therapeutic agents are administered over a period of time. The length of time for the course of treatment depends on several factors, including the type of therapeutic agent being administered, the type of cancer being treated, the severity of the cancer being treated, and the age and health of the patient, among other reasons.

[0099] In some embodiments, the cancer is an FcyRllb-positive B-cell cancer. "FcyRllb-positive cancer" includes any cancer that expresses FcγRIIB, even if at different levels. FcγRIIB expression is most prominent in chronic lymphocytic leukemia and mantle cell lymphoma, moderate in diffuse large B-cell lymphoma, and least prominent in follicular lymphoma. However, in some cases, subjects with cancers that generally express low levels of FcyRIIB (e.g., follicular lymphoma) may have very high levels of FcγRIIB expression. The expression levels of FcγRIIB in different types of B-cell cancers (especially those mentioned above) correlate with the internalization rate of the antibody molecule rituximab. Thus, the expression of FcyRIIB and the associated internalization of the antibody molecule are believed to be a common mechanism shared by B-cell cancers (Lim et al., 2011, Blood, 118(9):2530-40). FcyRIIB-dependent reprogramming of antibody molecules can be blocked by antibodies to FcyRIIB disclosed herein.

[0100] Thus, the antibody combinations disclosed herein can be used in the treatment of B-cell cancers, in particular relapsed and / or refractory mantle cell lymphoma, and / or relapsed and / or refractory follicular lymphoma, and / or relapsed diffuse large B-cell lymphoma and / or refractory diffuse large B-cell lymphoma.

[0101] In some other embodiments, which may be more preferred, the cancer is an FcγRIIb-negative cancer. "FcγRIIb-negative cancer" includes any cancer that does not present any FcγRIIb receptor. This can be examined by a variety of methods, including immunohistochemistry and flow cytometry, as shown in Tutt et al, J Immunol, 2015, 195(11) 5503-5516, using anti-FcγRIIB specific antibodies.

[0102] In some preferred embodiments, the cancer is selected from the group consisting of carcinoma, sarcoma, and lymphoma.

[0103] In some embodiments, the cancer is a carcinoma selected from the group consisting of adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, poorly differentiated or undifferentiated carcinoma, large cell carcinoma, and small cell carcinoma.

[0104] In some embodiments, the cancer is a sarcoma selected from the group consisting of osteosarcoma, chondrosarcoma, liposarcoma, and leiomyosarcoma.

[0105] The FcγRIIb negative cancer may be selected from the group consisting of melanoma, breast cancer, ovarian cancer, cervical cancer, prostate cancer, metastatic hormone refractory prostate cancer, colorectal cancer, lung cancer, small cell lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer, urothelial cancer, bladder cancer, kidney cancer, mesothelioma, Merkel cell carcinoma, head and neck cancer, and pancreatic cancer.

[0106] In further or alternative embodiments, the cancers described herein are intended to include any cancer for which treatment with an antibody that specifically binds to CTLA-4 and / or PD-1 and / or PD-L1 is indicated, where "indicated" means that the antibody has been approved for use in the treatment of that cancer, or is in clinical trials for those cancers, or has been suggested (e.g., from in vivo animal models or in vitro studies) as potentially useful in the treatment of those cancers.

[0107] Each of the above cancers is well known and the symptoms and cancer diagnostic markers are well described, as are the therapeutic agents used to treat those cancers. Thus, the symptoms, cancer diagnostic markers, and therapeutic agents used to treat the above-mentioned types of cancer will be known to those skilled in the art of medicine.

[0108] The clinical definition of diagnosis, prognosis, and progression of many cancers depends on a specific classification known as staging. These staging systems work by collating several different cancer diagnostic markers and cancer symptoms to provide an overview of the diagnosis and / or prognosis and / or progression of cancer. Those skilled in the oncology field will know how to use the staging systems to assess the diagnosis and / or prognosis and / or progression of cancer, and which cancer diagnostic markers and cancer symptoms to use to do so.

[0109] "Cancer staging" includes the Rai staging system, including stage 0, stage I, stage II, stage III, and stage IV; and / or the Binet staging system, including stage A, stage B, and stage C; and / or the Ann Arbour staging system, including stage I, stage II, stage III, and stage IV.

[0110] It is known that cancer can cause abnormalities in cell morphology. These abnormalities often occur reproducibly in certain cancers, meaning that examination of these changes in morphology (also known as histological examination) can be used to diagnose or prognose cancer. Techniques for visualizing and preparing samples for visualization to examine cell morphology, such as light microscopy or confocal microscopy, are well known in the art.

[0111] "Histological examination" includes the presence of small mature lymphocytes and / or small mature lymphocytes with narrow cytoplasmic borders, the presence of small mature lymphocytes with dense nuclei lacking discernible nucleoli and / or the presence of small mature lymphocytes with narrow cytoplasmic borders and dense nuclei lacking discernible nucleoli, and / or the presence of atypical cells and / or cleaved cells and / or prolymphocytes.

[0112] It is well known that cancer is the result of mutations in the DNA of cells, which allow cells to avoid cell death or grow uncontrollably. Therefore, testing for these mutations (also known as cytogenetic testing) can be a useful tool for evaluating the diagnosis and / or prognosis of cancer. An example of this is the deletion of chromosomal location 13q14.1, which is a hallmark of chronic lymphocytic leukemia. Techniques for testing cell mutations, such as fluorescent in situ hybridization (FISH), are well known in the art.

[0113] "Cytogenetic testing" includes testing of the DNA of cells (particularly chromosomes). Cytogenetic testing can be used to identify DNA alterations that may be associated with the presence of refractory and / or recurrent cancer. These may include: deletion of the long arm of chromosome 13, and / or deletion at chromosomal location 13q14.1, and / or trisomy of chromosome 12, and / or deletion of the long arm of chromosome 12, and / or deletion of the long arm of chromosome 11, and / or deletion of 11q, and / or deletion of the long arm of chromosome 6, and / or deletion of 6q, and / or deletion of the short arm of chromosome 17, and / or deletion of 17p, and / or t(11:14) translocation, and / or (q13:q32) translocation, and / or antigen gene receptor rearrangement, and / or BCL2 rearrangement, and / or BCL6 rearrangement, and / or t(14:18) translocation, and / or t(11:14) translocation, and / or (q13:q32) translocation, and / or (3:v) translocation, and / or (8:14) translocation, and / or (8:v) translocation, and / or t(11:14) and (q13:q32) translocations.

[0114] Cancer patients are known to exhibit certain physical symptoms, which are often the result of the burden that cancer places on the body. These symptoms often recur with the same cancer, and therefore may be characteristic of the diagnosis and / or prognosis and / or progression of the disease. Those skilled in the art of medicine will understand which physical symptoms are associated with which cancers, and how the evaluation of these body systems may correlate with the diagnosis and / or prognosis and / or progression of the disease. "Physical symptoms" include hepatomegaly and / or splenomegaly.

[0115] The combinations, uses, methods, pharmaceutical compositions, and kits described herein are useful for treating cancers that are resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4.

[0116] By "resistant to treatment" it is meant that a patient has a reduced level of responsiveness to treatment with an antibody molecule that specifically binds PD-1 or PD-L1, and / or an antibody molecule that specifically binds CTLA-4, compared to a previous or expected level of responsiveness, or compared to the level of responsiveness seen when treating other types of cancer. This includes situations where the patient has previously been treated with the antibody molecule (i.e., the patient has developed resistance), as well as situations where the patient has never been treated with the antibody molecule (i.e., the patient is inherently resistant).

[0117] Resistance to therapy can be measured in a variety of ways, for example, by monitoring patients to ensure that the cancer is regressing as expected and by identifying patients who do not respond to therapy at all. Resistance to therapy can be measured, for example, using immunoscore tests, as known in the art and described herein.

[0118] "Resistant to treatment" also includes cancer types for which treatment with antibodies that specifically bind PD-1, and / or PD-L1, and / or CTLA-4 has not yet been indicated, for example, where it has previously been found that these antibodies (or combinations of antibodies) have no measurable therapeutic effect.

[0119] Also included are cancers that may have a low tumor mutational burden (TMB). "Tumor mutational burden" refers to the number of genetic mutations in cancer cells. Such measurements can be determined by clinical tests known in the art. It is known that cells with high TMB are more likely to be recognized as abnormal and attacked by the immune system, and high TMB has been identified as a response biomarker for PD-1 / PD-L1 blockade (Goodman et al., 2017, Mol Cancer Ther., 16(11):2598-2608). Thus, cancers with low TMB may be successfully targeted with the combinations of the present invention, which can enhance the effects of such immune-blocking antibodies as described above. Multiple biomarkers have previously been associated with immune checkpoint inhibitor ("CPI") response, which can be broadly classified into the following categories: i) sources of antigens that trigger T cell responses, ii) mechanisms of immune evasion that drive resistance, and iii) markers of immune infiltration. Additional factors controlling response to immune checkpoint blockade and antibody-based cancer immunotherapy, and conversely, lack of response and resistance, have been described and are continually being identified. For example, a recent systematic pan-tumor analysis including Collat ​​whole-exome and transcriptome data from over 1000 CPI-treated patients across eight tumor types, utilizing a standardized bioinformatics workflow and clinical outcome measures to validate multivariate predictors of CPI sensitization, identified clonal TMB as the strongest predictor of CPI response, followed by TMB and CXCL9 expression

[23] . Discovery analysis identified two additional determinants of CPI response supported by prior functional evidence: 9q34.3 (TRAF2) loss and CCND1 amplification, both independently validated in over 1600 CPI-treated patients. Furthermore, scRNA sequencing of clonal neoantigen-reactive CD8-TILs, combined with bulk RNAseq analysis of CPI-responsive tumors, identified CCR5 and CXCL13 as T cell-intrinsic mediators of CPI sensitization.

[0120] Those skilled in the art will appreciate that new markers of response potential, and conversely, lack of response and resistance, are continually being identified and may be related, for example, to the source of antigen eliciting a T cell response, mechanisms of immune evasion driving tolerance, and markers of immune infiltration, as recently described and discussed

[23] .

[0121] It will be appreciated that in some embodiments, the cancer that is resistant to treatment may be a recurrent cancer and / or a refractory cancer.

[0122] A recurrent cancer is one that has been previously treated and that resulted in the subject's complete or partial recovery (i.e., the subject is said to be in remission), but that returns or worsens after the treatment is stopped. In other words, a recurrent cancer is one that has become resistant to a treatment after a period during which it was effective and the subject had a complete or partial recovery.

[0123] A refractory cancer is a cancer that has been treated but has not responded to the treatment and / or has been treated but has progressed during the treatment. In other words, a refractory cancer is a cancer that is resistant to treatment.

[0124] It will be appreciated that a cancer may be a refractory cancer due to inherent resistance, which includes the meaning that the cancer, and / or the subject, and / or the target cells are resistant to a particular treatment from the time it is first administered or even before it is administered.

[0125] It will be understood that the cancer may be a cancer that has relapsed due to acquired resistance, or a relapsed cancer and a refractory cancer. "Acquired resistance" includes that the cancer and / or subject and / or target cells were not resistant to a particular treatment prior to the first administration, but have become resistant after or during at least the first administration of the treatment (e.g., after the treatment has been administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 times).

[0126] Recurrent and / or refractory cancers may be readily diagnosed by one of ordinary skill in the medical arts.

[0127] The present invention may be particularly useful in the treatment of cancers that are typically not well targeted by the immune system (also known in the art as "cold tumours"). Such cold tumours can be divided into the following types: - immune deserted tumour: i.e. there is a complete lack of immune response in the tumour due to the absence of tumour infiltrating T cells. - immune excluded tumour: i.e. responsive T cells are generated but are unable to penetrate the tumour to mount a response against it. T cells may be present in the vicinity of the tumour. Tumors with poor immune infiltration: i.e., the level of infiltration of immune cells (T cells) into the tumor microenvironment is reduced or eliminated.

[0128] Methods for identifying and / or classifying such tumors will be known to those of skill in the art. For example, immunohistochemistry can be used to detect the presence or absence of CD8+ T cells within a tumor, and such approaches (albeit with different cutoffs and reagents) can be used to generate an "immunoscore."

[0129] Cancers that may fall into these "non-invasive tumor" subtypes include, but are not limited to, melanoma, pancreatic cancer, prostate cancer, colon cancer, hepatocellular carcinoma, lung cancer, bladder cancer, renal cancer, gastric cancer, cervical cancer, Merkel cell carcinoma, or ovarian cancer.

[0130] Thus, the present invention may be particularly useful in combating resistance to anti-CTLA-4, anti-PD1, and / or anti-PD-L1 therapy in patients with these types of tumors through the simultaneous blockade of FcγRIIb and enhanced activation of immune effector cells and, consequently, enhanced therapeutic efficacy of the second and / or third antibody molecules.

[0131] In some embodiments, a patient who is resistant to treatment with an antibody molecule that specifically binds PD-1 or PD-L1, and / or an antibody molecule that specifically binds CTLA-4 has previously been treated with an antibody molecule that specifically binds PD-1 or PD-L1, and / or an antibody molecule that specifically binds CTLA-4, and optionally the patient has become resistant following that treatment.

[0132] This embodiment includes the situation where the patient has previously been treated with a first antibody that specifically binds PD-1, and the second antibody molecule of the invention is a second antibody that specifically binds PD-1 (i.e., the second antibody molecule of the invention is different from the anti-PD-1 antibody previously used to treat the patient). In some alternative embodiments, the antibody that specifically binds PD-1 previously used to treat the patient is the same as the second antibody molecule of the invention that specifically binds PD-1.

[0133] This embodiment also includes the situation where the patient has previously been treated with a first antibody that specifically binds PD-L1, and the second antibody molecule of the invention is a second antibody that specifically binds PD-L1 (i.e., the second antibody molecule of the invention is different from the anti-PD-L1 antibody previously used to treat the patient).In some alternative embodiments, the antibody that specifically binds PD-L1 previously used to treat the patient is the same as the second antibody molecule of the invention that specifically binds PD-L1.

[0134] This embodiment also includes the situation where the patient has previously been treated with a first antibody that specifically binds to CTLA-4, and the third antibody molecule of the invention is a third antibody that specifically binds to CTLA-4 (i.e., the third antibody molecule of the invention is different from the anti-CTLA-4 antibody previously used to treat the patient). In some alternative embodiments, the antibody that specifically binds to CTLA-4 previously used to treat the patient is the same as the third antibody molecule of the invention that specifically binds to CTLA-4.

[0135] As discussed above, in some alternative embodiments, the patient has not been previously treated with an antibody molecule that specifically binds PD-1 or PD-L1 and / or an antibody molecule that specifically binds CTLA-4, in which embodiment the patient may be essentially resistant to such treatment.

[0136] In some embodiments, patients who may benefit from treatment with a combination of a first antibody molecule, a second antibody molecule, and a third antibody molecule as defined herein may be identified using an immunoscore test to determine whether a tumor is positive or negative for a particular target antigen, in this case CTLA-4 and / or PD-1 and / or PD-L1. Such a determination may be made by histological staining of the antigen in question, and if the percentage of cells expressing that antigen is above a predefined cutoff value (either by total or partial staining), the sample is described as positive. Such scoring is referred to as the Tumor Proportion Score (TPS). The TPS may be used to predict whether a patient will respond to a monoclonal antibody therapy targeting that antigen.

[0137] For example, for antibody molecules targeting PD-1 or PD-L1, it has been established that a sample is considered PD-L1 positive (for viable tumor cells showing membrane staining of any intensity) if the TPS is determined to be 50% or greater. See, e.g., FDA-approved tests at https: / / www.accessdata.fda.gov / cdrh_docs / pdf15 / P150013B.pdf.

[0138] Thus, to determine patients who may benefit from treatment with a combination of the first, second, and third antibody molecules defined herein, it may be advantageous to identify patients who have been determined to be PD-L1 negative (i.e., patients with less than 1%-50% viable tumor cells stained for PD-L1) using the tests described above. This group of patients is unlikely to respond to therapy with anti-PD-1 or anti-PD-L1 antibodies alone (or in combination with an antibody targeting CTLA-4), but are more likely to respond to the combination therapy described herein for the reasons described above. Thus, in some embodiments, patients as defined herein are defined as PD-L1 negative using established diagnostic tests or IHC methods. Such tests may include immunoscore tests (known in the art and discussed herein) to detect and assess the percentage of immune cells and / or tumor cells that are positive for a particular marker, such as PD-L1. Those skilled in the art will appreciate that similar tests can be performed to determine a patient's CTLA-4 status. Additionally, using similar methodologies, tumors can be analyzed for the status of T cells and additional tumor infiltrating lymphocytes to indicate whether a tumor is "hot" inflammatory T cell or "cold" immune excluded or abandoned, and whether a particular patient is resistant to anti-PD-1 / L1 and / or anti-CTLA-4 immune checkpoint blockade (but may respond to combination treatments disclosed herein).

[0139] In some additional or alternative embodiments, patients who may benefit from treatment with a combination of a first antibody molecule, a second antibody molecule, and a third antibody molecule as defined herein may be identified by immunohistochemistry to determine whether the number of immune cells infiltrating the tumor is reduced, where "reduced" means that the number of infiltrating immune cells (e.g., T cells) in the tumor is lower than would be expected for a normal tumor in which immune infiltration is observed.

[0140] The use of such tests is particularly advantageous in situations where patients have not previously been treated with antibodies specific for PD-1, PD-L1, or CTLA-4. In this case, the standard tests described above would classify many patients as non-responsive to these treatments, which may not be used. The present invention can expand the potential use of these treatments to patient groups previously thought to be non-responsive.

[0141] In some embodiments, a first antibody molecule that specifically binds to FcγRIIb, and a second antibody molecule, and / or a third antibody molecule are administered to a patient simultaneously, meaning that they are administered together at the same time or separately within a very close time period of each other.

[0142] In some embodiments, the antibody molecule that specifically binds FcγRIIb is administered to the patient prior to administration of the second antibody molecule, hi some embodiments, the antibody molecule that specifically binds FcγRIIb is administered to the patient prior to administration of the third antibody molecule.

[0143] Such sequential administration can be achieved by separating the antibodies in time. Alternatively, or in combination with the first option, sequential administration can also be achieved by spatial separation of the antibody molecules. An antibody molecule that specifically binds to FcγRIIb is administered by a method such as intratumoral administration so that it reaches the cancer before the second and / or third antibody molecule, and then an antibody molecule is administered by a method such as systemic administration so that it reaches the cancer after the antibody molecule that specifically binds to FcγRIIb.

[0144] In some embodiments, the second antibody molecule is administered to the patient prior to administration of the antibody molecule that specifically binds FcγRIIb. In some embodiments, the third antibody molecule is administered to the patient prior to administration of the antibody molecule that specifically binds FcγRIIb.

[0145] For example, it will be known to those skilled in the art of medicine that drugs can be modified with different additives to alter the rate at which they are absorbed by the body, and can be modified in different forms, for example to allow for particular routes of administration to the body.

[0146] Thus, the antibodies and compositions described herein include those which may be combined with an excipient, and / or a pharma- ceutically acceptable carrier, and / or a pharma- ceutically acceptable diluent, and / or an adjuvant.

[0147] The combinations, and / or compositions, and / or antibodies, and / or drugs of the invention include those which may be suitable for parenteral administration, including aqueous and / or non-aqueous sterile injection solutions, which may contain antioxidants, and / or buffers, and / or bacteriostats, and / or solutes which render the formulation isotonic with the blood of the intended recipient, and / or aqueous and / or non-aqueous sterile suspensions which may contain suspending agents and / or thickening agents. The combinations, and / or compositions, and / or antibodies, and / or drugs, and / or drugs of the invention may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (i.e. lyophilized) condition requiring only the addition of a sterile liquid carrier, for example water for injections, immediately prior to use.

[0148] Extemporaneous injection solutions and suspensions may be prepared from sterile powders and / or granules and / or tablets of the kind previously described.

[0149] For parenteral administration to human patients, the daily dosage level of the antibody molecule specifically binding to FcγRIIb, and / or the second antibody molecule, and / or the third antibody molecule is typically 1 mg / kg to 20 mg / kg (of patient body weight), or in some cases up to 100 mg / kg, administered in a single or divided dose. In some embodiments, the dose of the antibody molecule is 10 mg / kg, 3 mg / kg, or 1 mg / kg. Lower doses may be used under special circumstances, for example in combination with chronic administration. In any event, the physician will determine the actual dosage that will be most suitable for an individual patient, which will vary with the age, weight, and response of the particular patient. The dosages described above are exemplary of the average case. There may, of course, be individual cases in which higher or lower dosage ranges are merited, and are within the scope of the invention.

[0150] Typically, the composition and / or drug of the present invention will contain the antibody molecule that specifically binds to FcγRIIb and / or the second / third antibody at a concentration of about 2 mg / ml to 150 mg / ml, or about 2 mg / ml to 200 mg / ml. In a preferred embodiment, the drug and / or composition of the present invention will contain the antibody molecule that specifically binds to FcγRIIb and / or the second / third antibody molecule at a concentration of 10 mg / ml.

[0151] Generally, in humans, oral or parenteral administration of the compositions, and / or antibodies, and / or agents, and / or drugs of the invention is the preferred route and is the most convenient. For veterinary use, the compositions, and / or antibodies, and / or agents, and / or drugs of the invention are administered in a suitably acceptable formulation in accordance with normal veterinary practice, and the veterinarian will determine the dosing regime and route of administration that will be most appropriate for a particular animal. Thus, the invention provides pharmaceutical formulations comprising the antibodies and / or agents of the invention in an amount effective to treat various conditions (as described above and further below). Preferably, the compositions, and / or antibodies, and / or agents, and / or drugs are adapted for delivery by a route selected from the group including intravenous (IV), subcutaneous (SC), intramuscular (IM), or intratumoral. In some preferred embodiments, administration is intravenous.

[0152] In some embodiments, the first antibody molecule, and / or the second antibody, and / or the third antibody molecule may be administered through the use of a plasmid or a virus. Such a plasmid then comprises a nucleotide sequence encoding either the first antibody molecule, and / or the second antibody, and / or the third antibody molecule. In some embodiments, a nucleotide sequence encoding a portion or the complete sequence of the first antibody molecule, and / or the second antibody, and / or the third antibody molecule is incorporated into a cell or a viral genome or a viral virome, and such a cell or virus then acts as a delivery vehicle for the first antibody molecule, and / or the second antibody, and / or the third antibody molecule (or a delivery vehicle for a nucleotide sequence encoding the first antibody molecule, and / or the second antibody, and / or the third antibody molecule). For example, in some embodiments, such a virus may be in the form of a therapeutic oncolytic virus comprising a nucleotide sequence encoding at least one of the antibody molecules described herein. In some embodiments, such an oncolytic virus comprises a nucleotide sequence encoding a full-length human IgG antibody. Oncolytic viruses are known to those skilled in the art of medicine and virology.

[0153] The present invention also includes compositions comprising pharma- ceutically acceptable acid or base addition salts of the polypeptide binding moieties, and / or antibodies, and / or agents, and / or drugs. The acids used to prepare pharma- ceutically acceptable acid addition salts of the aforementioned base compounds useful in the present invention are, inter alia, those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate, [i.e., 1,1'-methylene-bis-(2-hydroxy-3 naphthoate)] salts. Pharmaceutically acceptable base addition salts may also be used to generate pharma-ceutically acceptable salt forms of the agents according to the invention. Chemical bases that may be used as reagents to prepare pharma-ceutically acceptable base salts of the agents, which are acidic in nature, are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts (e.g., N-methylglucamine-(meglumine) and lower alkanolammonium), and other pharma-ceutically acceptable organic amine base salts. The agents and / or polypeptide binding moieties of the invention may be lyophilized for storage and reconstituted in a suitable carrier prior to use. Any suitable lyophilization method (e.g., spray drying, cake drying) and / or reconstitution technique may be used. Those of skill in the art will understand that lyophilization and reconstitution may lead to varying degrees of loss of antibody activity (e.g., in conventional immunoglobulins, IgM antibodies tend to experience greater loss of activity than IgG antibodies) and usage levels may need to be adjusted upward to compensate.In one embodiment, a lyophilized (freeze-dried) polypeptide binding moiety, when rehydrated, loses about 20% or less, or about 25% or less, or about 30% or less, or about 35% or less, or about 40% or less, or about 45% or less, or about 50% or less of its activity (before lyophilization).

[0154] The present invention also generally relates to combinations comprising a first antibody and a second antibody as described herein in the eighth to fourteenth aspects of the invention.

[0155] In a further eighth aspect, the present invention provides the use of a first antibody molecule which specifically binds FcyRllb via its Fab region and lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region for treating cancer in a patient. The first antibody molecule is characterized in that it reduces and / or prevents resistance in the cancer to treatment with the second antibody molecule that specifically binds to CTLA-4. In one particular embodiment of this aspect, the dose of the antibody molecule that specifically binds to CTLA-4 is lower than the therapeutic dose.

[0156] In a ninth aspect, the present invention also provides a combination for use in the treatment of cancer in a patient comprising: - a first antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, The combination includes a dose of the second antibody molecule that is lower than the tolerated therapeutic dose.

[0157] In a tenth aspect, the present invention provides a method for the manufacture of a medicament for treating cancer in a patient, comprising: - a first antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, The combination includes a dose of the second antibody molecule that is lower than the tolerated therapeutic dose.

[0158] In an eleventh aspect, the present invention provides a method for treating cancer in an individual, the method comprising administering to a patient: a first antibody molecule which specifically binds to FcyRllb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, - administering a second antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, The dose of the second antibody molecule administered is lower than the tolerated therapeutic dose.

[0159] In a twelfth aspect, the present invention provides a first antibody for treating cancer in a patient, the first antibody specifically binds to FcyRllb via its Fab region and lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; - for use in combination with a second antibody molecule that specifically binds CTLA-4 and binds via its Fc region to at least one Fcγ receptor; A first antibody is provided in which the dose of the second antibody molecule used is lower than the tolerated therapeutic dose.

[0160] In a thirteenth aspect, the present invention provides a pharmaceutical composition comprising: a first antibody molecule which specifically binds to FcyRllb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, a second antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, The second antibody molecule is present at a dose that is lower than the tolerated therapeutic dose.

[0161] In a fourteenth aspect, the present invention provides a kit comprising: a first antibody molecule which specifically binds to FcyRllb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, a second antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, The second antibody molecule is present at a dose that is lower than the tolerated therapeutic dose.

[0162] As discussed above, the dosage of the second antibody according to the above embodiments may be lower or less than the tolerated therapeutic dose.

[0163] Thus, in the eighth to fourteenth aspects of the present invention, when a first antibody molecule is combined with a second antibody molecule, the second antibody molecule can be used at a lower, more tolerated dose, and the therapeutic effect is maintained or is greater, compared to when the second antibody is used alone at the same or a higher dose.

[0164] "Tolerated therapeutic dose" means any dose that is considered to be therapeutically active (i.e., produces a desired therapeutic effect in a patient or subject as defined herein) but is also considered to be tolerable (i.e., does not produce an unacceptable level of toxicity or side effects in the patient). One of skill in the art will appreciate that the dose selected will often be a compromise between achieving a therapeutic effect and not causing unacceptable toxicity to the patient.

[0165] "Therapeutically active" includes when a dose produces a desired therapeutic effect in a patient or subject. In the case of a second antibody molecule that specifically binds to CTLA-4 and binds to at least one Fcγ receptor via its Fc region, such a therapeutic effect can be a reduction in tumor volume in a patient.

[0166] "Therapeutic effect" includes all effects that are directly or indirectly attributable to the use of the treatment in question. This may be a measurable therapeutic effect, such as a reduction in tumor volume or a reduction in tumor size (e.g., as may be determined by CT scan). In other cases, this may be a more subjective effect, such as a reduction in the severity of symptoms reported by the patient. Measurement of therapeutic effect in cancer patients in response to administration of therapeutic antibodies is well known in the art. Furthermore, the survival level of a patient or group of patients over a given period of time is a surrogate readout of therapeutic effect.

[0167] In some cases, the dose lower than the tolerated therapeutic dose is lower than the recommended tolerated therapeutic dose. Those skilled in the art will recognize that for approved antibody therapeutics, a particular dose (typically expressed in mg / kg) is recommended for use in a particular patient group or in patients with a particular type of cancer. In many cases, the recommended therapeutic dose is described in the label or prescribing information of the approved antibody therapeutic. In other cases, it will be clear to those skilled in the art how to determine the recommended tolerated therapeutic dose using techniques known in the art.

[0168] In some other cases, the lower than tolerated therapeutic dose is lower than the calculated therapeutic dose, which may be calculated for a particular patient, i.e., based on the type of cancer, the stage of the cancer, the patient's weight, Body Mass Index (BMI), and other factors.

[0169] In some other cases, the dose that is lower than the tolerated therapeutic dose is lower than the maximum (or maximum approved) tolerated therapeutic dose, which means the highest dose that does not cause unacceptable side effects.

[0170] In some other cases, the lower tolerated therapeutic dose is lower than the minimum therapeutic dose (otherwise known as the minimum effective dose), which means the lowest dose believed to produce a measurable therapeutic effect in patients, as defined above.

[0171] In some other cases, the dose that is lower than the tolerated therapeutic dose is lower than the recommended tolerated therapeutic dose, which in some embodiments may include the recommended dose for an indication contained in the drug label.

[0172] Those skilled in the art will appreciate that the actual dosage values ​​of the acceptable therapeutic doses defined above will vary depending on the identity of the antibody that specifically binds to CTLA-4 and the patient in whom the combination is used or is suitable for use.

[0173] It will be understood that the recommended dose is the dose approved by a regulatory agency such as the FDA or EMEA. This dose is typically identified after review of both efficacy and tolerability data, often from late-stage placebo-controlled blinded trials and randomized clinical trials, which may include different dose levels. In cancer, the approved dose will have therapeutic benefit and exhibit acceptable toxicity. Throughout development (early to late-stage clinical trials), higher antibody doses may be found to be more effective, but may also be accompanied by unacceptable toxicity.

[0174] Generally, it will be clear to one of skill in the art how a particular acceptable therapeutic dose is defined for any particular antibody using dose escalation studies during clinical trials. For example, the acceptable therapeutic dose of ipilimumab, an exemplary antibody that specifically binds to CTLA-4, is set forth in the drug label (see FDA label for ipilimumab: https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2018 / 125377s094lbl.pdf).

[0175] As discussed herein, acceptable therapeutic doses of ipilimumab may be as follows: For unresectable or metastatic melanoma: 3 mg / kg intravenously over 90 minutes every 3 weeks for a total of 4 doses. For adjuvant melanoma: 10 mg / kg intravenously over 90 minutes every 3 weeks for four doses, followed by 10 mg / kg intravenously every 12 weeks for up to 3 years or until disease recurrence or unacceptable toxicity. For advanced renal cell carcinoma: Nivolumab 3 mg / kg intravenously over 30 minutes followed by ipilimumab 1 mg / kg intravenously over 30 minutes on the same day, every 3 weeks for up to 4 doses, then nivolumab 240 mg intravenously over 30 minutes every 2 weeks or 480 mg intravenously over 30 minutes every 4 weeks.

[0176] Thus, an acceptable therapeutic dose of ipilimumab may be, in some embodiments, 1 mg / kg, 3 mg / kg, or 10 mg / kg.

[0177] The acceptable therapeutic dose for an antibody that has not yet been approved may be based on the acceptable therapeutic dose of a similar antibody that is approved or has undergone extensive clinical trials.

[0178] By providing a combination of a first and second antibody as described in the preceding embodiment, where the second antibody is used at a dose lower than the tolerated therapeutic dose, the inventors have devised a way to achieve a similar or equivalent therapeutic effect when the same antibody targeting CTLA-4 is used in isolation at a much higher dose.

[0179] Using high doses of antibodies targeting CTLA-4 is generally undesirable from a tolerance standpoint. CTLA-4 is expressed by activated T cells and transmits an inhibitory signal to T cells, thereby downregulating T cell responses. Blocking CTLA-4 using therapeutic antibodies that specifically bind to CTLA-4 prevents this inhibitory signal, thereby activating more T cells that can target cancer. However, this mechanism is indiscriminate and can activate more T cells that target self-specific antigens not found on tumor cells, i.e., initiate an autoimmune response. It is therefore possible to alleviate problems associated with tolerance by reducing the dose of anti-CTLA-4 antibodies required to produce a therapeutic effect.

[0180] Using lower doses and achieving the same therapeutic effect can be achieved using a combination with a first antibody molecule that specifically binds FcyRllb via the Fab region and lacks an Fc region or has reduced binding to Fcγ receptors via the Fc region. The first antibody molecule blocks binding to the inhibitory FcyRllb, which in turn can activate effector immune cells (e.g., CD8 effector T cells) that can target cancer cells.

[0181] This is surprising because reducing the dose of an anti-CTLA-4 antibody would not be expected to provide the same therapeutic effect as using a much higher dose of the same antibody, particularly in patients who are resistant to or have developed resistance to, or who may develop resistance to, anti-CTLA-4 therapy.

[0182] Thus, using lower doses of antibody molecules that specifically bind to CTLA-4 is advantageous because using lower doses reduces the likelihood that patients will have problems related to tolerance (i.e., improved tolerance), toxicity, and unpleasant side effects. Also, the cost-effectiveness of the treatment is improved because less antibody is required for administration.

[0183] In some embodiments, continued use of lower doses of antibodies targeting CTLA-4 can reduce the risk of a subject developing resistance. Without being bound by theory, the inventors believe that combining enhanced Treg depletion (using a combination of the first and second antibody molecules described herein) with low-level blockade of inhibitory signaling in effector T cells can reduce and / or prevent resistance, for example, where intratumoral Treg depletion is better achieved and a more therapeutically effective mechanism of action occurs at lower (lower) anti-CTLA-4 doses.

[0184] Thus, the present invention makes it possible to extend the therapeutic window of an antibody specific for CTLA-4. By "therapeutic window" is meant the range of drug doses that can effectively treat a disease without toxic effects or tolerability problems. Thus, the present invention makes it possible to use lower doses of an anti-CTLA-4 antibody, achieving the same or similar therapeutic effect while reducing the possibility of adverse effects due to the lower dose.

[0185] In some embodiments, the dosage of the second antibody molecule can be expressed as a percentage of the tolerated therapeutic dose as defined herein. In some embodiments, the dosage of the second antibody is at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% lower than the tolerated therapeutic dose of the second antibody molecule. In some preferred embodiments, the dosage of the second antibody is at least 50% lower than the tolerated therapeutic dose of the second antibody. In some other preferred embodiments, the dosage of the second antibody is at least 70% lower than the tolerated therapeutic dose of the second antibody.

[0186] In some preferred embodiments, the dose of the second antibody is at least 80% lower (ie, 80% or less) than the tolerated therapeutic dose of the second antibody.

[0187] As discussed above, in some embodiments, the result of using the second antibody molecule at a dose lower than the tolerated therapeutic dose is that the therapeutic effect of the first antibody molecule and the second antibody molecule used at the lower dose is comparable to the therapeutic effect of the second antibody molecule at the maximum tolerated therapeutic dose of the second antibody molecule in the absence of the first antibody molecule, which effect would be readily determined by one of skill in the art, as discussed above with respect to the meaning of therapeutic effect.

[0188] Also, as discussed above, using a second antibody molecule at a dose lower than the tolerated therapeutic dose can, in some embodiments, improve the tolerance of the second antibody molecule in a subject.

[0189] As used herein, the term "tolerability" refers to the degree to which an adverse effect of a therapeutic agent can be tolerated by a subject. An "adverse effect" includes any effect caused directly or indirectly by a therapeutic agent that is not the desired therapeutic effect, or any other beneficial effect that is attributable directly or indirectly to a therapeutic agent.

[0190] In the context of a second antibody that specifically binds CTLA-4, these side effects may include one or more of infusion-related reactions (IRR), fatigue, diarrhea, enterocolitis, nausea, vomiting, pruritus, rash, colitis, cough, headache, unintentional weight loss, decreased appetite, insomnia, fever, hepatitis, dermatitis, immune-mediated neuropathy, and immune-mediated endocrinopathies.

[0191] Tolerance problems can be of different grades (i.e. different severity) for the patients who experience them. They can result in discomfort for the patient or they can cause serious problems that prevent the continuation of treatment with the therapeutic antibody molecule. In severe cases, toxicities can manifest as: Intestinal disorders (colitis) that can cause tears or holes (perforations) in the intestine, liver damage (hepatitis) which can lead to liver failure, Skin disorders that may cause severe skin reactions, Nerve damage that can lead to paralysis, Disorders of the hormonal glands (especially the pituitary, adrenal and thyroid glands), Lung problems (pneumonia), Kidney problems, including nephritis and renal failure, Inflammation of the brain (encephalitis), In the worst case, tolerability issues may even lead to patient death.

[0192] It will be appreciated that the most severe types of tolerance problems are not acute, but rather take time to manifest (days to weeks) (consistent with the immune system requiring up to two weeks to mount a specific T cell-mediated immune response) and include gastrointestinal perforation.

[0193] A tolerability issue that may be improved as described herein are the adverse events that may arise in association with intravenous administration of a therapeutic antibody molecule to a subject.

[0194] In some embodiments, using a dose of the second antibody that is lower than the tolerated therapeutic dose reduces side effects and / or reduces toxicity in the subject associated with use of the second antibody molecule.

[0195] "Side effects" include any of the "adverse effects" caused by a therapeutic agent discussed above in relation to tolerability. Reducing the dose of a therapeutic antibody is known to reduce the associated side effects, but it is also known that this reduces the therapeutic effect (for ipilimumab, see Wolchok et al., 2010, Lancet Oncol., 11(2):155-164).

[0196] "Toxicity" refers to the degree to which a therapeutic substance can cause damage to an organism. Those skilled in the art will understand that toxicity and tolerability are interrelated and both depend on the dose administered.

[0197] In the case of the therapeutic antibodies discussed herein, accumulation of large amounts of therapeutic antibodies in the body can result in toxicity, and therefore it is advantageous to administer lower doses of the antibody therapeutic to minimize any problems associated with toxicity.

[0198] In some other embodiments, using a dose of the second antibody that is lower than the tolerated therapeutic dose may reduce any off-target effects and / or autoimmune responses in the subject associated with the use of the second antibody molecule.

[0199] As described herein, the second antibody molecule specifically binds to CTLA-4 and binds to at least one Fcγ receptor via its Fc region. CTLA-4 is constitutively expressed in regulatory T cells, but increases only in conventional T cells after activation - a notable phenomenon, especially in cancer. In some embodiments, the second antibody molecule is ipilimumab (such as Yervoy® from Bristol-Myers Squibb). In some embodiments, the second antibody molecule is tremelimumab (CP-675,206, formerly known as ticilimumab), a fully human monoclonal antibody against CTLA-4, previously under development by Pfizer and currently in clinical development by MedImmune.

[0200] Thus, in some embodiments, the second antibody molecule is ipilimumab. Those skilled in the art will understand that the standard acceptable therapeutic dose of ipilimumab can be determined from the approved drug label. In some embodiments, when the second antibody molecule is ipilimumab, the acceptable therapeutic dose is 10 mg / kg. Thus, the dose of the second antibody that is lower than the acceptable therapeutic dose is any dose that is lower than 10 mg / kg. In this case, the treatment can be adjuvant therapy, i.e., adjuvant therapy for the treatment of cancer that has already been treated with one or more first-line treatments (e.g., surgery).

[0201] In some embodiments, when the second antibody molecule is ipilimumab, the acceptable therapeutic dose is 3 mg / kg. Thus, a dose of the second antibody that is lower than the acceptable therapeutic dose is any dose lower than 3 mg / kg. For example, in some preferred embodiments, the dose of the second antibody may be about 2 mg / kg or less than 2 mg / kg, for example, in the range of 1.5 mg / kg to 2.5 mg / kg. In some embodiments, the dose of the second antibody is 2 mg / kg. In some embodiments, the dose of the second antibody is 1 mg / kg when the second antibody is ipilimumab.

[0202] In some embodiments, the acceptable therapeutic dose of the second antibody molecule is 1 mg / kg when the second antibody molecule is ipilimumab.Thus, in this embodiment, the dose of the second antibody that is lower than the acceptable therapeutic dose is any dose that is lower than 1 mg / kg.In this embodiment, ipilimumab is approved for use in combination with another therapeutic antibody, for example, nivolumab.

[0203] Thus, in some embodiments, the uses or methods described with respect to the eighth to fourteenth aspects do not involve administration of an antibody molecule that specifically binds to PD-1 or PD-L1, and / or the pharmaceutical composition or kit does not comprise an antibody molecule that specifically binds to PD-1 or PD-L1.In these embodiments, the accepted therapeutic dose of ipilimumab is typically 3 mg / kg or higher.

[0204] In embodiments where the second antibody molecule is ipilimumab, the second antibody molecule may be administered according to the dosage schedule provided in the approved label, or alternatively, a different dosage schedule may be possible using lower doses as contemplated herein.

[0205] In some further or alternative embodiments, the second antibody molecule is tremelimumab.

[0206] In some embodiments, when the second antibody molecule is tremelimumab, the acceptable therapeutic dose is 750 mg. Thus, the dose of the second antibody that is lower than the acceptable therapeutic dose is any dose that is lower than 750 mg. In some other embodiments, the acceptable therapeutic dose is 300 mg. Thus, the dose of the second antibody that is lower than the acceptable therapeutic dose is any dose that is lower than 300 mg. In some other embodiments, the acceptable therapeutic dose is 75 mg. Thus, the dose of the second antibody that is lower than the acceptable therapeutic dose is any dose that is lower than 75 mg.

[0207] In some embodiments, when the second antibody molecule is tremelimumab, the acceptable therapeutic dose is 10 mg / kg. Thus, a dose of the second antibody that is lower than the acceptable therapeutic dose is any dose lower than 10 mg / kg.

[0208] In some embodiments, when the second antibody molecule is tremelimumab, the acceptable therapeutic dose is 3 mg / kg. Thus, a dose of the second antibody that is lower than the acceptable therapeutic dose is any dose lower than 3 mg / kg. For example, in some preferred embodiments, the dose of the second antibody may be about 2 mg / kg or less than 2 mg / kg, for example, in the range of 1.5 mg / kg to 2.5 mg / kg. In some embodiments, the dose of the second antibody is 2 mg / kg. In some embodiments, the dose of the second antibody is 1 mg / kg when the second antibody is tremelimumab.

[0209] In some embodiments, the acceptable therapeutic dose of the second antibody molecule is 1 mg / kg when the second antibody molecule is tremelimumab. Thus, in this embodiment, a dose of the second antibody that is lower than the acceptable therapeutic dose is any dose lower than 1 mg / kg.

[0210] In embodiments in which the second antibody molecule is tremelimumab, the second antibody molecule may be administered according to the dosage schedule provided in the approved labeling, or alternatively, a different dosage schedule may be possible using lower doses as contemplated herein.

[0211] One skilled in the art will appreciate that the second antibody molecule may be a combination of any of the CTLA-4 specific antibodies discussed herein, for example, a second antibody molecule that specifically binds to CTLA-4 may be a combination of ipilimumab and tremelimumab.

[0212] It will also be understood that other antibodies specific for CTLA-4 are contemplated by the present invention, except as specifically discussed.

[0213] As discussed above, the second antibody molecule may reduce and / or prevent resistance in the cancer to treatment with a second antibody molecule that specifically binds to CTLA-4.

[0214] In some embodiments, the invention described in the eighth to fourteenth embodiments is for use in treating a subject with a cancer that is resistant to treatment. In some embodiments, the cancer may be a recurrent or refractory cancer. In some embodiments, the cancer may be resistant to treatment with an antibody that targets immune checkpoint blockade (e.g., an antibody specific for CTLA-4).

[0215] "Resistant," "resistant," or "resistant to treatment" means that a patient has a reduced level of responsiveness to treatment with an antibody molecule that specifically binds CTLA-4 compared to a previous or expected level of responsiveness. This includes situations where the patient has been previously treated with the antibody molecule (i.e., the patient has developed resistance) as well as situations where the patient has never been treated with the antibody molecule (i.e., the patient is inherently resistant). In some further or alternative embodiments, the patient may have a reduced level of responsiveness to an antibody molecule that specifically binds PD-1 and / or PD-L1.

[0216] Resistance to treatment can be measured in a variety of ways, for example, by monitoring patients to ensure that the cancer is regressing as expected and by identifying patients who do not respond to treatment at all.

[0217] "Resistant to treatment" also includes cancer types for which treatment with antibodies that specifically bind CTLA-4 has not yet been indicated, for example, where it has previously been found that these antibodies (or combinations of antibodies) have no measurable therapeutic effect.

[0218] Also included are cancers that may have a low tumor mutational burden (TMB). "Tumor mutational burden" refers to the number of genetic mutations in cancer cells. Such measurements can be determined by clinical tests known in the art. It is known that cells with high TMB are more likely to be recognized as abnormal and attacked by the immune system, and high TMB has been identified as a response biomarker for PD-1 / PD-L1 blockade (Goodman et al., 2017, Mol Cancer Ther., 16(11):2598-2608). Thus, cancers with low TMB can be successfully targeted with the combination of the present invention, which can enhance the effect of such immune blocking antibodies as described above.

[0219] It will be appreciated that in some embodiments, the cancer that is resistant to treatment may be a recurrent cancer and / or a refractory cancer.

[0220] A recurrent cancer is one that has been previously treated and that resulted in the subject's complete or partial recovery (i.e., the subject is said to be in remission), but that returns or worsens after the treatment is stopped. In other words, a recurrent cancer is one that has become resistant to a treatment after a period during which it was effective and the subject had a complete or partial recovery.

[0221] A refractory cancer is one that has been treated but has not responded to the treatment and / or has been treated but has progressed during the treatment. In other words, a refractory cancer is one that is resistant to treatment.

[0222] It will be appreciated that a cancer may be a refractory cancer due to inherent resistance, which includes the meaning that the cancer, and / or the subject, and / or the target cells are resistant to a particular treatment from the time it is first administered or even before it is administered.

[0223] It will be understood that the cancer may be a cancer that has relapsed due to acquired resistance, or a relapsed cancer and a refractory cancer. "Acquired resistance" includes that the cancer and / or subject and / or target cells were not resistant to a particular treatment prior to the first administration, but have become resistant after or during at least the first administration of the treatment (e.g., after the treatment has been administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 times).

[0224] Recurrent and / or refractory cancers may be readily diagnosed by one of ordinary skill in the medical arts.

[0225] In some embodiments, a patient who is resistant to treatment with an antibody molecule that specifically binds to CTLA-4 has previously been treated with an antibody molecule that specifically binds CTLA-4, and optionally, the patient has become resistant following that treatment.

[0226] This embodiment also includes the situation where the patient has previously been treated with a first antibody that specifically binds to CTLA-4, and the second antibody molecule of the invention is a second antibody that specifically binds to CTLA-4 (i.e., the second antibody molecule of the invention is different from the anti-CTLA-4 antibody previously used to treat the patient). In some alternative embodiments, the antibody that specifically binds to CTLA-4 previously used to treat the patient is the same as the second antibody molecule of the invention that specifically binds to CTLA-4.

[0227] As discussed above, in some alternative embodiments, the patient has not been previously treated with an antibody molecule that specifically binds to CTLA-4, in which embodiment, the patient may be essentially resistant to such treatment.

[0228] In some embodiments, the cancer is an FcyRllb-positive B-cell cancer. An "FcyRllb-positive cancer" is any cancer that expresses FcyRIIb, even if at different levels. FcγRIIB expression is most prominent in chronic lymphocytic leukemia and mantle cell lymphoma, moderate in diffuse large B-cell lymphoma, and least prominent in follicular lymphoma. However, in some cases, subjects with cancers that generally express low levels of FcγRIIB (e.g., follicular lymphoma) may have very high levels of FcγRIIb expression. The expression levels of FcγRIIB in different types of B-cell cancers (especially those mentioned above) correlate with the internalization rate of the antibody molecule rituximab. Thus, the expression of FcγRIIB and the associated internalization of the antibody molecule are believed to be a common mechanism shared by B-cell cancers (Lim et al., 2011). FcγRIIB-dependent initialization of antibody molecules can be blocked by antibodies to FcγRIIB disclosed herein.

[0229] Thus, the combinations disclosed herein can be used in the treatment of B-cell cancers, in particular relapsed and / or refractory mantle cell lymphoma, and / or relapsed and / or refractory follicular lymphoma, and / or relapsed diffuse large B-cell lymphoma and / or refractory diffuse large B-cell lymphoma.

[0230] In some other more preferred embodiments, the cancer is an FcγRIIb-negative cancer. "FcγRIIb-negative cancer" includes any cancer that does not present any FcγRIIb receptor. This can be examined by a variety of methods, including immunohistochemistry and flow cytometry, as shown in Tutt et al, J Immunol, 2015, 195(11) 5503-5516, using anti-FcγRIIB specific antibodies.

[0231] In some preferred embodiments, the cancer is selected from the group consisting of carcinoma, sarcoma, and lymphoma.

[0232] In some embodiments, the cancer is a carcinoma selected from the group consisting of adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, poorly differentiated or undifferentiated carcinoma, large cell carcinoma, and small cell carcinoma.

[0233] In some embodiments, the cancer is a sarcoma selected from the group consisting of osteosarcoma, chondrosarcoma, liposarcoma, and leiomyosarcoma.

[0234] The FcγRIIb negative cancer is selected from the group consisting of melanoma, breast cancer, ovarian cancer, prostate cancer, metastatic hormone refractory prostate cancer, colorectal cancer, lung cancer, small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC), non-small cell lung cancer, urothelial cancer, bladder cancer, renal cancer, mesothelioma, Merkel cell carcinoma, head and neck cancer, and pancreatic cancer.

[0235] Each of the above cancers is well known and the symptoms and cancer diagnostic markers are well described, as are the therapeutic agents used to treat those cancers. Thus, the symptoms, cancer diagnostic markers, and therapeutic agents used to treat the above-mentioned types of cancer will be known to those skilled in the art of medicine, as discussed above with respect to the first to seventh aspects of the present invention.

[0236] In some embodiments, a first antibody molecule that specifically binds FcγRIIb and a second antibody molecule that specifically binds CTLA-4 are administered to a patient simultaneously, meaning that they are administered together at one time or separately within a very close time period of each other.

[0237] In some embodiments, an antibody molecule that specifically binds FcγRIIb is administered to a patient prior to administration of a second antibody molecule that specifically binds CTLA-4.

[0238] Such sequential administration can be achieved by temporal separation of the antibodies. Alternatively, or in combination with the first option, sequential administration can also be achieved by spatial separation of the antibody molecules. An antibody molecule that specifically binds to FcγRIIb is administered by a method such as intratumoral administration so that it reaches the cancer before a second antibody molecule, and then an antibody molecule is administered by a method such as systemic administration so that it reaches the cancer after the antibody molecule that specifically binds to FcγRIIb.

[0239] In some embodiments, a second antibody molecule that specifically binds to CTLA-4 is administered to a patient prior to administration of an antibody molecule that specifically binds FcγRIIb, e.g., using the spatial or temporal modes described above.

[0240] For example, it will be known to those skilled in the art of medicine that drugs can be modified with different additives to alter the rate at which they are absorbed by the body, and can be modified in different forms, for example to allow for particular routes of administration to the body.

[0241] Thus, the antibodies and compositions described herein include those which may be combined with an excipient, and / or a pharma- ceutically acceptable carrier, and / or a pharma- ceutically acceptable diluent, and / or an adjuvant.

[0242] The combinations, and / or compositions, and / or antibodies, and / or drugs of the invention include those which may be suitable for parenteral administration, including aqueous and / or non-aqueous sterile injection solutions, which may contain antioxidants, and / or buffers, and / or bacteriostats, and / or solutes which render the formulation isotonic with the blood of the intended recipient, and / or aqueous and / or non-aqueous sterile suspensions which may contain suspending agents and / or thickening agents. The compositions, and / or antibodies, and / or drugs, and / or drugs of the invention may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (i.e. lyophilized) condition requiring only the addition of a sterile liquid carrier, for example water for injections, immediately prior to use.

[0243] Extemporaneous injection solutions and suspensions may be prepared from sterile powders and / or granules and / or tablets of the kind previously described.

[0244] For parenteral administration to human patients, unless otherwise defined, the daily dosage level of the antibody molecule specifically binding to FcγRIIb, and / or the second antibody molecule, and / or the third antibody molecule, as defined herein, is typically 1 mg / kg to 20 mg / kg (of patient body weight), or in some cases up to 100 mg / kg, administered in a single or divided dose. In some preferred embodiments, the dose of the antibody molecule specifically binding to FcγRIIb will be 10 mg / kg. In some circumstances, lower doses may be used, for example in combination with chronic administration. In any event, the physician will determine the actual dosage that will be most suitable for an individual patient, which will vary with the age, weight, and response of the particular patient. The dosages described above are exemplary of the average case. Of course, there may be individual cases in which higher or lower dosage ranges are merited, and are within the scope of the invention.

[0245] Typically, the composition and / or drug of the present invention will contain an antibody molecule that specifically binds to FcγRIIb at a concentration of about 2 mg / ml to 150 mg / ml, or about 2 mg / ml to 200 mg / ml. In a preferred embodiment, the drug and / or composition of the present invention will contain an antibody molecule that specifically binds to FcγRIIb at a concentration of 10 mg / ml.

[0246] Generally, in humans, oral or parenteral administration of the compositions, and / or antibodies, and / or agents, and / or drugs of the invention is the preferred route and is the most convenient. For veterinary use, the compositions, and / or antibodies, and / or agents, and / or drugs of the invention are administered in a suitably acceptable formulation in accordance with normal veterinary practice, and the veterinarian will determine the dosing regime and route of administration that will be most appropriate for a particular animal. Thus, the invention provides pharmaceutical formulations comprising the antibodies and / or agents of the invention in an amount effective to treat various conditions (as described above and further below). Preferably, the compositions, and / or antibodies, and / or agents, and / or drugs are adapted for delivery by a route selected from the group including intravenous (IV), subcutaneous (SC), intramuscular (IM), or intratumoral. In some preferred embodiments, administration is intravenous.

[0247] In some embodiments, either the first antibody molecule or the second antibody, or both, may be administered using a plasmid or a virus. Such a plasmid then comprises a nucleotide sequence encoding either the first antibody molecule or the second antibody, or both. In some embodiments, a nucleotide sequence encoding a portion or the complete sequence of either the first antibody molecule or the second antibody, or both, is incorporated into a cell or viral genome or viral virome, and such a cell or virus then acts as a delivery vehicle for either the first antibody molecule or the second antibody, or both (or a delivery vehicle for a nucleotide sequence encoding either the first antibody molecule or the second antibody, or both). For example, in some embodiments, such a virus may be in the form of a therapeutic oncolytic virus comprising a nucleotide sequence encoding at least one of the antibody molecules described herein. In some embodiments, such an oncolytic virus comprises a nucleotide sequence encoding a full-length human IgG antibody. Oncolytic viruses are known to those skilled in the art of medicine and virology.

[0248] The present invention also includes compositions comprising pharma- ceutically acceptable acid or base addition salts of the polypeptide binding moieties of the present invention, and / or antibodies, and / or pharmaceutical agents, and / or drugs. The acids used to prepare pharma- ceutically acceptable acid addition salts of the aforementioned base compounds useful in the present invention are, inter alia, those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3 naphthoate)] salts. Pharmaceutically acceptable base addition salts may also be used to generate pharma-ceutically acceptable salt forms of the agents according to the invention. Chemical bases that may be used as reagents to prepare pharma-ceutically acceptable base salts of the agents, which are acidic in nature, are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts (e.g., N-methylglucamine-(meglumine) and lower alkanolammonium), and other pharma-ceutically acceptable organic amine base salts. The agents and / or polypeptide binding moieties of the invention may be lyophilized for storage and reconstituted in a suitable carrier prior to use. Any suitable lyophilization method (e.g., spray drying, cake drying) and / or reconstitution technique may be used. Those of skill in the art will understand that lyophilization and reconstitution may lead to varying degrees of loss of antibody activity (e.g., in conventional immunoglobulins, IgM antibodies tend to experience greater loss of activity than IgG antibodies) and usage levels may need to be adjusted upward to compensate.In one embodiment, a lyophilized (freeze-dried) polypeptide binding moiety, when rehydrated, loses about 20% or less, or about 25% or less, or about 30% or less, or about 35% or less, or about 40% or less, or about 45% or less, or about 50% or less of its activity (before lyophilization).

[0249] The first antibody as defined herein with respect to the eighth to fourteenth aspects may be the same antibody as defined herein with respect to the preceding aspects. All of the embodiments and examples relating to the identity and antibody sequence of the first antibody apply equally to the invention described in the eighth to fourteenth aspects.

[0250] The second antibody as defined herein in relation to the eighth to fourteenth aspects may be the same antibody as the third antibody molecule as defined herein in relation to the preceding first to seventh aspects. All of the embodiments and examples relating to the identity of the third antibody that specifically binds to CTLA-4 apply equally to the invention described in the eighth to fourteenth aspects insofar as the second antibody molecule of these aspects is concerned.

[0251] The antibody molecules referred to herein (i.e., first antibody molecule, second antibody molecule, and third antibody molecule) are well known to those skilled in the art of immunology and molecular biology. Typically, an antibody comprises two heavy chains (H) and two light chains (L). This complete antibody molecule is sometimes referred to herein as a full-size antibody or full-length antibody. The heavy chain of the antibody comprises one variable domain (VH) and three constant domains (CH1, CH2, and CH3), and the light chain of the antibody molecule comprises one variable domain (VL) and one constant domain (CL). The variable domains (sometimes referred to as F) are located at the end of the antibody chain and the end of the light chain. VThe variable domains (collectively called the constant regions) bind the antibody's target, or antigen. Each variable domain contains three loops, called complementarity determining regions (CDRs), which are involved in target binding. The constant domains are not directly involved in binding the antibody to the antigen, but exhibit various effector functions. Depending on the amino acid sequence of the constant regions of their heavy chains, antibodies or immunoglobulins can be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and in humans, some of these are further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, and IgG4, as well as IgA1 and IgA2.

[0252] Another part of an antibody is the Fc region (also known as the fragment crystallizable domain), which contains the two constant domains of each of the antibody's heavy chains. As mentioned above, the Fc region is involved in the interaction between the antibody and the Fc receptor.

[0253] As used herein, the term antibody molecule encompasses full-length or full-size antibodies, as well as functional fragments of full-length antibodies and derivatives of such antibody molecules.

[0254] A functional fragment of a full-sized antibody has the same antigen-binding characteristics as the corresponding full-sized antibody, and contains either the same variable domains (i.e., VH and VL sequences) and / or the same CDR sequences as the corresponding full-sized antibody. A functional fragment has the same antigen-binding characteristics as the corresponding full-sized antibody, meaning that it binds to the same epitope on the target as the full-sized antibody. Such a functional fragment may correspond to the Fv portion of a full-sized antibody. Alternatively, such a fragment may be a Fab (also designated F(ab)), which is a monovalent antigen-binding fragment that does not contain an Fc portion, or a F(ab')2, which is a bivalent antigen-binding fragment that contains two antigen-binding Fab portions linked together by disulfide bonds, or a F(ab') (i.e., a monovalent variant of F(ab')2). Such a fragment may also be a single chain variable fragment (scFv).

[0255] Functional fragments do not always contain all six CDRs of the corresponding full-size antibody. It is understood that molecules containing three or less CDR regions (sometimes only a single CDR or a part thereof) can retain the antigen binding activity of the antibody derived from that CDR. For example, Gao et al., 1994, J.Biol.Chem., 269:32389-93, describes that the whole VL chain (including all three CDRs) has high affinity for its substrate.

[0256] Molecules containing two CDR regions are described, for example, in Vaughan & Sollazzo 2001, Combinatorial Chemistry & High Throughput Screening, 4:417-430. On page 418 (right column-3 (our strategy for design)), a minibody is described that contains only H1 and H2 CDR hypervariable regions interspersed within framework regions. The minibody is described as being capable of binding to a target. Pessi et al., 1993, Nature, 362:367-9 and Bianchi et al., 1994, J. Mol. Biol., 236:649-59 are referenced by Vaughan & Sollazzo and describe H1 and H2 minibodies and their properties in more detail. Qiu et al., 2007, Nature Biotechnology, 25:921-9 show that a molecule consisting of two linked CDRs is capable of binding to an antigen. Quiocho 1993, Nature, 362:293-4 provides an overview of "minibody" technology. Ladner 2007, Nature Biotechnology, 25:875-7 comments that molecules containing two CDRs can retain antigen-binding activity.

[0257] Antibody molecules containing a single CDR region are described, for example, in Laune et al., 1997, JBC, 272:30937-44, where it is demonstrated that various hexapeptides derived from CDRs exhibit antigen-binding activity, and it is noted that synthetic peptides of complete single CDRs exhibit strong binding activity. Monnet et al., 1999, JBC, 274:3789-96, where it is shown that various 12-mer peptides and related framework regions have antigen-binding activity, commenting that CDR3-like peptides alone are capable of binding to antigens. Heap et al., 2005, J. Gen. Virol., 86:1791-1800, where it is reported that "microantibodies" (molecules containing a single CDR) are capable of binding to antigens, and where it is shown that cyclic peptides from anti-HIV antibodies have antigen-binding activity and function. Nicaise et al., 2004, Protein Science, 13:1882-91, show that a single CDR can confer antigen-binding activity and affinity for its lysozyme antigen.

[0258] Thus, antibody molecules having five, four, three or fewer CDRs can retain the antigen-binding properties of the full-length antibody from which they are derived.

[0259] The antibody molecule may be a derivative of a full-length antibody or a fragment of such an antibody. If a derivative is used, it should have the same antigen-binding characteristics as the corresponding full-length antibody, in the sense that it binds to the same epitope on the target as the full-length antibody.

[0260] Thus, as used herein, the term "antibody molecule" includes all types of antibody molecules, as well as functional fragments and derivatives thereof, including monoclonal antibodies, polyclonal antibodies, synthetic antibodies, recombinantly produced antibodies, multispecific antibodies, bispecific antibodies, human antibodies, antibodies of human origin, humanized antibodies, chimeric antibodies, single chain antibodies, single chain Fv (scFv), Fab fragments, F(ab')2 fragments, F(ab') fragments, disulfide-linked Fv (sdFv), antibody heavy chains, antibody light chains, antibody heavy chain homodimers, antibody light chain homodimers, antibody heavy chain heterodimers, antibody light chain heterodimers, and antigen-binding functional fragments of such homodimers and heterodimers.

[0261] Furthermore, as used herein, the term "antibody molecule" includes all classes of antibody molecules and functional fragments, including (unless otherwise specified) IgG, IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgD, and IgE.

[0262] In some embodiments, the antibody is human IgG1. Those skilled in the art will recognize that mouse IgG2a and human IgG1 share the ability to bind activating Fc gamma receptors and activate target cell deletion by activation of immune cells bearing activating Fc gamma receptors, for example, by ADCP and ADCC. Thus, in embodiments where mouse IgG2a is the preferred isotype for deletion in mice, human IgG1 is the preferred isotype for deletion in humans in such embodiments.

[0263] As outlined above, different types and forms of antibody molecules are encompassed by the present invention and will be known to those skilled in the art of immunology. It is well known that antibodies used for therapeutic purposes are often modified with additional moieties that modify the properties of the antibody molecule.

[0264] Thus, we include that the antibody molecules of the invention or used in accordance with the invention (e.g. monoclonal and / or polyclonal and / or bispecific antibody molecules) comprise a detectable moiety and / or a cytotoxic moiety.

[0265] A "detectable moiety" includes one or more from the group consisting of an enzyme, a radioactive atom, a fluorescent moiety, a chemiluminescent moiety, a bioluminescent moiety. A detectable moiety allows for visualization of the antibody molecule in vitro, and / or in vivo, and / or ex vivo.

[0266] "Cytotoxic moieties" include radioactive moieties and / or enzymes, where the enzymes are caspases and / or toxins, where the toxins are bacterial toxins or venoms, and where the cytotoxic moieties are capable of inducing cell lysis.

[0267] We further include that the antibody molecule may be in isolated and / or purified form and / or may be PEGylated, which is the method of adding polyethylene glycol polymers to a molecule such as an antibody molecule or derivative to modify its behavior, e.g., to increase its hydrodynamic size and prevent renal clearance, thereby increasing its half-life.

[0268] As discussed above, the CDRs of an antibody bind to the antibody target. The amino acid assignments for each CDR described herein are as defined by Kabat EA et al. 1991, In"Sequences of Proteins of Immunological Interest"Fifth Edition, NIH Publication No. 91-3242, pp xv-xvii.

[0269] As those skilled in the art will recognize, there are other methods for assigning amino acids to each CDR, such as the International ImMunoGeneTics information system (IMGT®) (http: / / www.imgt.org / and Lefranc and Lefranc "The Immunoglobulin Facts Book" published by Academic Press, 2001).

[0270] In a further embodiment, the antibody molecule of the invention or for use in accordance with the invention is an antibody molecule that is capable of competing with a particular antibody provided herein for binding to a particular target, e.g. an antibody molecule comprising any of the amino acid sequences set out in SEQ ID NOs: 1-194.

[0271] By "capable of competing" it is meant that a competing antibody is capable of at least partially inhibiting or otherwise interfering with the binding of an antibody molecule as defined herein to a particular target.

[0272] For example, such a competing antibody molecule may be capable of inhibiting binding of an antibody molecule described herein by at least about 10%, e.g., at least about 20%, or at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 100% and / or may be capable of inhibiting the binding ability of an antibody described herein to prevent or reduce binding to a specific target by at least about 10%, e.g., at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or about 100%.

[0273] Competitive binding can be determined by methods well known to those of skill in the art, such as the enzyme linked immunosorbent assay (ELISA).

[0274] ELISA assays can be used to evaluate epitope-modified or blocking antibodies. Additional methods suitable for identifying competing antibodies are disclosed in Antibodies: A Laboratory Manual, Harlow & Lane, which is incorporated herein by reference (see, e.g., pages 567-569, 574-576, 583, and 590-612, 1988, CSHL, NY, ISBN 0-87969-314-2).

[0275] It is well known that antibodies specifically bind to or interact with a defined target molecule or antigen, i.e., they bind preferentially and selectively to their target and not to non-target molecules.

[0276] Methods for assessing protein binding are known to those skilled in the art of biochemistry and immunology. Those skilled in the art will understand that such methods can be used to assess the binding of an antibody to a target and / or the binding of an Fc region of an antibody to an Fc receptor, as well as the relative strength, or specificity, or inhibition, prevention, or reduction of these interactions. Examples of methods that can be used to assess protein binding include, for example, immunoassays, BIAcore, Western blots, radioimmunoassays (RIA), and enzyme-linked immunosorbent assays (ELISA) (for a discussion of antibody specificity, see Fundamental Immunology Second Edition, Raven Press, New York, pp. 332-336 (1989)).

[0277] Thus, an "antibody molecule that specifically binds" includes an antibody molecule that specifically binds to a target but does not bind to a non-target, or that binds weaker (e.g., with lower affinity) to the non-target than to the target.

[0278] It also includes the meaning that an antibody specifically binds to a target more than to a non-target at least 2 times stronger, or at least 5 times stronger, or at least 10 times stronger, or at least 20 times stronger, or at least 50 times stronger, or at least 100 times stronger, or at least 200 times stronger, or at least 500 times stronger, or at least about 1000 times stronger.

[0279] In addition, the antibody binds to the target and -1 K d , or at least about 10 -2 K d , or at least about 10 -3 K d , or at least about 10 -4 K d , or at least about 10 -5 K d , or at least about 10 -6 K d , or at least about 10 -7 K d , or at least about 10 -8 K d , or at least about 10 -9 K d , or at least about 10 -10 K d , or at least about 10 -11 K d , or at least about 10 -12 K d , or at least about 10 -13 K d , or at least about 10 -14 K d , or at least about 10 -15 K d K d By binding, it is meant that the antibody specifically binds to the target.

[0280] Reference will now be made to the following figures and examples to describe preferred, non-limiting examples embodying certain aspects of the present invention. [Brief description of the drawings]

[0281] [Figure 1]Fc:FcγR binding proficient FcγRIIB (AT-130-2 mIgG2a and mIgG1), but not Fc:FcγR binding impaired anti-FcγRIIB (AT-130-2 mIgG1 NA), enhances the therapeutic efficacy and in vivo survival of anti-PD-1 antibodies. MC38 tumor-bearing mice were treated three times (days 8, 12, and 15 after subcutaneous inoculation of 5×105 tumor cells in 100 μl PBS) with 200 μg of anti-PD-1 (clone 29F.1A12; Bioxcell) antibody alone or in combination with 200 μg of the indicated anti-FcγRIIB antibody variant or isotype control (WR17). For the first treatment, AT130-2 was administered 6 hours before the anti-PD1 antibody. For subsequent treatments, both antibodies were administered together. All injections were given intraperitoneally in 200 μl of PBS. Tumors were considered terminal when they reached an area of ​​225 mm2 for MC38. Graphs show tumor growth and survival of animals. (**P<0.01; log-rank test). Experiments were performed in female mice aged 8-14 weeks. [Diagram 2] Fc:FcγR-binding anti-FcγRIIB (AT-130-2 mIgG2a and mIgG1), but not Fc:FcγR-nonbinding anti-FcγRIIB (AT-130-2 mIgG1 NA), enhances the therapeutic efficacy and in vivo survival of anti-PD-1 antibodies. CT26 tumor-bearing mice were treated three times (days 8, 12, and 15 after subcutaneous inoculation of 5×105 tumor cells in 100 μl PBS) with 200 μg of anti-PD-1 (clone 29F.1A12; Bioxcell) antibody alone or in combination with 200 μg of the indicated anti-FcγRIIB antibody variants or isotype control (WR17). For the first treatment, AT130-2 was administered 6 hours before the anti-PD1 antibody. For subsequent treatments, both antibodies were administered together. All injections were administered intraperitoneally in 200 μl PBS. Tumors were considered terminal when they reached an area of ​​400 mm2 for CT26. Graphs show tumor growth and survival of animals. (**P<0.01; log-rank test). Experiments were performed in female mice aged 8-14 weeks. [Diagram 3] Combined treatment of α-CTLA-4 with the BI-1607 surrogate AT130-2 mIgG1 N297A results in improved survival in the MC38 tumor model. 1×106 MC38 cells were injected subcutaneously (sc) into C57BL / 6 mice and allowed to establish. Mice were treated when tumors reached 6 mm in diameter. Mice were treated with 200 μg of anti-FcγRIIB antibody (clone AT130-2) as mIgG2a, or 400 μg of mIgG1 N297A and / or 200 μg of anti-CTLA-4 antibody (clone 9H10). Mice were then treated with single or combined mAbs 3 and 7 days after the first dose. All antibodies were administered intraperitoneally (ip) in 200 μl of PBS. Tumors were measured 3 times a week and sizes are presented as tumor volume (width2 x length x 0.52) for individual mice in each treatment group. N=X per group. This figure is a summary of X different experiments. [Figure 4]Combination therapy with anti-CTLA-4 and FcγRIIB blockade. 5×105 CT26 cells were injected subcutaneously into female BALB / c mice. Mice were randomized into treatment groups when tumor width×length was approximately 100 mm2. Treatments were administered on days 0, 2, 4, and 11. 9H10 (hamster anti-mouse CTLA4) only mice were administered 200 μg of antibody in 200 μl PBS intraperitoneally daily. On day 0, combination mice were administered 100 μg of AT130-2N297A (anti-mouse CD32) in 200 μl PBS intraperitoneally, followed 6 hours later by 200 μg of 9H10 in 200 μl PBS intraperitoneally. On days 2, 4, and 11, combination mice received a single 200 μl intraperitoneal injection of both antibodies (200 μg 9H10 and 100 μg AT130-2NA). Tumor width and length were measured and mice were sacrificed when tumor length x width exceeded 400 mm2. Figure A) Represents the treatment schedule. Group 1: no antibody, Group 2: anti-mCD32 (AT130-2NA; 100 μg), Group 3: anti-CTLA-4 (9H10; 200 μg), Group 4: combination of AT130-2 6 hours later (PC61). Tumors were allowed to establish and treated at 100 mm2. An additional dose was administered on day 12. Figure B) Shows the growth of individual tumors. Figure C) Shows the mean tumor area + / - SD or SEM. Figure D) Shows the survival of the animals. Figure E) Composite from two separate experiments (n=10 / group) showing survival. The combination of 9H10 and AT130-2NA (NA combo) was shown to be significantly more potent in extending survival than 9H10 alone (p=0.0179). [Diagram 5] Mice were inoculated with MC38 tumor cells and injected with antibodies when tumors reached a size of approximately 7x7mm. Mice were sacrificed 24 hours after three antibody injections, 7-8 days after treatment initiation, and tumors were harvested. Tumor single cell suspensions were analyzed for immune cell content by FACS. Figures 5A-C show the percentages of different cell populations in the tumor, and Figure 5D shows the CD8+ / Treg ratio. Combined treatment with anti-CTLA4 and BI-1607 surrogate (AT130-2 mIgG1 N297A) results in a reduction in the number of CD4+ / CD25+ cells and an improvement in the CD8 / Treg ratio. [Figure 6]After 10-12 days, spleens were removed from the mice, single cell suspensions were prepared, and then injected intraperitoneally into SCID mice (10-15x106 / mouse). One hour later, SCID mice were treated intraperitoneally with either 10mg / kg Yervoy, anti-CD25 (basiliximab), Yervoy+BI-1607 surrogate (AT130-2 mIgG1 N297A), or isotype control mAb. 24 hours after intraperitoneal injection of antibodies, fluids were collected from the mice and cells in the fluids were analyzed using FACS. Figure 6A shows the percentage of stained Tregs, defined as CD45+CD3+CD4+CD25+CD127 low / negative, out of the total number of human CD45+ cells. Figure 6B shows the percentage of effector T cells (CD8+) out of the total number of human CD45+ cells. Figure 6C shows the CD8+ / Treg ratio. Combining Yervoy with BI-1607 surrogate (AT130-2 mIgG1 N297A) reduced the percentage of Tregs, increased the proportion of CD8+, and improved the CD8+ / Treg ratio compared to Yervoy alone. n=4-5 per group. [Figure 7] Assessment of Treg deletion by anti-IL2R mAb+ / -FcγRIIB blockade with wild-type or NA mutant mAbs. Wild-type AT130-2 does not show any enhancement of deletion, whereas NA variants do. 100 μg of AT130-2NA or mIgG1 wild-type AT130-2 were administered intraperitoneally to female Balb / c mice. Six hours later, 100 μg of PC61 was administered intraperitoneally. Four days later, Tregs (FoxP3+) in the spleen were determined by FAC. Mice were sacrificed and single cell suspensions obtained from the spleen were stained with antibodies against CD4, CD8 and B220 prior to intracellular FoxP3 staining before analysis by FAC canto. Leukocyte counts in each tissue were determined. Tregs were defined as CD8-CD4+FoxP3+ and the number of Tregs was calculated using the leukocyte count. Compared with wild-type mIgG1 AT130-2, the number of Tregs was significantly lower in the spleens of mice treated with the N297A antibody in combination with PC61 for 4 days (unpaired T test, P=0.044). [Figure 8]Combination treatment of α-CTLA-4 with BI-1607 surrogate AT130-2 mIgG1 N297A results in enhanced efficacy and preserved survival with lower doses of anti-CTLA-4. 1×106 MC38 cells were injected subcutaneously into C57BL / 6 mice and established. Mice were treated when tumors reached a diameter of 6 mm. Mice were treated with 2 or 0.4 mg / kg anti-CTLA-4 (clone 9H10) alone or anti-FcγRIIB antibody (clone AT130-2) as mIgG1 N297A at 20 mg / kg in combination with anti-CTLA-4 at 10 mg / kg, AT130-2 as mIgG1 N297A at 20 mg / kg, or isotype control. Mice were then treated with single or combined mAbs 3 and 7 days after the first dose. All antibodies were administered intraperitoneally in 200 μl of PBS. Figure 8A) Tumors were measured 3 times a week and size presented as tumor volume (width2 x length x 0.52) for individual mice in each treatment group. N=10 per group. Figure 8B) Survival of mice in different groups (not all groups shown). [Figure 9] Addition of BI-1607 surrogate AT130-2 mIgG1 N297A to combination CTLA-4 / PD-1 treatment improves therapeutic efficacy in treatment-resistant B16 model. 1x106 B16 cells were subcutaneously injected into C57BL / 6 mice. Four days after tumor inoculation, mice were treated. Mice were treated with 10mg / kg anti-PD-1+2 or 0.4mg / kg anti-CTLA-4 (clone 9H10) alone or in combination with 20mg / kg anti-FcγRIIB antibody (clone AT130-2) as mIgG1 N297A. Additionally, control groups were treated with 10mg / kg anti-PD-1, 10mg / kg anti-PD-1+20mg / kg AT130-2-N297A, or isotype control. Mice were then treated with single or combined mAbs 3 and 7 days after the first dose. All antibodies were administered intraperitoneally in 200 μl of PBS. Tumors were measured 3 times weekly and sizes presented as tumor volume (width2×length×0.52) for individual mice in each treatment group. N=4-10 per group. [Figure 10]Addition of BI-1607 surrogate AT130-2 mIgG1 N297A to combination CTLA-4 / PD-1 treatment improves survival in a treatment-resistant B16 model. 1x106 B16 cells were injected subcutaneously into C57BL / 6 mice. Four days after tumor inoculation, mice were treated. Mice were treated with 10mg / kg anti-PD-1+2 or 0.4mg / kg anti-CTLA-4 (clone 9H10) alone or in combination with 20mg / kg anti-FcγRIIB antibody (clone AT130-2) as mIgG1 N297A. Additionally, control groups were treated with 10mg / kg anti-PD-1, 10mg / kg anti-PD-1+20mg / kg AT130-2-N297A, or isotype control. Mice were then treated with single or combined mAbs 3 and 7 days after the first dose. All antibodies were administered intraperitoneally in 200 μl PBS. Tumors were measured three times a week until they reached a size that was predefined as the ethical endpoint. N=4-10 per group. EXAMPLES

[0282] background Generation of mFcγRIIB-blocking surrogate mAbs The present inventors have previously generated human antibodies that can effectively block inhibitory FcγRIIB. Two antibody variants derived from the hFcγRIIB-specific antibody 6G11, hIgG1 with a wild-type Fc domain capable of binding to both activating and inhibitory FcγRs, and hIgG1 with severely impaired Fc-binding ability to all FcγRs. N297A was generated.

[24]

[0283] To evaluate the therapeutic potential of blocking FcγR to enhance the activity of immunomodulatory antibodies (e.g., anti-PD-1 and anti-CTLA-4 antibodies) in solid tumors, we previously generated surrogate murine FcγRIIB blocking antibodies suitable for studies in immune competent syngeneic mouse tumor models.

[0284] The Fc:FcγR binding (proficient) antibody and the Fc:FcγR non-binding (deficient) antibody that match the human lead clinical candidate antibody to FcγRIIB are obtained by substituting the Fv sequence of the mouse FcγRIIB-specific antibody AT-130 with mouse IgG2a (Fc:FcγR binding) and mouse IgG1, respectively. N297A Anti-FcγR mIgG1 isotype antibodies were generated that bind only to one of the activating FcγRs (mFcγRIII) and the inhibitory mFcγRII, thus exhibiting "moderate" Fc:FcγR binding capabilities. All generated antibodies showed highly specific, high affinity, Fv-mediated binding to mouse FcγRIIB as assessed by ELISA using recombinant protein, in vitro cell binding, and blocking assays

[25] .

[0285] Materials and Methods cell MC38 and CT26 mouse colon cancer cell lines, and B16 mouse melanoma cell line were obtained from ATCC. Cells were maintained in RPMI1640 medium supplemented with 10% fetal calf serum (FCS) and containing 2 mM L-glutamine. Before harvesting cells for transplantation, cells were ensured to be in logarithmic growth phase.

[0286] Human PBMCs (Hospital of Halmstad) were isolated using Ficoll Paque PLUS and after washing, the cells were cultured at 75 × 10 6 Cells / ml were resuspended in sterile PBS.

[0287] Test and control substances Anti-mouse CTLA-4 clone 9H10 and anti-mouse PD-1 clone 29F.1A12 were purchased from Bioxcell, and Yervoy (ipilimumab) and basiliximab were purchased from Apoteket. AT130-2 (anti-FcγRIIB) antibody was purified from hybridoma. Isotype variants of AT130-2 and isotype control antibodies were transiently expressed in HEK293 cells.

[0288] The specificity of the purified research batches was demonstrated by luminescence-based ELISA or FACS analysis. Endotoxin levels of the antibodies were found to be <0.1 IU / mL as determined by the LAL-amoebocyte test.

[0289] Mouse model Subcutaneous MC38 tumor model Female C57 / BL6 mice (n=10) aged 6-8 weeks (17-20 g) (bred at Taconic, Denmark) were incubated with 1 million (1 × 10 6 ) MC38 tumor cells were injected subcutaneously in the flank. Treatment began when tumors reached a diameter of 6 × 6–8 × 8 mm (measured with a vernier caliper) (day 1). Treatment was initiated according to the following treatment schedule (day 1):

[0290] Subcutaneous CT26 tumor model Female Balb / c mice (n=10), aged 6-8 weeks (17-20 g) (bred at Southampton University, originally bred by Charles River), were incubated at 5 × 10 5 CT26 tumor cells were injected subcutaneously in the flank. Treatment began (day 1) when tumors reached x mm in diameter (measured with a caliper).

[0291] Subcutaneous B16 tumor model Female C57 / BL6 mice (n = 10), 6-8 weeks old (17-20 g), were obtained from Taconic. One million (1 × 10 6 ) B16 tumor cells were injected subcutaneously in the flank. Treatment began 4 days after tumor cell inoculation (day 1) according to the following treatment schedule:

[0292] NOG-PBMC-SCID mouse model 15–20 × 10 6 PBMC cells were injected intravenously (iv). Two weeks after injection, spleens were isolated and made into single cell suspensions. Cells were 50 × 10 6The cells were resuspended in sterile PBS at 10 × 10 cells / ml. SCID mice were then injected with 10 × 10 6 200 μl of the suspension corresponding to cells / mouse were injected intraperitoneally (ip). After 1 h, mice were treated with 10 mg / kg Yervoy, basiliximab, BI-1607 surrogate (AT130-2 mIgG1 N297A) or isotype control mAb (according to the second treatment schedule below). After 24 h, mice peritoneal fluid was harvested. Human T cell subsets were identified and quantified by FACS using the following markers: CD45, CD3, CD4, CD8, CD25, CD127 (all from BD Biosciences).

[0293] Treatment Schedule [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]

[0294] Animal monitoring Tumor size was measured twice a week with a caliper and expressed as tumor area (width × length) or tumor volume (width × length). 2 × length × 0.52) was calculated.

[0295] Animals were euthanized by CO2 or cervical dislocation when tumors reached the ethical endpoint or if any of the following occurred: ·hunting Dirty fur Reduced mobility

[0296] Analysis of tumor immune infiltrates Tumors were cut into small pieces and enzymatically digested with a mixture of DNAse and Liberase at 37°C. The tumor solution was then filtered through a cell strainer to obtain a single cell solution. The cell solution was stained after blocking with IVIG. Immune cells were identified and quantified by FACS using the following markers: CD45, CD3, CD4, CD8, CD25 (all from BD Biosciences).

[0297] statistical analysis Statistical analysis of antibody-mediated mouse survival was calculated using the log-rank (Mantel-Cox) test (GraphPad Prism). Statistical significance was considered as follows: *=p<0.05, **=p<0.01, ***=p<0.001.

[0298] Example 1 - FcγRIIB blocking mAbs differentially modulate anti-PD-1 and anti-CTLA-4 anti-tumor activity in vivo We also previously evaluated the ability of Fc:FcγR-binding and Fc:FcγR-nonbinding anti-FcγRIIB to improve the therapeutic activity of anti-PD-1 in immune-competent C57BL / 6 mice implanted with syngeneic MC38 tumors or Balb / C mice implanted with syngeneic CT26 tumors. Both tumor models are infiltrated by immune cells including CD8+ T cells, Tregs, and macrophages and are known to be partially responsive (MC38) or non-responsive (CT26) to anti-PD-1 antibody therapy, reflecting the partial responsiveness observed in human cancers and leaving room for improving efficacy. Surprisingly, combined treatment with FcγR-binding anti-FcγRIIB significantly improved anti-tumor activity and survival of anti-PD-1-treated animals in the responsive MC38 model (Figure 1A-F) and induced anti-tumor activity and survival in the anti-PD-1-resistant CT26 tumor model (Figure 2). Conversely, combined treatment with non-Fc:FcγR binding anti-FcγRIIB and anti-PD-1 failed to improve or even impaired anti-PD-1 therapeutic activity.

[0299] Conversely, in stark contrast to what was found with anti-PD-1, we determined that combination therapy with non-FcγR binding, but not FcγR binding, anti-FcγRIIB improved the efficacy of anti-CTLA-4, as demonstrated by reduced tumor growth and increased survival in MC38 tumor-bearing animals (Figure 3). A similar anti-CTLA-4 enhancing effect of non-FcγR binding anti-FcγRIIB was previously observed in CT26 tumor-bearing Balb / c mice (Figure 4).

[0300] Collectively, these findings demonstrated that different variants of anti-FcγRIIB antibodies are necessary and useful for enhancing the in vivo therapeutic activity of immune checkpoint blockade antibodies against CTLA-4 and PD-1.

[0301] Example 2 - FcγR silencing anti-FcγRIIB enhancement of anti-CTLA-4 anti-tumor activity correlates with Treg depletion in vivo We decided to evaluate the cellular mechanisms underlying FcγR silencing anti-FcγRIIB enhancement of anti-CTLA-4 anti-tumor activity by evaluating antibody modulation of tumor infiltrating lymphocytes (TILs). Previous studies have established that anti-CTLA-4 antibody therapy depends on antibody-Fc interactions with activating Fc gamma receptors

[21] and that improved therapy with antibody constant domains optimized for Fc gamma receptor binding correlates with enhanced Treg depletion and associated higher intratumoral CD8+:Treg ratios

[18] .

[0302] Furthermore, previous studies have established that depletion of antibody-coated target cells is regulated by competition of antibody Fc for binding to activating and inhibitory (FcγRIIB) FcgRs, which promote and counteract depletion, respectively.

[0303] Consistent with these observations, treatment with anti-CTLA-4 alone reduced the number of intratumoral Tregs and improved the CD8+:Treg ratio (Figure 5). Treatment with FcγR-silencing anti-FcγRIIB alone did not affect the number of CD8+ T cells or Tregs, but combined treatment with anti-CTLA-4 and FcγR-silencing anti-FcγRIIB further reduced the number of intratumoral Tregs and improved the CD8+:Treg ratio (Figure 5).

[0304] Further supporting an in vivo mechanism of action involving FcγR silencing anti-FcγRIIB enhancement of Treg depletion, combined treatment of PBMC-humanized mice with non-FcγR binding anti-human FcγRIIB (6G11N297Q) and anti-human CTLA-4 (ipilimumab) resulted in stronger human Treg depletion and improved human CD8+ T cell:Treg ratios compared to ipilimumab alone (Figure 6).

[0305] Importantly, this model features expression of human intratumor-associated CTLA-4 on both Treg and CD8+ T effector cells (Figure 6). Finally, as previously shown, FcγR-silencing anti-FcγRIIB enhanced anti-IL-2 antibody depletion of Treg cells in wild-type C57BL / 6 mice (Figure 7), similar to that observed after genetic deletion of FcγRIIB

[26] .

[0306] Collectively, these data suggested that FcγR-silencing anti-FcγRIIB acts to enhance the anti-tumor activity of anti-CTLA-4 antibodies through selective blockade of inhibitory FcγRIIB, improving the activation of FcγR-dependent anti-CTLA-4 Treg depletion, resulting in improved CD8+:Treg ratios. Therefore, we sought to exploit this finding to determine whether it would improve the therapeutic window of CTLA-4.

[0307] Example 3 - FcγRIIB blockade improves anti-CTLA-4 therapeutic window in vivo Along with PD-1 and PD-L1, CTLA-4 is one of the few clinically validated targets for immune checkpoint blockade, and ipilimumab is the only approved anti-CTLA-4 antibody for cancer immunotherapy. Despite the ability of anti-CTLA-4 antibodies to induce long-lasting responses and appear to be curative in patients with advanced cancers, including melanoma, severe and potentially autoimmune tolerability concerns have limited their widespread use and led to the development of therapies involving lower submaximal effective doses. Emerging data indicate that anti-CTLA-4 antibodies can exert antitumor activity, acting on both effector T cells and Treg cells. Specifically, it is believed that blockade of CTLA-4:B7 family interactions and blockade of immunosuppressive signaling in CD4+ and CD8+ effector T cells in the central compartment contribute to the initiation of anti-CTLA-4-induced adaptive antitumor immunity, but may also contribute to the induction of nontumor, autoimmune responses, and autoimmune symptoms [27, 28]. In tumors, anti-CTLA-4 antibodies have been shown to result in Fc gamma receptor-dependent depletion of highly immunosuppressive Treg cells, which overexpress CTLA-4 compared to (intratumoral) effector T cells and peripheral Treg cells

[18] .

[0308] Therefore, enhancing Fc gamma receptor-dependent Treg depletion with lower and better tolerated anti-CTLA-4 doses may be an attractive strategy to achieve potent, yet safe, anti-CTLA-4 antibody immunotherapy.

[0309] It is well established that the therapeutic activity and toxicity of ipilimumab are related and dose-dependent

[29] . Thus, depending on the cancer type and as a single agent or in combination with anti-PD-1 approved ipilimumab, the dose ranges from 1 to 10 mg / kg.

[0310] To investigate the possible immune enhancing effect of non-FcγR binding anti-human FcγRIIB on the effective ipilimumab dose that can be safely administered, we treated MC38 tumor-bearing mice with anti-CTLA-4 antibody alone at a dose of 2 or 0.4 mg / kg or in combination with a full therapeutic dose of non-FcγR binding anti-human FcγRIIB at 10 mg / kg and recorded the anti-tumor effect as the impairment of tumor growth and survival. Treatment with control IgG or with the maximally effective dose of anti-CTLA-4 at 10 mg / kg served as negative and positive controls. Surprisingly, when combined with non-FcγR binding anti-human FcγRIIB (BI-1607 surrogate), a 5-fold lower dose of ipilimumab (mg) was equally effective to the maximally effective dose of ipilimumab at 10 mg / kg, as assessed by both inhibition of tumor growth and survival conferred (Figures 8A and 8B). Monotherapy with non-FcγR binding anti-human FcγRIIB had no effect on tumor growth or survival compared to control antibody treatment.

[0311] These findings demonstrated that non-FcγR binding anti-human FcγRIIB can indeed improve the therapeutic window of anti-CTLA-4 in vivo.

[0312] Example 4 - FcγRIIB blockade overcomes resistance to immune checkpoint inhibition by both anti-CTLA-4 and anti-PD-1 in vivo. Although the overall contribution of ICB to patient survival cannot be overstated, many patients do not respond or acquire resistance during treatment. Although much is still unknown about what determines responsiveness or resistance to ICB, it is widely accepted that patients with immune-inflammatory tumors are more likely to respond than those with tumors with poor immune infiltration. Patients with immune-excluded or "non-invasive" tumors are less likely to respond to ICB. Regardless of the mechanism, patients who are resistant to both anti-CTLA-4 and anti-PD-1 / PD-L1 have a particularly grave prognosis.

[0313] In light of these observations, resistance to ICB constitutes an important unmet medical need, and drugs that could help overcome resistance are of great therapeutic promise. While the above studies clearly demonstrated the need for different types of anti-FcγRIIB antibodies to boost anti-CTLA-4 and anti-PD-1 per se, we evaluated the potential anti-tumor immune-boosting effect of FcγR non-binding anti-FcγRIIB on the combination of anti-CTLA-4 and anti-PD-1. To this end, C57BL / 6 mice were implanted with syngeneic B16 tumor cells (a model of "non-invasive tumor" type that is poorly immune infiltrated and known to be resistant to both anti-CTLA-4 and anti-PD-1 ICB). Consistent with the highly resistant nature of this model, neither treatment with a full therapeutic dose of anti-PD-1 (10 mg / kg) alone nor combined treatment with clinically relevant doses of 2 mg / kg anti-CTLA-4 and 10 mg / kg anti-PD-1 conferred a survival advantage in this setting (Figures 9 and 10). Only the combination of CTLA-4 at the maximally effective dose of 10 mg / kg with anti-PD-1 at 10 mg / kg demonstrated anti-tumor activity in this model of a highly resistant tumor microenvironment.

[0314] Strikingly, combination treatment with non-FcγR binding anti-FcγRIIB then converted the non-effective doses of 2 mg / kg anti-CTLA-4 and 10 mg / kg anti-PD-1 into highly effective doses that overcame resistance and induced cures in 30% of animals (Figures 9 and 10A), and approximately doubled survival times of the high (10+10 mg / kg) anti-CTLA-4 / anti-PD-1 dosing regimen (Figures 9 and 10B).

[0315] Although the dose of mouse surrogate antibodies in mouse tumor models cannot be directly extrapolated to approved human antibodies in cancer subjects, the combined data in the B16 / C57BL6 mouse tumor model demonstrates that: First, consistent with an independent report by an independent investigator (Jiao et al., Int. J. Mol. Sci., (2020) 21, 773: doi:10.3390 / ijms21030773), the B16 model tolerates full therapeutic maximal effective doses of anti-CTLA-4 or anti-PD-1, and tolerates human therapeutically relevant combination doses (submaximal effective doses) of anti-CTLA-4 (e.g., 2 mg / kg) and anti-PD-1 (full therapeutic doses). Second, combination treatment with low doses (2 mg / kg) of anti-CTLA-4 and non-FcγR binding anti-FcγRIIB was equally effective compared to the maximally effective dose (10 mg / kg) of anti-CTLA-4 alone. This indicates that non-FcγR binding anti-FcγRIIB improves the therapeutic window of anti-CTLA-4 and can convert well-tolerated doses of anti-CTLA-4 from submaximal to full therapeutically active equivalents compared to (toxic) anti-CTLA-4 monotherapy. Third, and most importantly, these data demonstrate that combination treatment with non-FcγR binding anti-FcγRIIB and anti-CTLA-4 / anti-PD-1 overcomes the resistance of "non-invasive tumors" to immune checkpoint blockade.

[0316] References 1. Cheson,BDand JPLeonard,Monoclonal antibody therapy for B-cell non-Hodgkin's lymphoma.N Engl J Med,2008.359(6): p.613-26. 2. Gradishar, WJ, HER2 therapy--an abundance of riches.N Engl J Med,2012.366(2): p.176-8. 3. Jonker,D.J.,et al.,Cetuximab for the treatment of colorectal cancer.N Engl J Med,2007.357(20): p.2040-8. 4. Lokhorst,H.M.,et al.,Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma.N Engl J Med,2015.373(13): p.1207-19. 5. Hodi,F.S.,et al.,Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med,2010.363(8): p.711-23. 6. Larkin,J.,F.S.Hodi,and J.D.Wolchok,Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.N Engl J Med,2015.373(13): p.1270-1. 7. Brahmer,J.R.,et al.,Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.N Engl J Med,2012.366(26): p.2455-65. 8. Topalian,S.L.,et al.,Safety,activity,and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med,2012.366(26): p.2443-54. 9. Ribas,A.,et al.,Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised,controlled,phase 2 trial.Lancet Oncol,2015.16(8): p.908-18. 10. Robert,C.,et al.,Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.N Engl J Med,2011.364(26): p.2517-26. 11. Robert,C.,et al.,Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial.Lancet,2014.384(9948): p.1109-17. 12. Robert,C.,et al.,Nivolumab in previously untreated melanoma without BRAF mutation.N Engl J Med,2015.372(4): p.320-30. 13. Weber,J.S.,et al.,Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised,controlled,open-label,phase 3 trial.Lancet Oncol,2015.16(4): p.375-84. 14. Sharma,P.,et al.,Primary,Adaptive,and Acquired Resistance to Cancer Immunotherapy.Cell,2017.168(4): p.707-723. 15. Goede,V.,et al.,Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.N Engl J Med,2014.370(12): p.1101-10. 16. Baselga,J.,et al.,Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.N Engl J Med,2012.366(2): p.109-19. 17. Gopal,A.K.,et al.,PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma.N Engl J Med,2014.370(11): p.1008-18. 18. Arce Vargas,F.,et al.,Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.Cancer Cell,2018.33(4): p.649-663 e4. 19. Dahan,R.,et al.,FcgammaRs Modulate the Anti-tumor Activity of Antibodies Targeting the PD-1 / PD-L1 Axis.Cancer Cell,2015.28(3): p.285-95. 20. Arlauckas,S.P.,et al.,In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy.Sci Transl Med,2017.9(389). 21. Simpson,T.R.,et al.,Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.J Exp Med,2013.210(9): p.1695-710. 22. Sow,H.S.,et al.,FcgammaR interaction is not required for effective anti-PD-L1 immunotherapy but can add additional benefit depending on the tumor model.Int J Cancer,2019.144(2): p.345-354. 23. Litchfield,K.,et al.,Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition.Cell,2021.184(3): p.596-614 e14. 24. Roghanian,A.,et al.,Antagonistic human FcgammaRIIB (CD32B) antibodies have anti-tumor activity and overcome resistance to antibody therapy in vivo.Cancer Cell,2015.27(4): p.473-88. 25. Tutt, AL, et al., Development and Characterization of Monoclonal Antibodies Specific for Mouse and Human Fcgamma Receptors.J Immunol,2015.195(11): p.5503-16. 26. Arce Vargas,F.,et al.,Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.Immunity,2017.46(4): p.577-586. 27. Tivol, EA, et al., Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4.Immunity, 1995.3(5): p.541-7. 28. Waterhouse, P., et al., Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4.Science, 1995.270(5238): p.985-8. 29. Bertrand, A., et al., Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. Systematic BMC Med, 2015.13: p.211.

[0317] Embodiments of the invention are also described in the following numbered paragraphs. 1. A combination for use in treating cancer in a patient, comprising: - a first antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to PD-1 or PD-L1; and a third antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, The combination, wherein the cancer is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4. 2. In the manufacture of a medicament for treating cancer in a patient, - a first antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to PD-1 or PD-L1; and a third antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, The use, wherein the cancer is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4. 3. A method for treating cancer in a patient, the method comprising administering to the patient: - a first antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to PD-1 or PD-L1; and - a third antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor; The method, wherein the cancer is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4. 4. A first antibody molecule for treating cancer in a patient, the first antibody molecule specifically binds to FcyRllb via its Fab region and lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to PD-1 or PD-L1, and - for use in combination with a third antibody molecule that specifically binds CTLA-4 and binds via its Fc region to at least one Fcγ receptor; A first antibody molecule, wherein the cancer is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4. 5. A first antibody molecule for use in treating cancer in a patient, the first antibody molecule specifically binds FcyRllb via its Fab region and lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; A first antibody molecule, characterized in that the first antibody molecule reduces and / or prevents resistance in cancer to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4. 6. A pharmaceutical composition comprising: - a first antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to PD-1 or PD-L1; and - a third antibody molecule that specifically binds to CTLA-4 and binds to at least one Fcγ receptor via its Fc region. 7. A kit comprising: - a first antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to PD-1 or PD-L1; and - a third antibody molecule that specifically binds to CTLA-4 and binds to at least one Fcγ receptor via its Fc region. 8. The combination for use, use, method for use, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 7, wherein the first antibody molecule lacks an Fc region. 9. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 7, wherein the first antibody molecule has reduced binding to Fcγ receptors via its Fc region and has a non-glycosylated Fc region. 10. The combination for use, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 9, wherein the first antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin. 11. The combination for use, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 10, wherein the first antibody molecule is a monoclonal antibody molecule or a monoclonal-derived antibody molecule. 12. The combination for use, method for use, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 11, wherein the first antibody molecule is selected from the group consisting of a full-length antibody, a chimeric antibody, a single-chain antibody, a Fab fragment, a (Fab')2 fragment, a Fab' fragment, a (Fab')2 fragment, an Fv fragment, and an scFv fragment. 13. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit described in any one of paragraphs 1 to 12, wherein the first antibody molecule is a human IgG antibody molecule having an aglycosylated Fc region or a human-derived IgG antibody molecule having an aglycosylated Fc region. 14. The combination for use, the method for use, the first antibody molecule for use, the pharmaceutical composition or the kit according to paragraph 13, wherein the IgG antibody molecule is an IgG1 or an IgG2 antibody molecule. 15. The combination, use, method, first antibody molecule for use, pharmaceutical composition or kit according to paragraph 14, wherein the IgG antibody molecule is non-glycosylated human IgG1, or non-glycosylated humanized mouse antibody, or non-glycosylated humanized llama hclgG antibody, or non-glycosylated chimerized mouse IgG. 16. The combination for use, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to paragraph 15, wherein the first antibody is aglycosylated by an amino acid substitution at position 297. 17. The combination for use, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to paragraph 16, wherein the first antibody is aglycosylated with an N297Q substitution. 18. The combination, use, method, first antibody for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 17, wherein the first antibody molecule comprises a variable heavy chain (VH) comprising the following CDRs: (i) SEQ ID NO: 51 and SEQ ID NO: 52 and SEQ ID NO: 53, or (ii) SEQ ID NO: 57 and SEQ ID NO: 58 and SEQ ID NO: 59, or (iii) SEQ ID NO: 63, SEQ ID NO: 64, and SEQ ID NO: 65, or (iv) SEQ ID NO: 69 and SEQ ID NO: 70 and SEQ ID NO: 71, or (v) SEQ ID NO: 75 and SEQ ID NO: 76 and SEQ ID NO: 77, or (vi) SEQ ID NO: 81 and SEQ ID NO: 82 and SEQ ID NO: 83, or (vii) SEQ ID NO: 87, SEQ ID NO: 88, and SEQ ID NO: 89, or (viii) SEQ ID NO: 93 and SEQ ID NO: 94 and SEQ ID NO: 95, or (ix) SEQ ID NO: 99 and SEQ ID NO: 100 and SEQ ID NO: 101, or (x) SEQ ID NO: 105 and SEQ ID NO: 106 and SEQ ID NO: 107, or (xi) SEQ ID NO: 111 and SEQ ID NO: 112 and SEQ ID NO: 113, or (xii) SEQ ID NO: 117 and SEQ ID NO: 118 and SEQ ID NO: 119, or (xiii) SEQ ID NO: 123 and SEQ ID NO: 124 and SEQ ID NO: 125, or (xiv) SEQ ID NO: 129 and SEQ ID NO: 130 and SEQ ID NO: 131, or (xv) SEQ ID NO: 135 and SEQ ID NO: 136 and SEQ ID NO: 137, or (xvi) SEQ ID NO: 141 and SEQ ID NO: 142 and SEQ ID NO: 143, or (xvii) SEQ ID NO: 147 and SEQ ID NO: 148 and SEQ ID NO: 149, or (xviii) SEQ ID NO: 153 and SEQ ID NO: 154 and SEQ ID NO: 155, or (xix) SEQ ID NO: 159 and SEQ ID NO: 160 and SEQ ID NO: 161, or (xx) SEQ ID NO: 165 and SEQ ID NO: 166 and SEQ ID NO: 167, or (xxi) SEQ ID NO: 171 and SEQ ID NO: 172 and SEQ ID NO: 173, or (xxii) SEQ ID NO: 177 and SEQ ID NO: 178 and SEQ ID NO: 179, or (xxiii) SEQ ID NO: 183 and SEQ ID NO: 184 and SEQ ID NO: 185, or (xxiv) SEQ ID NO: 189, SEQ ID NO: 190, and SEQ ID NO: 191. 19. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 18, wherein the first antibody molecule comprises a variable light chain (VL) comprising the following CDRs: (i) SEQ ID NO: 54 and SEQ ID NO: 55 and SEQ ID NO: 56, or (ii) SEQ ID NO: 60 and SEQ ID NO: 61 and SEQ ID NO: 62, or (iii) SEQ ID NO: 66, SEQ ID NO: 67, and SEQ ID NO: 68, or (iv) SEQ ID NO: 72 and SEQ ID NO: 73 and SEQ ID NO: 74, or (v) SEQ ID NO: 78 and SEQ ID NO: 79 and SEQ ID NO: 80, or (vi) SEQ ID NO: 84 and SEQ ID NO: 85 and SEQ ID NO: 86, or (vii) SEQ ID NO: 90 and SEQ ID NO: 91 and SEQ ID NO: 92, or (viii) SEQ ID NO: 96 and SEQ ID NO: 97 and SEQ ID NO: 98, or (ix) SEQ ID NO: 102 and SEQ ID NO: 103 and SEQ ID NO: 104, or (x) SEQ ID NO: 108 and SEQ ID NO: 109 and SEQ ID NO: 110, or (xi) SEQ ID NO: 114 and SEQ ID NO: 115 and SEQ ID NO: 116, or (xii) SEQ ID NO: 120 and SEQ ID NO: 121 and SEQ ID NO: 122, or (xiii) SEQ ID NO: 126 and SEQ ID NO: 127 and SEQ ID NO: 128, or (xiv) SEQ ID NO: 132 and SEQ ID NO: 133 and SEQ ID NO: 134, or (xv) SEQ ID NO: 138 and SEQ ID NO: 139 and SEQ ID NO: 140, or (xvi) SEQ ID NO: 144 and SEQ ID NO: 145 and SEQ ID NO: 146, or (xvii) SEQ ID NO: 150 and SEQ ID NO: 151 and SEQ ID NO: 152, or (xviii) SEQ ID NO: 156 and SEQ ID NO: 157 and SEQ ID NO: 158, or (xix) SEQ ID NO: 162 and SEQ ID NO: 163 and SEQ ID NO: 164, or (xx) SEQ ID NO: 168 and SEQ ID NO: 169 and SEQ ID NO: 170, or (xxi) SEQ ID NO: 174 and SEQ ID NO: 175 and SEQ ID NO: 176, or (xxii) SEQ ID NO: 180 and SEQ ID NO: 181 and SEQ ID NO: 182, or (xxiii) SEQ ID NO: 186 and SEQ ID NO: 187 and SEQ ID NO: 188, or (xxiv) SEQ ID NO: 192, SEQ ID NO: 193, and SEQ ID NO: 194. 20. The combination, use, method for use, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 19, wherein the first antibody molecule comprises a variable heavy chain (VH) amino acid sequence selected from the group consisting of: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26. 21. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 20, wherein the first antibody molecule comprises a variable light chain (VL) amino acid sequence selected from the group consisting of: SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, and SEQ ID NO:50. 22. The combination for use, the method for use, the first antibody molecule for use, the pharmaceutical composition, or the kit according to any one of paragraphs 1 to 21, wherein the first antibody molecule comprises the following CDR amino acid sequence: (i) SEQ ID NO: 51 and SEQ ID NO: 52 and SEQ ID NO: 53 and SEQ ID NO: 54 and SEQ ID NO: 55 and SEQ ID NO: 56, or (ii) SEQ ID NO:57 and SEQ ID NO:58 and SEQ ID NO:59 and SEQ ID NO:60 and SEQ ID NO:61 and SEQ ID NO:62, or (iii) SEQ ID NO: 63 and SEQ ID NO: 64 and SEQ ID NO: 65 and SEQ ID NO: 66 and SEQ ID NO: 67 and SEQ ID NO: 68, or (iv) SEQ ID NO: 69 and SEQ ID NO: 70 and SEQ ID NO: 71 and SEQ ID NO: 72 and SEQ ID NO: 73 and SEQ ID NO: 74, or (v) SEQ ID NO: 75 and SEQ ID NO: 76 and SEQ ID NO: 77 and SEQ ID NO: 78 and SEQ ID NO: 79 and SEQ ID NO: 80, or (vi) SEQ ID NO: 81 and SEQ ID NO: 82 and SEQ ID NO: 83 and SEQ ID NO: 84 and SEQ ID NO: 85 and SEQ ID NO: 86, or (vii) SEQ ID NO: 87 and SEQ ID NO: 88 and SEQ ID NO: 89 and SEQ ID NO: 90 and SEQ ID NO: 91 and SEQ ID NO: 92, or (viii) SEQ ID NO: 93 and SEQ ID NO: 94 and SEQ ID NO: 95 and SEQ ID NO: 96 and SEQ ID NO: 97 and SEQ ID NO: 98, or (ix) SEQ ID NO: 99 and SEQ ID NO: 100 and SEQ ID NO: 101 and SEQ ID NO: 102 and SEQ ID NO: 103 and SEQ ID NO: 104, or (x) SEQ ID NO: 105 and SEQ ID NO: 106 and SEQ ID NO: 107 and SEQ ID NO: 108 and SEQ ID NO: 109 and SEQ ID NO: 110, or (xi) SEQ ID NO:111 and SEQ ID NO:112 and SEQ ID NO:113 and SEQ ID NO:114 and SEQ ID NO:115 and SEQ ID NO:116, or (xii) SEQ ID NO: 117 and SEQ ID NO: 118 and SEQ ID NO: 119 and SEQ ID NO: 120 and SEQ ID NO: 121 and SEQ ID NO: 122, or (xiii) SEQ ID NO: 123 and SEQ ID NO: 124 and SEQ ID NO: 125 and SEQ ID NO: 126 and SEQ ID NO: 127 and SEQ ID NO: 128, or (xiv) SEQ ID NO: 129 and SEQ ID NO: 130 and SEQ ID NO: 131 and SEQ ID NO: 132 and SEQ ID NO: 133 and SEQ ID NO: 134, or (xv) SEQ ID NO: 135 and SEQ ID NO: 136 and SEQ ID NO: 137 and SEQ ID NO: 138 and SEQ ID NO: 139 and SEQ ID NO: 140, or (xvi) SEQ ID NO: 141 and SEQ ID NO: 142 and SEQ ID NO: 143 and SEQ ID NO: 144 and SEQ ID NO: 145 and SEQ ID NO: 146, or (xvii) SEQ ID NO: 147 and SEQ ID NO: 148 and SEQ ID NO: 149 and SEQ ID NO: 150 and SEQ ID NO: 151 and SEQ ID NO: 152, or (xviii) SEQ ID NO: 153 and SEQ ID NO: 154 and SEQ ID NO: 155 and SEQ ID NO: 156 and SEQ ID NO: 157 and SEQ ID NO: 158, or (xix) SEQ ID NO: 159 and SEQ ID NO: 160 and SEQ ID NO: 161 and SEQ ID NO: 162 and SEQ ID NO: 163 and SEQ ID NO: 164, or (xx) SEQ ID NO: 165 and SEQ ID NO: 166 and SEQ ID NO: 167 and SEQ ID NO: 168 and SEQ ID NO: 169 and SEQ ID NO: 170, or (xxi) SEQ ID NO: 171 and SEQ ID NO: 172 and SEQ ID NO: 173 and SEQ ID NO: 174 and SEQ ID NO: 175 and SEQ ID NO: 176, or (xxii) SEQ ID NO: 177 and SEQ ID NO: 178 and SEQ ID NO: 179 and SEQ ID NO: 180 and SEQ ID NO: 181 and SEQ ID NO: 182, or (xxiii) SEQ ID NO: 183 and SEQ ID NO: 184 and SEQ ID NO: 185 and SEQ ID NO: 186 and SEQ ID NO: 187 and SEQ ID NO: 188, or (xxiv) SEQ ID NO: 189 and SEQ ID NO: 190 and SEQ ID NO: 191 and SEQ ID NO: 192 and SEQ ID NO: 193 and SEQ ID NO: 194. 23. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 22, wherein the first antibody molecule comprises the following amino acid sequence: (i) SEQ ID NO: 3 and SEQ ID NO: 27, or (ii) SEQ ID NO: 4 and SEQ ID NO: 28, or (iii) SEQ ID NO: 5 and SEQ ID NO: 29, or (iv) SEQ ID NO: 6 and SEQ ID NO: 30, or (v) SEQ ID NO: 7 and SEQ ID NO: 31, or (vi) SEQ ID NO: 8 and SEQ ID NO: 32, or (vii) SEQ ID NO: 9 and SEQ ID NO: 33, or (viii) SEQ ID NO: 10 and SEQ ID NO: 34, or (ix) SEQ ID NO: 11 and SEQ ID NO: 35, or (x) SEQ ID NO: 12 and SEQ ID NO: 36, or (xi) SEQ ID NO: 13 and SEQ ID NO: 37, or (xii) SEQ ID NO: 14 and SEQ ID NO: 38, or (xiii) SEQ ID NO: 15 and SEQ ID NO: 39, or (xiv) SEQ ID NO: 16 and SEQ ID NO: 40, or (xv) SEQ ID NO: 17 and SEQ ID NO: 41, or (xvi) SEQ ID NO: 18 and SEQ ID NO: 42, or (xvii) SEQ ID NO: 19 and SEQ ID NO: 43, or (xviii) SEQ ID NO: 20 and SEQ ID NO: 44, or (xix) SEQ ID NO: 21 and SEQ ID NO: 45, or (xx) SEQ ID NO: 22 and SEQ ID NO: 46, or (xxi) SEQ ID NO: 23 and SEQ ID NO: 47, or (xxii) SEQ ID NO: 24 and SEQ ID NO: 48, or (xxiii) SEQ ID NO: 25 and SEQ ID NO: 49, or (xxiv) SEQ ID NO: 26 and SEQ ID NO: 50. 24. A combination for use, use, method for use, first antibody molecule for use, pharmaceutical composition or kit described in any one of paragraphs 1 to 17, wherein the first antibody molecule is an antibody molecule capable of competing with an antibody molecule described in any one of paragraphs 18 to 23 for binding to FcyRllb. 25. The combination for use, the method for use, or the first antibody molecule for use according to any one of paragraphs 1 to 5 and 8 to 24, wherein the cancer is an FcyRllb positive B cell cancer. 26. The combination for use, the method for use, or the first antibody molecule for use according to any one of paragraphs 1 to 5 and 8 to 24, wherein the cancer is an FcyRllb-negative cancer. 27. The combination for use, the method for use, or the first antibody molecule for use according to paragraph 26, wherein the FcyRllb negative cancer is a solid cancer. 28. The combination for use, the method for use, or the first antibody molecule for use according to paragraph 27, wherein the solid cancer is selected from the group comprising carcinoma, sarcoma, and lymphoma. 29. The combination for use, use, method or first antibody molecule for use according to paragraph 27 or 28, wherein the solid cancer is selected from the group comprising melanoma, prostate cancer, colorectal cancer, hepatocellular carcinoma, lung cancer, bladder cancer, renal cancer, gastric cancer, cervical cancer, Merkel cell carcinoma or ovarian cancer, and / or the solid cancer is an immune-abandoned tumor, or an immune-excluded tumor, or a tumor with poor immune infiltration. 30. The combination for use, use, method, or first antibody molecule for use according to any one of paragraphs 1 to 4 and 8 to 29, wherein the cancer that is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4 is a recurrent cancer and / or a refractory cancer. 31. The combination for use, use, method, or first antibody molecule for use according to any one of paragraphs 1 to 5 and 8 to 30, wherein the patient has previously been treated with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4, and optionally the patient has become resistant following said treatment. 32. The combination for use, use, method, or first antibody molecule for use according to any one of paragraphs 1 to 5 and 8 to 30, wherein the patient has not been previously treated with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4, and optionally the patient is essentially resistant to such treatment. 33. The combination, use, method for use, or first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 32, wherein the second antibody molecule and / or the third antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin. 34. The combination, use, method for use, or first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 33, wherein the second antibody molecule and / or the third antibody molecule is a monoclonal antibody molecule or a monoclonal-derived antibody molecule. 35. The combination, use, method for use, or first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 34, wherein the second antibody molecule and / or the third antibody molecule is selected from the group consisting of full size antibodies, chimeric antibodies, single chain antibodies, and antigen-binding fragments thereof, which retain the ability to bind to an Fcγ receptor via its Fc region. 36. The combination, use, method for use, or first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 35, wherein the second antibody molecule and / or the third antibody molecule is a human IgG antibody, a humanized IgG antibody molecule, or an IgG antibody molecule of human origin. 37. The combination, use, method for use, or first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 36, wherein the second antibody molecule and / or the third antibody molecule binds to at least one activating Fcγ receptor via its Fc region. 38. The combination, use, method for use, or first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 1 to 36, wherein the second antibody molecule and / or the third antibody molecule have been engineered to improve binding to an activating Fc gamma receptor. 39. Use of a first antibody molecule to treat cancer in a patient, the first antibody molecule specifically binds to FcyRllb via its Fab region and lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; 13. The use of a first antibody molecule for reducing and / or preventing resistance in a cancer to treatment with a second antibody molecule that specifically binds to CTLA-4. 40. The use of paragraph 39, wherein the second antibody molecule is administered at a dose lower than the tolerated therapeutic dose. 41. A combination for use in treating cancer in a patient, comprising: - a first antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, A combination, characterized in that the combination comprises a dose of the second antibody molecule that is lower than the tolerated therapeutic dose. 42. In the manufacture of a medicament for treating cancer in a patient, - a first antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; - a second antibody molecule which specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, The use, wherein the combination comprises a dose of the second antibody molecule that is lower than the tolerated therapeutic dose. 43. A method for treating cancer in an individual, the method comprising administering to the patient: a first antibody molecule which specifically binds to FcyRllb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, - administering a second antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, The method is characterized in that the dose of the second antibody molecule administered is lower than the tolerated therapeutic dose. 44. A first antibody molecule for treating cancer in a patient, the first antibody molecule specifically binds to FcyRllb via its Fab region and lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; - for use in combination with a second antibody molecule that specifically binds CTLA-4 and binds via its Fc region to at least one Fcγ receptor; A first antibody molecule, characterized in that the dose of the second antibody molecule used is lower than the tolerated therapeutic dose. 45. A pharmaceutical composition comprising: a first antibody molecule which specifically binds to FcyRllb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, a second antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, A pharmaceutical composition, wherein the second antibody molecule is present in a dose that is lower than the tolerated therapeutic dose. 46. ​​A kit comprising: a first antibody molecule which specifically binds to FcyRllb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, a second antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, A kit, wherein the second antibody molecule is present at a dose lower than the tolerated therapeutic dose. 47. The combination, use, method for use, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 40 to 46, wherein the dose of the second antibody molecule is lower than the maximum tolerated therapeutic dose. 48. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 40 to 47, wherein the dose of the second antibody molecule is at least 50% lower than the tolerated therapeutic dose. 49. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 40 to 48, wherein the dose of the second antibody molecule is at least 70% lower than the tolerated therapeutic dose. 50. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 40 to 49, wherein the dose of the second antibody molecule is at least 80% lower than the tolerated therapeutic dose. 51. The combination, use, method for use, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 40 to 50, wherein the dose of the second antibody molecule is lower than the minimum effective therapeutic dose. 52. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 40 to 51, wherein the therapeutic effect of the first antibody molecule and the second antibody molecule used at a lower dose is comparable to the therapeutic effect of the second antibody molecule at the maximum tolerated therapeutic dose of the second antibody molecule in the absence of the first antibody molecule. 53. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 40 to 52, wherein use of a lower dose of the second antibody molecule improves the tolerability of the second antibody molecule. 54. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 40 to 53, wherein the use of a lower dose of the second antibody molecule reduces side effects and / or reduces toxicity in the subject associated with the use of the second antibody molecule. 55. The combination for use, use, method for use, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 39 to 54, wherein the second antibody molecule is ipilimumab and / or tremelimumab. 56. The combination for use, use, method for use, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 39 to 56, wherein the dose of the second antibody molecule is lower than 10 mg / kg. 57. The combination for use, use, method, first antibody for use, pharmaceutical composition, or kit according to any one of paragraphs 39 to 56, wherein the dose of the second antibody molecule is 3 mg / kg or lower than 3 mg / kg. 58. The combination for use, use, method for use, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 39 to 57, wherein the dose of the second antibody molecule is 2 mg / kg or lower than 2 mg / kg. 59. The combination for use, use, method for use, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 39 to 58, wherein the dose of the second antibody molecule is 1 mg / kg or lower than 1 mg / kg. 60. The combination for use, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 39 to 59, wherein the use or method does not also involve administration of an antibody molecule that specifically binds to PD-1 or PD-L1 and / or the pharmaceutical composition or kit does not also comprise an antibody molecule that specifically binds to PD-1 or PD-L1. 61. The combination for use, use, method for use, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 39 to 60, wherein the first antibody molecule lacks an Fc region. 62. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit described in any one of paragraphs 39 to 60, wherein the first antibody molecule has reduced binding to Fcγ receptors via its Fc region and has a non-glycosylated Fc region. 63. The combination for use, use, method, first antibody molecule for use, pharmaceutical composition, or kit described in any one of paragraphs 39 to 62, wherein the first antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin. 64. The combination for use, use, method, first antibody molecule for use, pharmaceutical composition, or kit described in any one of paragraphs 39 to 63, wherein the first antibody molecule is a monoclonal antibody molecule or a monoclonal-derived antibody molecule. 65. The combination for use, method for use, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 39 to 64, wherein the first antibody molecule is selected from the group consisting of a full-length antibody, a chimeric antibody, a single-chain antibody, a Fab fragment, a (Fab')2 fragment, a Fab' fragment, a (Fab')2 fragment, an Fv fragment, and an scFv fragment. 66. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit described in any one of paragraphs 39 to 65, wherein the first antibody molecule is a human IgG antibody molecule having an aglycosylated Fc region or a human-derived IgG antibody molecule having an aglycosylated Fc region. 67. The combination for use, the use, the method for use, the first antibody molecule for use, the pharmaceutical composition for use, or the kit for use according to paragraph 66, wherein the IgG antibody molecule is an IgG1 or an IgG2 antibody molecule. 68. The combination, use, method, first antibody molecule for use, pharmaceutical composition or kit according to paragraph 67, wherein the IgG antibody molecule is non-glycosylated human IgG1, or non-glycosylated humanized mouse antibody, or non-glycosylated humanized llama hclgG antibody, or non-glycosylated chimerized mouse IgG. 69. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to paragraph 68, wherein the first antibody molecule is aglycosylated by an amino acid substitution at position 297. 70. The combination for use, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to paragraph 69, wherein the first antibody molecule is aglycosylated with an N297Q substitution. 71. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 39 to 70, wherein the first antibody molecule comprises a variable heavy chain (VH) comprising the following CDRs: (i) SEQ ID NO: 51 and SEQ ID NO: 52 and SEQ ID NO: 53, or (ii) SEQ ID NO: 57 and SEQ ID NO: 58 and SEQ ID NO: 59, or (iii) SEQ ID NO: 63, SEQ ID NO: 64, and SEQ ID NO: 65, or (iv) SEQ ID NO: 69 and SEQ ID NO: 70 and SEQ ID NO: 71, or (v) SEQ ID NO: 75 and SEQ ID NO: 76 and SEQ ID NO: 77, or (vi) SEQ ID NO: 81 and SEQ ID NO: 82 and SEQ ID NO: 83, or (vii) SEQ ID NO: 87, SEQ ID NO: 88, and SEQ ID NO: 89, or (viii) SEQ ID NO: 93 and SEQ ID NO: 94 and SEQ ID NO: 95, or (ix) SEQ ID NO: 99 and SEQ ID NO: 100 and SEQ ID NO: 101, or (x) SEQ ID NO: 105 and SEQ ID NO: 106 and SEQ ID NO: 107, or (xi) SEQ ID NO: 111 and SEQ ID NO: 112 and SEQ ID NO: 113, or (xii) SEQ ID NO: 117 and SEQ ID NO: 118 and SEQ ID NO: 119, or (xiii) SEQ ID NO: 123 and SEQ ID NO: 124 and SEQ ID NO: 125, or (xiv) SEQ ID NO: 129 and SEQ ID NO: 130 and SEQ ID NO: 131, or (xv) SEQ ID NO: 135 and SEQ ID NO: 136 and SEQ ID NO: 137, or (xvi) SEQ ID NO: 141 and SEQ ID NO: 142 and SEQ ID NO: 143, or (xvii) SEQ ID NO: 147 and SEQ ID NO: 148 and SEQ ID NO: 149, or (xviii) SEQ ID NO: 153 and SEQ ID NO: 154 and SEQ ID NO: 155, or (xix) SEQ ID NO: 159 and SEQ ID NO: 160 and SEQ ID NO: 161, or (xx) SEQ ID NO: 165 and SEQ ID NO: 166 and SEQ ID NO: 167, or (xxi) SEQ ID NO: 171 and SEQ ID NO: 172 and SEQ ID NO: 173, or (xxii) SEQ ID NO: 177 and SEQ ID NO: 178 and SEQ ID NO: 179, or (xxiii) SEQ ID NO: 183 and SEQ ID NO: 184 and SEQ ID NO: 185, or (xxiv) SEQ ID NO: 189, SEQ ID NO: 190, and SEQ ID NO: 191. 72. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 39 to 71, wherein the first antibody molecule comprises a variable light chain (VL) comprising the following CDRs: (i) SEQ ID NO: 54 and SEQ ID NO: 55 and SEQ ID NO: 56, or (ii) SEQ ID NO: 60 and SEQ ID NO: 61 and SEQ ID NO: 62, or (iii) SEQ ID NO: 66, SEQ ID NO: 67, and SEQ ID NO: 68, or (iv) SEQ ID NO: 72 and SEQ ID NO: 73 and SEQ ID NO: 74, or (v) SEQ ID NO: 78 and SEQ ID NO: 79 and SEQ ID NO: 80, or (vi) SEQ ID NO: 84 and SEQ ID NO: 85 and SEQ ID NO: 86, or (vii) SEQ ID NO: 90 and SEQ ID NO: 91 and SEQ ID NO: 92, or (viii) SEQ ID NO: 96 and SEQ ID NO: 97 and SEQ ID NO: 98, or (ix) SEQ ID NO: 102 and SEQ ID NO: 103 and SEQ ID NO: 104, or (x) SEQ ID NO: 108 and SEQ ID NO: 109 and SEQ ID NO: 110, or (xi) SEQ ID NO: 114 and SEQ ID NO: 115 and SEQ ID NO: 116, or (xii) SEQ ID NO: 120 and SEQ ID NO: 121 and SEQ ID NO: 122, or (xiii) SEQ ID NO: 126 and SEQ ID NO: 127 and SEQ ID NO: 128, or (xiv) SEQ ID NO: 132 and SEQ ID NO: 133 and SEQ ID NO: 134, or (xv) SEQ ID NO: 138 and SEQ ID NO: 139 and SEQ ID NO: 140, or (xvi) SEQ ID NO: 144 and SEQ ID NO: 145 and SEQ ID NO: 146, or (xvii) SEQ ID NO: 150 and SEQ ID NO: 151 and SEQ ID NO: 152, or (xviii) SEQ ID NO: 156 and SEQ ID NO: 157 and SEQ ID NO: 158, or (xix) SEQ ID NO: 162 and SEQ ID NO: 163 and SEQ ID NO: 164, or (xx) SEQ ID NO: 168 and SEQ ID NO: 169 and SEQ ID NO: 170, or (xxi) SEQ ID NO: 174 and SEQ ID NO: 175 and SEQ ID NO: 176, or (xxii) SEQ ID NO: 180 and SEQ ID NO: 181 and SEQ ID NO: 182, or (xxiii) SEQ ID NO: 186 and SEQ ID NO: 187 and SEQ ID NO: 188, or (xxiv) SEQ ID NO: 192, SEQ ID NO: 193, and SEQ ID NO: 194. 73. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 39 to 72, wherein the first antibody molecule comprises a variable heavy chain (VH) amino acid sequence selected from the group consisting of: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26. 74. The combination, use, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 39 to 73, wherein the first antibody molecule comprises a variable light chain (VL) amino acid sequence selected from the group consisting of: SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, and SEQ ID NO:50. 75. The combination, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 39 to 74, wherein the first antibody molecule comprises the following CDR amino acid sequence: (i) SEQ ID NO: 51 and SEQ ID NO: 52 and SEQ ID NO: 53 and SEQ ID NO: 54 and SEQ ID NO: 55 and SEQ ID NO: 56, or (ii) SEQ ID NO:57 and SEQ ID NO:58 and SEQ ID NO:59 and SEQ ID NO:60 and SEQ ID NO:61 and SEQ ID NO:62, or (iii) SEQ ID NO: 63 and SEQ ID NO: 64 and SEQ ID NO: 65 and SEQ ID NO: 66 and SEQ ID NO: 67 and SEQ ID NO: 68, or (iv) SEQ ID NO: 69 and SEQ ID NO: 70 and SEQ ID NO: 71 and SEQ ID NO: 72 and SEQ ID NO: 73 and SEQ ID NO: 74, or (v) SEQ ID NO: 75 and SEQ ID NO: 76 and SEQ ID NO: 77 and SEQ ID NO: 78 and SEQ ID NO: 79 and SEQ ID NO: 80, or (vi) SEQ ID NO: 81 and SEQ ID NO: 82 and SEQ ID NO: 83 and SEQ ID NO: 84 and SEQ ID NO: 85 and SEQ ID NO: 86, or (vii) SEQ ID NO: 87 and SEQ ID NO: 88 and SEQ ID NO: 89 and SEQ ID NO: 90 and SEQ ID NO: 91 and SEQ ID NO: 92, or (viii) SEQ ID NO: 93 and SEQ ID NO: 94 and SEQ ID NO: 95 and SEQ ID NO: 96 and SEQ ID NO: 97 and SEQ ID NO: 98, or (ix) SEQ ID NO: 99 and SEQ ID NO: 100 and SEQ ID NO: 101 and SEQ ID NO: 102 and SEQ ID NO: 103 and SEQ ID NO: 104, or (x) SEQ ID NO: 105 and SEQ ID NO: 106 and SEQ ID NO: 107 and SEQ ID NO: 108 and SEQ ID NO: 109 and SEQ ID NO: 110, or (xi) SEQ ID NO:111 and SEQ ID NO:112 and SEQ ID NO:113 and SEQ ID NO:114 and SEQ ID NO:115 and SEQ ID NO:116, or (xii) SEQ ID NO: 117 and SEQ ID NO: 118 and SEQ ID NO: 119 and SEQ ID NO: 120 and SEQ ID NO: 121 and SEQ ID NO: 122, or (xiii) SEQ ID NO: 123 and SEQ ID NO: 124 and SEQ ID NO: 125 and SEQ ID NO: 126 and SEQ ID NO: 127 and SEQ ID NO: 128, or (xiv) SEQ ID NO: 129 and SEQ ID NO: 130 and SEQ ID NO: 131 and SEQ ID NO: 132 and SEQ ID NO: 133 and SEQ ID NO: 134, or (xv) SEQ ID NO: 135 and SEQ ID NO: 136 and SEQ ID NO: 137 and SEQ ID NO: 138 and SEQ ID NO: 139 and SEQ ID NO: 140, or (xvi) SEQ ID NO: 141 and SEQ ID NO: 142 and SEQ ID NO: 143 and SEQ ID NO: 144 and SEQ ID NO: 145 and SEQ ID NO: 146, or (xvii) SEQ ID NO: 147 and SEQ ID NO: 148 and SEQ ID NO: 149 and SEQ ID NO: 150 and SEQ ID NO: 151 and SEQ ID NO: 152, or (xviii) SEQ ID NO: 153 and SEQ ID NO: 154 and SEQ ID NO: 155 and SEQ ID NO: 156 and SEQ ID NO: 157 and SEQ ID NO: 158, or (xix) SEQ ID NO: 159 and SEQ ID NO: 160 and SEQ ID NO: 161 and SEQ ID NO: 162 and SEQ ID NO: 163 and SEQ ID NO: 164, or (xx) SEQ ID NO: 165 and SEQ ID NO: 166 and SEQ ID NO: 167 and SEQ ID NO: 168 and SEQ ID NO: 169 and SEQ ID NO: 170, or (xxi) SEQ ID NO: 171 and SEQ ID NO: 172 and SEQ ID NO: 173 and SEQ ID NO: 174 and SEQ ID NO: 175 and SEQ ID NO: 176, or (xxii) SEQ ID NO: 177 and SEQ ID NO: 178 and SEQ ID NO: 179 and SEQ ID NO: 180 and SEQ ID NO: 181 and SEQ ID NO: 182, or (xxiii) SEQ ID NO: 183 and SEQ ID NO: 184 and SEQ ID NO: 185 and SEQ ID NO: 186 and SEQ ID NO: 187 and SEQ ID NO: 188, or (xxiv) SEQ ID NO: 189 and SEQ ID NO: 190 and SEQ ID NO: 191 and SEQ ID NO: 192 and SEQ ID NO: 193 and SEQ ID NO: 194. 76. The combination, method, first antibody molecule for use, pharmaceutical composition, or kit according to any one of paragraphs 39 to 75, wherein the first antibody molecule comprises the following amino acid sequence: (i) SEQ ID NO: 3 and SEQ ID NO: 27, or (ii) SEQ ID NO: 4 and SEQ ID NO: 28, or (iii) SEQ ID NO: 5 and SEQ ID NO: 29, or (iv) SEQ ID NO: 6 and SEQ ID NO: 30, or (v) SEQ ID NO: 7 and SEQ ID NO: 31, or (vi) SEQ ID NO: 8 and SEQ ID NO: 32, or (vii) SEQ ID NO: 9 and SEQ ID NO: 33, or (viii) SEQ ID NO: 10 and SEQ ID NO: 34, or (ix) SEQ ID NO: 11 and SEQ ID NO: 35, or (x) SEQ ID NO: 12 and SEQ ID NO: 36, or (xi) SEQ ID NO: 13 and SEQ ID NO: 37, or (xii) SEQ ID NO: 14 and SEQ ID NO: 38, or (xiii) SEQ ID NO: 15 and SEQ ID NO: 39, or (xiv) SEQ ID NO: 16 and SEQ ID NO: 40, or (xv) SEQ ID NO: 17 and SEQ ID NO: 41, or (xvi) SEQ ID NO: 18 and SEQ ID NO: 42, or (xvii) SEQ ID NO: 19 and SEQ ID NO: 43, or (xviii) SEQ ID NO: 20 and SEQ ID NO: 44, or (xix) SEQ ID NO: 21 and SEQ ID NO: 45, or (xx) SEQ ID NO: 22 and SEQ ID NO: 46, or (xxi) SEQ ID NO: 23 and SEQ ID NO: 47, or (xxii) SEQ ID NO: 24 and SEQ ID NO: 48, or (xxiii) SEQ ID NO: 25 and SEQ ID NO: 49, or (xxiv) SEQ ID NO: 26 and SEQ ID NO: 50. 77. A combination for use, use, method, first antibody molecule for use, pharmaceutical composition or kit described in any one of paragraphs 39 to 70, wherein the first antibody molecule is an antibody molecule capable of competing with an antibody molecule described in any one of paragraphs 71 to 76 for binding to FcyRllb. 78. The combination for use, the method for use, or the first antibody molecule for use according to any one of paragraphs 39 to 44 and 47 to 77, wherein the cancer is an FcyRllb-positive B-cell cancer. 79. The combination for use, the method for use, or the first antibody molecule for use according to any one of paragraphs 39 to 44 or 47 to 77, wherein the cancer is an FcyRllb-negative cancer. 80. The combination for use, the method for use, or the first antibody molecule for use according to paragraph 79, wherein the FcyRllb negative cancer is a solid cancer. 81. The combination for use, the method for use, or the first antibody molecule for use according to paragraph 80, wherein the solid cancer is selected from the group comprising carcinoma, sarcoma, and lymphoma. 82. The combination for use, the method for use, or the first antibody molecule for use according to paragraph 80 or 81, wherein the solid cancer is selected from the group comprising melanoma, pancreatic cancer, breast cancer, prostate cancer, colorectal cancer, lung cancer, bladder cancer, renal cancer, mesothelioma, Merkel cell carcinoma, gastric cancer, cervical cancer, ovarian cancer, and head and neck cancer. 83. A combination, use, method for use, first antibody molecule for use, pharmaceutical composition, or kit substantially as claimed herein with reference to the accompanying numbered paragraphs, claims, specification, examples, and drawings.

Claims

1. 1. A combination for use in the treatment of cancer in a patient, comprising: - a first antibody molecule which specifically binds FcyRllb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; - a second antibody molecule that specifically binds to PD-1 or PD-L1; and a third antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, The combination, wherein the cancer is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4.

2. 1. A pharmaceutical composition for treating cancer in a patient, said pharmaceutical composition comprising a first antibody molecule that specifically binds FcyRllb via its Fab region and lacks an Fc region or has reduced binding to an Fcγ receptor via its Fc region, said first antibody molecule comprising: - a second antibody molecule that specifically binds to PD-1 or PD-L1, and a third antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor; It is intended to be used in combination with The pharmaceutical composition, wherein the cancer is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4.

3. 1. A pharmaceutical composition for use in treating cancer in a patient, said pharmaceutical composition comprising a first antibody molecule that specifically binds FcyRllb via its Fab region and lacks an Fc region or has reduced binding to an Fcγ receptor via its Fc region; wherein the first antibody molecule reduces and / or prevents resistance in the cancer to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4.

4. 1. A pharmaceutical composition comprising: - a first antibody molecule which specifically binds FcyRllb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; - a second antibody molecule that specifically binds to PD-1 or PD-L1; and - a third antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor.

5. A kit comprising: - a first antibody molecule which specifically binds FcyRllb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; - a second antibody molecule that specifically binds to PD-1 or PD-L1; and - a third antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor.

6. The combination, pharmaceutical composition or kit according to any one of claims 1 to 5, wherein the first antibody molecule lacks an Fc region or has an aglycosylated Fc region.

7. The combination, pharmaceutical composition or kit according to any one of claims 1 to 6, wherein the first antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin.

8. The combination, pharmaceutical composition or kit according to any one of claims 1 to 7, wherein said first antibody molecule comprises a variable heavy chain (VH) comprising the following CDRs: (i) SEQ ID NO: 51 and SEQ ID NO: 52 and SEQ ID NO: 53, or (ii) SEQ ID NO: 57, SEQ ID NO: 58, and SEQ ID NO: 59; or (iii) SEQ ID NO: 63, SEQ ID NO: 64, and SEQ ID NO: 65; or (iv) SEQ ID NO: 69 and SEQ ID NO: 70 and SEQ ID NO: 71, or (v) SEQ ID NO: 75 and SEQ ID NO: 76 and SEQ ID NO: 77, or (vi) SEQ ID NO: 81 and SEQ ID NO: 82 and SEQ ID NO: 83, or (vii) SEQ ID NO: 87 and SEQ ID NO: 88 and SEQ ID NO: 89; or (viii) SEQ ID NO:93 and SEQ ID NO:94 and SEQ ID NO:95, or (ix) SEQ ID NO: 99 and SEQ ID NO: 100 and SEQ ID NO: 101, or (x) SEQ ID NO: 105, SEQ ID NO: 106, and SEQ ID NO: 107, or (xi) SEQ ID NO: 111 and SEQ ID NO: 112 and SEQ ID NO: 113, or (xii) SEQ ID NO: 117, SEQ ID NO: 118, and SEQ ID NO: 119, or (xiii) SEQ ID NO: 123, SEQ ID NO: 124, and SEQ ID NO: 125, or (xiv) SEQ ID NO: 129 and SEQ ID NO: 130 and SEQ ID NO: 131, or (xv) SEQ ID NO: 135 and SEQ ID NO: 136 and SEQ ID NO: 137, or (xvi) SEQ ID NO: 141 and SEQ ID NO: 142 and SEQ ID NO: 143, or (xvii) SEQ ID NO: 147 and SEQ ID NO: 148 and SEQ ID NO: 149, or (xviii) SEQ ID NO: 153 and SEQ ID NO: 154 and SEQ ID NO: 155, or (xix) SEQ ID NO: 159 and SEQ ID NO: 160 and SEQ ID NO: 161, or (xx) SEQ ID NO: 165 and SEQ ID NO: 166 and SEQ ID NO: 167, or (xxi) SEQ ID NO: 171 and SEQ ID NO: 172 and SEQ ID NO: 173, or (xxii) SEQ ID NO: 177 and SEQ ID NO: 178 and SEQ ID NO: 179, or (xxiii) SEQ ID NO: 183, SEQ ID NO: 184, and SEQ ID NO: 185, or (xxiv) SEQ ID NO: 189 and SEQ ID NO: 190 and SEQ ID NO:

191.

9. The combination, pharmaceutical composition or kit according to any one of claims 1 to 8, wherein the first antibody molecule comprises a variable light chain (VL) comprising the following CDRs: (i) SEQ ID NO: 54 and SEQ ID NO: 55 and SEQ ID NO: 56, or (ii) SEQ ID NO: 60 and SEQ ID NO: 61 and SEQ ID NO: 62, or (iii) SEQ ID NO: 66, SEQ ID NO: 67, and SEQ ID NO: 68; or (iv) SEQ ID NO: 72 and SEQ ID NO: 73 and SEQ ID NO: 74, or (v) SEQ ID NO: 78 and SEQ ID NO: 79 and SEQ ID NO: 80, or (vi) SEQ ID NO: 84 and SEQ ID NO: 85 and SEQ ID NO: 86, or (vii) SEQ ID NO: 90 and SEQ ID NO: 91 and SEQ ID NO: 92, or (viii) SEQ ID NO:96 and SEQ ID NO:97 and SEQ ID NO:98, or (ix) SEQ ID NO: 102 and SEQ ID NO: 103 and SEQ ID NO: 104, or (x) SEQ ID NO: 108, SEQ ID NO: 109, and SEQ ID NO: 110; or (xi) SEQ ID NO: 114 and SEQ ID NO: 115 and SEQ ID NO: 116, or (xii) SEQ ID NO: 120 and SEQ ID NO: 121 and SEQ ID NO: 122, or (xiii) SEQ ID NO: 126, SEQ ID NO: 127, and SEQ ID NO: 128, or (xiv) SEQ ID NO: 132 and SEQ ID NO: 133 and SEQ ID NO: 134, or (xv) SEQ ID NO: 138 and SEQ ID NO: 139 and SEQ ID NO: 140, or (xvi) SEQ ID NO: 144 and SEQ ID NO: 145 and SEQ ID NO: 146, or (xvii) SEQ ID NO: 150 and SEQ ID NO: 151 and SEQ ID NO: 152, or (xviii) SEQ ID NO: 156, SEQ ID NO: 157, and SEQ ID NO: 158, or (xix) SEQ ID NO: 162 and SEQ ID NO: 163 and SEQ ID NO: 164, or (xx) SEQ ID NO: 168 and SEQ ID NO: 169 and SEQ ID NO: 170, or (xxi) SEQ ID NO: 174 and SEQ ID NO: 175 and SEQ ID NO: 176, or (xxii) SEQ ID NO: 180 and SEQ ID NO: 181 and SEQ ID NO: 182, or (xxiii) SEQ ID NO: 186, SEQ ID NO: 187, and SEQ ID NO: 188, or (xxiv) SEQ ID NO:192 and SEQ ID NO:193 and SEQ ID NO:

194.

10. The combination, pharmaceutical composition or kit of any one of claims 1 to 9, wherein the first antibody molecule comprises a variable heavy (VH) amino acid sequence selected from the group consisting of: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:

26.

11. The combination, pharmaceutical composition or kit of any one of claims 1 to 10, wherein the first antibody molecule comprises a variable light (VL) amino acid sequence selected from the group consisting of: SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, and SEQ ID NO:

50.

12. The combination, pharmaceutical composition or kit according to any one of claims 1 to 11, wherein said first antibody molecule comprises the following CDR amino acid sequences: (i) SEQ ID NO:51 and SEQ ID NO:52 and SEQ ID NO:53 and SEQ ID NO:54 and SEQ ID NO:55 and SEQ ID NO:56, or (ii) SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, and SEQ ID NO:62; or (iii) SEQ ID NO:63, and SEQ ID NO:64, and SEQ ID NO:65, and SEQ ID NO:66, and SEQ ID NO:67, and SEQ ID NO:68, or (iv) SEQ ID NO:69 and SEQ ID NO:70 and SEQ ID NO:71 and SEQ ID NO:72 and SEQ ID NO:73 and SEQ ID NO:74, or (v) SEQ ID NO: 75 and SEQ ID NO: 76 and SEQ ID NO: 77 and SEQ ID NO: 78 and SEQ ID NO: 79 and SEQ ID NO: 80, or (vi) SEQ ID NO:81 and SEQ ID NO:82 and SEQ ID NO:83 and SEQ ID NO:84 and SEQ ID NO:85 and SEQ ID NO:86, or (vii) SEQ ID NO:87 and SEQ ID NO:88 and SEQ ID NO:89 and SEQ ID NO:90 and SEQ ID NO:91 and SEQ ID NO:92, or (viii) SEQ ID NO:93 and SEQ ID NO:94 and SEQ ID NO:95 and SEQ ID NO:96 and SEQ ID NO:97 and SEQ ID NO:98, or (ix) SEQ ID NO: 99 and SEQ ID NO: 100 and SEQ ID NO: 101 and SEQ ID NO: 102 and SEQ ID NO: 103 and SEQ ID NO: 104, or (x) SEQ ID NO: 105 and SEQ ID NO: 106 and SEQ ID NO: 107 and SEQ ID NO: 108 and SEQ ID NO: 109 and SEQ ID NO: 110, or (xi) SEQ ID NO:111 and SEQ ID NO:112 and SEQ ID NO:113 and SEQ ID NO:114 and SEQ ID NO:115 and SEQ ID NO:116, or (xii) SEQ ID NO: 117 and SEQ ID NO: 118 and SEQ ID NO: 119 and SEQ ID NO: 120 and SEQ ID NO: 121 and SEQ ID NO: 122, or (xiii) SEQ ID NO: 123, and SEQ ID NO: 124, and SEQ ID NO: 125, and SEQ ID NO: 126, and SEQ ID NO: 127, and SEQ ID NO: 128, or (xiv) SEQ ID NO: 129 and SEQ ID NO: 130 and SEQ ID NO: 131 and SEQ ID NO: 132 and SEQ ID NO: 133 and SEQ ID NO: 134, or (xv) SEQ ID NO: 135 and SEQ ID NO: 136 and SEQ ID NO: 137 and SEQ ID NO: 138 and SEQ ID NO: 139 and SEQ ID NO: 140, or (xvi) SEQ ID NO: 141 and SEQ ID NO: 142 and SEQ ID NO: 143 and SEQ ID NO: 144 and SEQ ID NO: 145 and SEQ ID NO: 146, or (xvii) SEQ ID NO: 147 and SEQ ID NO: 148 and SEQ ID NO: 149 and SEQ ID NO: 150 and SEQ ID NO: 151 and SEQ ID NO: 152, or (xviii) SEQ ID NO: 153, and SEQ ID NO: 154, and SEQ ID NO: 155, and SEQ ID NO: 156, and SEQ ID NO: 157, and SEQ ID NO: 158, or (xix) SEQ ID NO: 159 and SEQ ID NO: 160 and SEQ ID NO: 161 and SEQ ID NO: 162 and SEQ ID NO: 163 and SEQ ID NO: 164, or (xx) SEQ ID NO: 165 and SEQ ID NO: 166 and SEQ ID NO: 167 and SEQ ID NO: 168 and SEQ ID NO: 169 and SEQ ID NO: 170, or (xxi) SEQ ID NO: 171 and SEQ ID NO: 172 and SEQ ID NO: 173 and SEQ ID NO: 174 and SEQ ID NO: 175 and SEQ ID NO: 176, or (xxii) SEQ ID NO: 177, and SEQ ID NO: 178, and SEQ ID NO: 179, and SEQ ID NO: 180, and SEQ ID NO: 181, and SEQ ID NO: 182, or (xxiii) SEQ ID NO: 183, and SEQ ID NO: 184, and SEQ ID NO: 185, and SEQ ID NO: 186, and SEQ ID NO: 187, and SEQ ID NO: 188, or (xxiv) SEQ ID NO:189 and SEQ ID NO:190 and SEQ ID NO:191 and SEQ ID NO:192 and SEQ ID NO:193 and SEQ ID NO:

194.

13. The combination, pharmaceutical composition or kit according to any one of claims 1 to 12, wherein said first antibody molecule comprises the following amino acid sequence: (i) SEQ ID NO: 3 and SEQ ID NO: 27, or (ii) SEQ ID NO: 4 and SEQ ID NO: 28, or (iii) SEQ ID NO:5 and SEQ ID NO:29, or (iv) SEQ ID NO: 6 and SEQ ID NO: 30, or (v) SEQ ID NO: 7 and SEQ ID NO: 31, or (vi) SEQ ID NO: 8 and SEQ ID NO: 32, or (vii) SEQ ID NO: 9 and SEQ ID NO: 33, or (viii) SEQ ID NO: 10 and SEQ ID NO: 34, or (ix) SEQ ID NO: 11 and SEQ ID NO: 35, or (x) SEQ ID NO: 12 and SEQ ID NO: 36, or (xi) SEQ ID NO: 13 and SEQ ID NO: 37, or (xii) SEQ ID NO: 14 and SEQ ID NO: 38, or (xiii) SEQ ID NO: 15 and SEQ ID NO: 39, or (xiv) SEQ ID NO: 16 and SEQ ID NO: 40, or (xv) SEQ ID NO: 17 and SEQ ID NO: 41, or (xvi) SEQ ID NO: 18 and SEQ ID NO: 42, or (xvii) SEQ ID NO: 19 and SEQ ID NO: 43, or (xviii) SEQ ID NO: 20 and SEQ ID NO: 44, or (xix) SEQ ID NO:21 and SEQ ID NO:45, or (xx) SEQ ID NO: 22 and SEQ ID NO: 46, or (xxi) SEQ ID NO: 23 and SEQ ID NO: 47, or (xxii) SEQ ID NO: 24 and SEQ ID NO: 48, or (xxiii) SEQ ID NO: 25 and SEQ ID NO: 49, or (xxiv) SEQ ID NO:26 and SEQ ID NO:

50.

14. The combination, pharmaceutical composition or kit according to any one of claims 1 to 13, wherein the cancer is an FcyRllb positive B cell cancer or an FcyRllb negative cancer.

15. The combination, pharmaceutical composition or kit of claim 14, wherein the FcyRllb negative cancer is a solid cancer, for example a solid cancer selected from the group including carcinoma, sarcoma and lymphoma, for example a solid cancer selected from the group including melanoma, prostate cancer, colon cancer, hepatocellular carcinoma, lung cancer, bladder cancer, renal cancer, gastric cancer, cervical cancer, Merkel cell carcinoma or ovarian cancer, and / or the solid cancer is an immune deserted tumor, or an immune excluded tumor, or a tumor with poor immune infiltration.

16. The combination, pharmaceutical composition, or kit according to any one of claims 1 to 15, wherein the cancer that is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and / or an antibody molecule that specifically binds to CTLA-4 is a recurrent cancer and / or a refractory cancer.

17. A combination, pharmaceutical composition, or kit described in any one of claims 1 to 16, wherein the second antibody molecule and / or the third antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin.

18. 1. A pharmaceutical composition for treating cancer in a patient, said pharmaceutical composition comprising a first antibody molecule that specifically binds FcyRllb via its Fab region and lacks an Fc region or has reduced binding to an Fcγ receptor via its Fc region; A pharmaceutical composition, characterized in that said first antibody molecule reduces and / or prevents resistance in said cancer to treatment with a second antibody molecule that specifically binds to CTLA-4.

19. 20. The pharmaceutical composition of claim 18, wherein the second antibody molecule is administered at a dose lower than the tolerated therapeutic dose.

20. 1. A combination for use in the treatment of cancer in a patient, comprising: - a first antibody molecule which specifically binds FcyRllb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; a second antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, The combination, characterized in that the combination comprises a dose of the second antibody molecule that is lower than the tolerated therapeutic dose.

21. 1. A pharmaceutical composition for treating cancer in a patient, said pharmaceutical composition comprising a first antibody molecule that specifically binds FcyRllb via its Fab region and lacks an Fc region or has reduced binding to an Fcγ receptor via its Fc region, said first antibody molecule comprising: - for use in combination with a second antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, A pharmaceutical composition characterized in that the dose of said second antibody molecule used is lower than the tolerated therapeutic dose.

22. 1. A pharmaceutical composition comprising: - a first antibody molecule which specifically binds to FcyRllb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, - a second antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, A pharmaceutical composition, wherein said second antibody molecule is present in a dose lower than the tolerated therapeutic dose.

23. A kit comprising: - a first antibody molecule which specifically binds to FcyRllb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, - a second antibody molecule that specifically binds to CTLA-4 and binds via its Fc region to at least one Fcγ receptor, The second antibody molecule is present in a dose that is lower than the tolerated therapeutic dose.

24. 24. The combination, pharmaceutical composition or kit of any one of claims 20 to 23, wherein said dose of said second antibody molecule is lower than the maximum tolerated therapeutic dose, such as at least 50% lower than said tolerated therapeutic dose.

25. The combination, pharmaceutical composition or kit according to any one of claims 20 to 24, wherein said dose of said second antibody molecule is lower than the minimum effective therapeutic dose.

26. 26. The combination, pharmaceutical composition or kit according to any one of claims 20 to 25, wherein the therapeutic effect of said first antibody molecule and said second antibody molecule used at a lower dose is comparable to the therapeutic effect of said second antibody molecule at a maximal tolerated therapeutic dose of said second antibody molecule in the absence of said first antibody molecule.

27. The combination, pharmaceutical composition, or kit of any one of claims 20 to 26, wherein the use of a lower dose of the second antibody molecule improves the tolerability of the second antibody molecule.

28. 28. The combination, pharmaceutical composition or kit according to any one of claims 20 to 27, wherein the use of said second antibody molecule at a lower dose reduces side effects and / or reduces toxicity in a subject associated with said use of said second antibody molecule.

29. The combination, pharmaceutical composition or kit according to any one of claims 20 to 28, wherein the second antibody molecule is ipilimumab and / or tremelimumab.

30. The combination, pharmaceutical composition or kit according to any one of claims 20 to 29, wherein the dose of the second antibody molecule is lower than 10 mg / kg.

31. The combination, pharmaceutical composition or kit according to any one of claims 20 to 30, wherein the first antibody molecule lacks an Fc region.

32. The combination, pharmaceutical composition or kit according to any one of claims 20 to 31, wherein said first antibody molecule has reduced binding to Fcγ receptors via its Fc region and has an aglycosylated Fc region.

33. The combination, pharmaceutical composition or kit according to any one of claims 20 to 32, wherein the first antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin.

34. The combination, pharmaceutical composition or kit according to any one of claims 20 to 33, wherein said first antibody molecule is as defined in any one of claims 8 to 13.

35. The combination or pharmaceutical composition according to any one of claims 20 to 34, wherein the cancer is as defined in any of claims 14 or 15.

36. The combination of claim 1, or the pharmaceutical composition of any one of claims 2 to 4, or the kit of claim 5, wherein the antibody molecule that specifically binds to CTLA-4 is administered at a dose lower than the tolerated therapeutic dose.

37. A pharmaceutical composition comprising an antibody molecule that specifically binds CTLA-4 and binds to at least one Fcγ receptor via its Fc region, for use in combination with a further antibody molecule that specifically binds FcyRllb via its Fab region and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, the pharmaceutical composition is for use in treating cancer in a patient; A pharmaceutical composition, wherein the dose of an antibody molecule that specifically binds to CTLA-4 is used at a dose lower than the tolerated therapeutic dose.

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