RU2800035C2 - New antibody combination and its use - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to the use of a new combination of antibodies. The application involves the use of a first antibody molecule that specifically binds FcγRIIb through its Fab region but lacks an Fc region or has reduced binding to Fc receptorsγ via its Fc region, for use in a combination with the second antibody molecule that specifically binds to a receptor present on an immune cell.

EFFECT: invention is effective for the treatment of FcγRIIb-negative cancer in patients.

33 cl, 10 dwg, 1 ex

Description

The field of technology to which the invention belongs

The present invention relates to the combined use of 1) an antibody molecule that specifically binds FcγRIIb through its Fab region, but lacks an Fc region or has reduced binding through its Fc region to at least one Fcγ receptor, and 2) an immune cell that depletes or deactivates an antibody molecule that specifically binds to a receptor present on an immune cell that suppresses anti-cancer immunity and in which an immune cell that depletes or deactivates deactivating antibody molecule has an Fc region that binds to at least one activating Fcγ receptor, in the treatment of FcγRIIb-negative cancers.

Prerequisites for the invention

It has long been known that the inhibitory Fc-gamma receptor (FcγR) IIB, expressed by numerous cells of the immune system, negatively regulates both innate and adaptive immunity through the involvement of immune complexes (ICs). Similarly, evidence that FcγRIIB inhibits monoclonal antibody immunotherapy has been known for over a decade. As such, FcγRIIB-deficient mice are able to more effectively cure tumors than wild-type (WT) mice when treated with mAb therapeutic antibodies, indicating that FcγRIIB expression on effector cells (i.e., macrophages and monocytes) leads to suppression of their phagocytic and cytotoxic potential in vivo. Moreover, FcγRIIB regulates the antigen-presenting potential of dendritic cells (DCs) and FcγRIIB-ve (van Montfoor et al., J. Immunol. 2012 Jul 1; 189 (1): 92-101). 2012 Jul 1; 189(1):92-101). Dendritic cells have an increased ability to activate intact T cells. Recently, antagonistic antibodies have been developed that block FcγRIIB signaling and internalization in B cells. Such antibodies exhibited efficient deletion of FcγRIIB-expressing B cells and effectively enhanced rituximab-mediated deletion of normal and malignant B cells, demonstrating a beneficial effect in hematologic cancer. However, it has not been investigated or shown whether such antibodies can also have a beneficial effect in the treatment of FcγRIIB-negative cancers, such as solid cancers.

The essence of the invention

In the present application, it was unexpectedly shown that only anti-FcγRIIB antibodies that do not have an Fc region or in which the Fc region shows reduced or impaired binding to FcγR receptors, for example, F(ab)'2 antibodies or aglycosylated antibodies, are able to enhance the therapeutic activity of antibodies used to treat FcγRIIB-negative cancers, including solid cancers. This finding was unexpected as previous studies have shown that anti-FcγRIIB wild-type IgG1 antibodies are equally capable of blocking FcγRIIB receptors and are equally capable of preventing rituximab internalization and rituximab-induced FcγRIIB phosphorylation in vitro.

According to the present invention, it is possible to enhance the therapeutic activity of immunomodulatory cancer antibodies whose therapeutic activity depends on the involvement of FcγR receptors. Such antibodies include, but are not limited to, antibodies against so-called immune checkpoint inhibitor targets such as CTLA-4, immune agonist targets such as OX40, 4-1BB and GITR, and interleukin-2 receptor (IL-2R).

Disclosed herein is a first antibody molecule that specifically binds to FcγRIIb via (or via) its Fab region and lacks an Fc region or has reduced binding to Fcγ receptors via (or via) its Fc region, for use in combination with a second antibody molecule that specifically binds to a receptor present on an immune cell, the immune cell being an immune cell that suppresses anti-cancer immunity, wherein the second antibody molecule has an Fc region that binds to at least one activating Fcγ receptor, wherein binding of the second antibody molecule to the receptor on an immune cell causes depletion and/or inactivation of that immune cell, in the treatment of an FcγRIIb-negative cancer in a patient.

The present application also discloses a pharmaceutical composition containing:

(i) a first antibody molecule that specifically binds FcγRIIb via its Fab region and lacks an Fc region or that has reduced binding to Fcγ receptors via its Fc region; And

(ii) a second antibody molecule that specifically binds to a receptor present on an immune cell, wherein the immune cell is an immune cell that suppresses anti-cancer immunity, wherein the second antibody molecule has an Fc region that binds to at least one activating Fcγ receptor, wherein binding of the second antibody to the receptor on the immune cell causes depletion and/or inactivation of that immune cell;

for use in the treatment of FcγRIIb-negative cancer in a patient.

Additionally disclosed herein is a kit for use in the treatment of FcγRIIb-negative cancer, comprising:

(i) a first antibody molecule that specifically binds FcγRIIb via its Fab region and lacks an Fc region or that has reduced binding to Fcγ receptors via its Fc region; And

(ii) a second antibody molecule that specifically binds to a receptor present on an immune cell, wherein the immune cell is an immune cell that suppresses anti-cancer immunity, wherein the second antibody molecule has an Fc region that binds to at least one activating Fcγ receptor, wherein binding of the second antibody molecule to a receptor on the immune cell causes depletion or inactivation of that immune cell.

Additionally, the present application discloses the use of:

(i) a first antibody molecule that specifically binds FcγRIIb via its Fab region and lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; And

(ii) a second antibody molecule that specifically binds to a receptor present on an immune cell, wherein the immune cell is an immune cell that suppresses anti-cancer immunity, wherein the second antibody molecule has an Fc region that binds to at least one activating Fcγ receptor, wherein binding of the second antibody to the receptor on the immune cell causes depletion or deactivation of the immune cell;

in the manufacture of a medicament for use in the treatment of FcγRIIb-negative cancer in a patient.

Also disclosed herein is a method for treating FcyRIIb-negative cancer in a patient, comprising administering:

(i) a first antibody molecule that specifically binds FcyRIIb via its Fab region and which lacks an Fc region or which has reduced binding to Fcy receptors via its Fc region; And

(ii) a second antibody molecule that specifically binds to a receptor present on an immune cell, wherein the immune cell is an immune cell that suppresses anti-tumor immunity, wherein the second antibody molecule has an Fc region that is capable of activating at least one activating Fcγ receptor, wherein binding of the second antibody to a receptor on that immune cell results in the depletion or deactivation of that immune cell.

Detailed description of the present invention

Thus, the present invention concerns the combined use of:

(i) an antibody molecule that specifically binds FcγRIIb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region (often referred to below as the first antibody molecule); And

(ii) an antibody molecule that specifically binds to a receptor present on an immune cell (often referred to below as a second antibody), wherein the immune cell is an immune cell that suppresses anti-cancer immunity, wherein the antibody molecule has an Fc region that binds to at least one activating Fcγ receptor, and wherein binding of the antibody molecule to a receptor on the immune cell causes depletion or inactivation of the immune cell. Thus, this second antibody molecule is an immune cell that depletes or deactivates the antibody molecule.

This combination is intended for use in the treatment of FcγRIIb-negative cancer in a patient to increase the therapeutic efficacy of the second antibody molecule through improved binding of its Fc region to activating FcγR receptors, with reduced binding/activation of the inhibitory FcγR receptor.

Fc receptors are membrane proteins that are found on the surface of immune effector cells such as macrophages. The name comes from the specificity of their binding to the Fc region of antibodies, which is the usual way that an antibody binds to a receptor. However, some antibodies can also bind Fc receptors via antibody CDR sequences in the case of antibodies that specifically bind to one or more Fc receptors.

A subgroup of Fc receptors are Fcγ receptors (Fc-gamma receptors, FcgammaR), which are specific for IgG antibodies. There are two types of Fcγ receptors: activating Fcγ receptors (also referred to as activation Fcγ receptors) and inhibitory Fcγ receptors. Activating and inhibitory receptors transmit their signals through immunoreceptor activating tyrosine motifs (ITAM) or immunoreceptor inhibitory tyrosine motifs (ITIM), respectively. In humans, FcγRIIb (CD32b) is an inhibitory Fcγ receptor, while FcγRI (CD64), FcγRIIa (CD32a), FcγRIIc (CD32c), FcγRIIIa (CD16a), and FcγRIV activate Fcγ receptors. FcγgRIIIb is a GPI-coupled receptor expressed on neutrophils that lacks the ITAM motif, but due to its ability to cross-link lipid rafts and interact with other receptors, it is also considered to be an activation receptor. In mice, the activating receptors are FcγRI, FcγRIII and FcγRIV.

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

By binding to an inhibitory Fcγ receptor, an antibody can inhibit, block and/or reduce the function of effector cells.

Binding the FCγ activating receptor, the antibodies can activate the functions of effector cells and thereby start mechanisms such as antibody -dependent cell cytotoxicity (ADCC), antibody -dependent cell phagocytosis (ADCP), the release of cytokines and/or antibody -dependent endocytosis, as well as non -voltage (i.e. Fish, neutrophilic extracellular traps) in the case of neutrophils. Binding of antibodies to the activating Fcγ receptor can also lead to an increase in some activation markers such as CD40, MHCII, CD38, CD80 and/or CD86.

An antibody molecule according to the present invention that specifically binds FcγRIIb, i.e. the first antibody binds or interacts with that Fcγ receptor through the Fab region of the antibody, i.e. through an antigen-binding site on an antibody that binds to antigens that consist of one constant and one variable domain of each heavy and light chain. In particular, it binds to FcγRIIb present on the immune effector cell, and in particular to FcγRIIb present on the surface of the immune effector cell. If this antibody had a regular or single Fc region, this antibody could also bind to the activating Fcγ receptor through the normal interaction between the Fc region and the Fc receptor. However, in accordance with the present invention, an antibody molecule that specifically binds FcγRIIb is completely devoid of an Fc region or has reduced binding to Fcγ receptors, meaning that an antibody molecule that specifically binds or interacts with FcγRIIb binds poorly or cannot bind or interact at all with Fcγ receptors. This appears to have at least two therapeutically important implications:

1) the lack of Fc-mediated binding to activating FcγR receptors leaves more activating Fc-gamma receptors available to bind to Fc of (other) therapeutic anti-cancer antibodies. This is important because the clustering of a growing number of activating FcγR receptors (as opposed to inhibitory FcγR receptors; Nimmerjahn et al.; Science. 2005 Dec 2; 310 (5753): 1510-2) is known to increase effector cell-mediated target cell deletion, a mechanism underlying activity as an immune response checkpoint inhibitor, immune agonist, and other immunomodulatory antibodies such as anti-IL-2R.

2) the absence or reduction of Fc-mediated binding to inhibitory FcγR has been shown to reduce inhibitory signaling in FcγR-expressing immune effector cells. Thus, the absence or reduction of Fc-mediated FcγR binding of an antibody targeting FcγRIIB likely enhances therapeutic efficacy through at least two mechanisms, including both improved FcγR activating signaling and reduced Fcγ inhibitory signaling in immune effector cells in response to a second immunomodulatory cancer antibody.

In this context, "reduced binding" or "reduced affinity binding" means that the antibody molecule has reduced Fc-mediated binding to Fcγ receptors, or, in other words, that the Fc region of the antibody molecule that specifically binds FcγRIIb binds to the Fcγ activating receptor with lower affinity than the Fc region of normal human IgG1. The reduction in binding can be assessed using methods such as surface plasmon resonance. In this context, "normal IgG1" means conventionally produced IgG1 with a wild-type Fc region that has not been produced to alter its glycosylation. Rituximab produced in Chinese Hamster Ovary (CHO) cells without any modification can be used as a reference for this "normal IgG1" (Tipton et al., Blood 2015 125: 1901-1909; rituximab is described inter alia in European Pharmacopoeia EP 0605442).

"Reduced binding" means that the binding of the Fc region of an antibody molecule that specifically binds FcγRIIb to the activating Fcγ receptor is at least 10-fold reduced for all Fc receptors compared to the binding of the Fc region of normal human IgG1 to the same receptors. In some embodiments of the invention, it is reduced by at least 20 times. In some embodiments of the invention, it is reduced by at least 30 times. In some embodiments of the invention, it is reduced by at least 40 times. In some embodiments of the invention, it is reduced by at least 50 times. In some embodiments of the invention, it is reduced by at least 60 times. In some embodiments of the invention, it is reduced by at least 70 times.

In some embodiments of the present invention, an antibody molecule that specifically binds FcγRIIb does not bind to its Fc region at all, and in some such cases, the antibody does not have an Fc region; then it can be Fab, Fab'2, scFv or their pegylated variants.

In some embodiments, the antibody molecule that specifically binds FcγRIIb may be a llama antibody, and in particular a llama hcIgG antibody. Like all mammals, the camelid produces conventional antibodies consisting of two heavy chains and two light chains linked together by disulfide bonds in the form of Y (IgG1). However, they also produce two unique immunoglobulin G subclasses, IgG2 and IgG3, also known as IgG heavy chains (hcIgG). These antibodies consist of only two heavy chains that do not have a CH1 region, but still have an antigen-binding domain at their N-terminus, called V _and H. Conventional Ig requires association of variable regions, both heavy and light chains, to allow for a wide variety of antigen-antibody interactions. Although isolated heavy and light chains still show this ability, they show a very low affinity ⁴ compared to paired heavy and light chains. A unique feature of hcIgG is the ability of their monomeric antigen-binding sites to bind antigens with a specificity, affinity, and especially diversity that is comparable to conventional antibodies, without the need to connect to another site.

In some embodiments, "reduced binding" means that the binding affinity of the antibody for FcγRI is reduced by 20-fold.

To obtain reduced binding of any IgG1 antibody, such as an IgG1 antibody, to the Fc receptor, the Fc region of the IgG antibody can be modified by aglycosylation. Such aglycosylation of, for example, an IgG1 antibody can be achieved, for example, by substituting the amino acid, asparagine, at position 297 (N297X) in the chain of this antibody. The substitution may be glutamine (N297Q) or alanine (N297A) or glycine (N297G) or asparagine (N297D) or serine (N297S).

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

L242C, N297G, K334C,

A287C, N297G, L306C,

R292C, N297G, V302C,

N297G, V323C, I332C and F71Y.

V259C, N297G, L306C;

Alternatively, the carbohydrate in the Fc region can be digested with enzymes; and/or the cells used to produce the antibody can be grown in a medium that impairs the addition of carbohydrate, and/or the cells genetically altered so that they cannot add sugar can be used to produce antibodies or by producing antibodies in host cells that do not glycosylate or functionally glycosylate antibodies, for example, in prokaryotic cells, including E. coli, as explained above.

Affinity reduction for Fc-gamma receptors can be further achieved by bioengineering the amino acids in the Fc region of the antibody (such modifications have been previously described, for example, by authors such as Xencor, Macrogenics and Genentech) or by producing antibodies in host cells that do not glycosylate or functionally glycosylate antibodies, for example, prokaryotes, including E. coli.

In addition to the antibody molecule having reduced binding to Fcy receptors via the Fc region, in some embodiments, it is preferable that an antibody molecule that specifically binds FcyRIIb does not cause FcyRIIb phosphorylation upon target binding. Phosphorylation of the immunoreceptor inhibitory tyrosine-containing motif (ITIM) of FcyRIIb is an inhibitory process that blocks activity in an immune cell.

An Fc-gamma receptor expressing an immune effector cell refers herein primarily to innate effector cells and includes, in particular, macrophages, neutrophils, monocytes, natural killer (NK) cells, basophils, eosinophils, mast cells, and platelets. Cytotoxic and memory T cells generally do not express FcyR receptors, but may do so under certain conditions. In some embodiments, the immune effector cell is an innate immune effector cell. In some embodiments of the invention, the immune effector cell is a macrophage.

Unlike an antibody molecule that specifically binds FcyRIIb, an antibody molecule that specifically binds or interacts with a receptor present on the target immune cell, i. the second antibody molecule or immune cell depleting or deactivating the antibody molecule has an Fc region that binds to or interacts with the activating Fcy receptor to a degree that is not reduced, or at least not significantly reduced. The immune cell to which the second antibody molecule binds, ie. an immune cell that depletes and deactivates an antibody molecule is an immune cell that suppresses anti-cancer immunity, and binding of the second antibody to the cell results in the depletion or deactivation of that immune cell, which may belong to the innate (e.g., TAM, TAN, or MDSC) or acquired arm (e.g., T cells) of the immune system.

Under the depletion of the cells in this application refers to the depletion, deletion or elimination of immune cells through the physical elimination of cells. In particular, this refers to the depletion of intratumoral immune cells or the depletion of tumor-associated immune cells, for example, those cells that were previously sent to the lymph nodes draining the tumor.

Under the deactivation of the immune cell in this application means blocked or reduced activity, such as reduced production of cytokines, growth factors, arginase or nitric oxide. In the context of the present application, deactivation of an immune cell also includes distorting immune cells such that their pro-tumor phenotype changes into an anti-tumor phenotype, for example, by reducing the release of anti-inflammatory cytokines, decreasing the release of pro-angiogenic growth factors, as well as increasing the release of pro-inflammatory cytokines and increasing reactive oxygen species (ROS), phagocytosis, or antibody-dependent cellular cytotoxicity (ADCC) activity.

The following explains how to determine if an antibody is an immune cell that depletes or deactivates the antibody.

The immune cell to which the second antibody molecule specifically binds is an immune cell that suppresses anti-cancer immunity. In this context, anti-cancer immunity includes, but is not limited to, the induction of acquired T-cell mediated anti-cancer immunity, including the development of an immune response to what is stored in immunological memory.

The immune cell to which the second antibody molecule specifically binds may be a regulatory T cell. Regulatory T cells, Treg cells (Tregs or Tregs) (formerly known as suppressor T cells, sometimes also called suppressive regulatory T cells) are a subpopulation of T cells that are capable of suppressing other immune cells under conditions of normal immunity and under conditions of pathological immunity. The immune cell to which the second antibody molecule specifically binds may alternatively be a myeloid cell, in particular a tumor-associated myeloid cell. In some embodiments, the tumor-associated myeloid cell is a tumor-associated macrophage, sometimes referred to as TAM. In some embodiments, this is a tumor-associated neutrophil, sometimes referred to as a TAN. In some embodiments of the invention, this is a dendritic cell. In some embodiments, this is a myeloid suppressor cell, which may be of the monocytic or granulocytic type.

In addition to binding specifically to any target on an immune cell, the second antibody molecule binds via its Fc region to an activating Fcγ receptor present on the same immune effector cell as the FcyRIIb to which the first antibody molecule binds and/or to an activating Fcγ receptor present on another immune effector cell. In order to be able to bind to the activating Fcy receptor, the Fc region of the second antibody must, in at least some embodiments, be glycosylated at position 297. The carbohydrate residue at this position facilitates binding to Fcy receptors. In some embodiments, these residues are preferably biantennary carbohydrates that contain GlnNAc, galactose-terminated mannose, and sialic acid. It must contain the CH2 region of the Fc molecule.

The cancer being treated or treatable according to the present invention is an FcyRIIb negative cancer, which means that it is a cancer in which there are no FcyRIIb receptors. This can be verified using specific anti-FcyRIIB antibodies in a variety of ways, including immunohistochemistry and flow cytometry, as shown by Tutt et al. J Immunol 2015, 195 (11) 5503-5516.

Antibodies are well known to those skilled in the art of immunology and molecular biology. Typically, an antibody consists of two heavy (H) chains and two light (L) chains. In this application, this full antibody molecule is sometimes referred to as a full-length antibody or a full-length antibody. The heavy chain of an antibody contains one variable domain (VH) and three constant domains (CH1, CH2 and CH3), while the light chain of an antibody molecule contains one variable domain (VL) and one constant domain (CL). Variable domains (sometimes collectively referred to as the F _V region) bind to an antibody target or antigen. Each variable domain consists of three loops called complementarity determining regions (CDRs) that are responsible for target binding. The constant domains are not directly involved in the binding of an antibody to an antigen, but exhibit various effector functions. Antibodies or immunoglobulins can be assigned to different classes depending on the amino acid sequence of the constant region of their heavy chains. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and in humans, some of these immunoglobulins are further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, and IgG4; IgA1 and IgA2.

The other part of an antibody is the Fc region (also known as the crystallizing domain fragment), which consists of the two constant domains of each of the heavy chains of the antibody. As mentioned above, the Fc region is responsible for the interaction between the antibody and the Fc receptor.

The term "antibody molecule" as used herein refers to full-length or full-length antibodies, as well as functional fragments of full-length antibodies and derivatives of such antibody molecules.

Functional fragments of a full length antibody have the same antigen binding characteristics as the corresponding full length antibody and include either the same variable domains (ie VH and VL sequences) or the same CDR sequences as the corresponding full length antibody. That a functional fragment has the same antigen binding characteristics as the corresponding full length antibody means that it binds to the same epitope on the target as the full length antibody. Such a functional fragment may correspond to the Fv region of a full length antibody. Alternatively, such a fragment may be a Fab, also referred to as F(ab), which is a monovalent antigen-binding fragment containing no Fc regions, or F(ab') ₂ , which is a bivalent antigen-binding fragment containing two disulfide-linked Fab antigen-binding regions, or F(ab'), i.e. monovalent version of F(ab') ₂ . Such a fragment may also be a single chain variable fragment (scFv).

A functional fragment does not always contain all six complementarity determining regions (CDRs) of the corresponding full length antibody. It should be noted that molecules containing three or fewer CDRs (in some cases even only one CDR or part thereof) are able to retain the antigen-binding activity of an antibody derived from complementarity determining regions (CDRs). For example, Gao et al., 1994, J. Biol. Chem., 269: 32389-93 indicates that the entire VL chain (including all three CDRs) has a high affinity for its substrate.

Molecules containing two CDRs are described, for example, in Vaughan & Sollazzo 2001, Combinatorial Chemistry & High Proposal Screening, 4: 417-430. On page 418 (right column - 3 "Our design strategy"), a mini-antibody is described that includes only the hypervariable regions of the H1 and H2 CDRs interspersed within the framework regions. This mini-antibody is described as being able to bind to a target. To Pessi et al., 1993, Nature, 362: 367-9, and Bianchi et al., 1994, J. Mol. Biol., 236: 649-59, refer to Vaughan and Sollazzo and describe the H1 and H2 miniantibodies and their properties in more detail. Qiu et al., 2007, Nature Biotechnology, 25:921-9 shows that a molecule consisting of two linked CDRs is capable of binding an antigen. Quiocho 1993, Nature, 362: 293-4, gives a brief description of the "minibody" technology. Ladner 2007, Nature Biotechnology, 25:875-7, comments that molecules containing two CDR regions are able to retain antigen-binding activity.

Antibody molecules containing a single CDR region are described, for example, in Laune et al., 1997, JBC, 272: 30937-44, which shows that a number of hexapeptides derived from the CDR region show antigen-binding activity, and it is noted that synthetic peptides of the complete single CDR region show strong binding activity. Monnet et al., 1999, JBC, 274: 3789-96, showed that a number of 12-mer peptides and their associated frameworks have antigen-binding activity and commented that a CDR3-like peptide alone was capable of binding antigen. In Heap et al., 2005, J. Gen. Virol., 86: 1791-1800, a "micro-antibody" (a molecule containing a single CDR region) is reported to be able to bind an antigen, and a cyclic peptide from an anti-HIV antibody has been shown to have antigen-binding activity and function. Nicaise et al., 2004, Protein Science, 13: 1882-91, shows that a single CDR region can confer antigen-binding activity and affinity for its lysozyme antigen.

Thus, antibody molecules having five, four, three, or fewer CDRs are able to retain the antigen-binding properties of the full-length antibodies from which they are derived.

Such an antibody molecule may also be a derivative of a full length antibody or a fragment of such an antibody. When a derivative is used, it must 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.

Thus, the term "antibody molecule", as used in this application, refers to all types of antibody molecules and their functional fragments, as well as their derivatives, 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 Fvs (sc Fv), fragments Fab, fragments F(ab')₂, F(ab'), Fvs (sdFv) fragments with a disulfide bond, antibody heavy chains, antibody light chains, antibody heavy chain homodimers, antibody light chain homodimers, antibody heavy chain heterodimers, antibody light chain heterodimers, antigen-binding functional fragments of such homo- and heterodimers.

In addition, the term "antibody molecule" as used in this application includes all classes of antibody molecules and functional fragments, including: IgG, IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgD and IgE, unless otherwise indicated.

In some embodiments, the antibody is human IgG1. A person skilled in immunology will state that mouse IgG2a immunoglobulin and human IgG1 immunoglobulin interact with activating Fc-gamma receptors and demonstrate the ability to activate target cell deletion by activating activating Fc-gamma receptors having immune cells such as ADCP and ADCC. Thus, in embodiments where murine IgG2a is the preferred isotype for deletion in the mouse, human IgG1 is the preferred isotype for deletion in humans in such embodiments.

As indicated above, the present invention includes various types and forms of antibody molecules, which should be known to a person skilled in the field of immunology. It is well known that antibodies used for therapeutic purposes are often modified with additional components that alter the properties of the antibody molecule.

Accordingly, this application contemplates that an antibody molecule of the present invention or an antibody molecule used in accordance with the present invention (e.g., a monoclonal antibody molecule and/or a polyclonal antibody molecule and/or a bispecific antibody molecule) contains a detectable molecular moiety and/or a cytotoxic molecular moiety.

By "detectable molecule fragment" we mean one or more groups consisting of: enzyme, radioactive atom, fluorescent molecule fragment, chemiluminescent molecule fragment, bioluminescent molecule fragment. The detectable fragment of the molecule allows visualization of the antibody molecule in vitro and/or in vivo and/or ex vivo.

Under the "cytotoxic fragment of the molecule" in the present invention means a radioactive part and/or enzyme, and the enzyme is a caspase; and/or a toxin, wherein the toxin is a bacterial toxin or poison; moreover, the cytotoxic fragment is capable of inducing cell lysis.

It is also contemplated in the present invention that the antibody molecule may be in isolated form and/or purified form, and/or may be pegylated. PEGylation is a method by which polyethylene glycol polymers are added to a molecule, such as an antibody molecule or derivative, in order to change its behavior, such as extending its half-life by increasing its hydrodynamic size, preventing excretion by the kidneys.

As discussed above, complementarity determining regions (CDRs) of an antibody bind to a target antibody. The assignment of amino acids to each CDR site described in this application corresponds to the definitions according to the work of Kabat EA et al. 1991, in Sequences of Proteins of Immunological Interest, fifth edition, NIH publication no. 91-3242, pp. xv-xvii.

As one of skill in immunology may be aware, there are other ways to assign amino acids to each CDR region. For example, the International Immunogenetics Information System (IMGT(R)) (http://www.imgt.org/ and immunological fact book, Lefranc and Lefranc, published by Academic Press, 2001).

In a further embodiment of the invention, an antibody molecule of the present invention, or used in accordance with the present invention, is an antibody molecule that is capable of competing with the specific antibodies provided herein, for example, with antibody molecules containing any of the amino acid sequences indicated, for example, in the sequences of SEQ ID NO: 1-194, for binding to a specific target.

By "capable of competing for" is meant that the competing antibody is capable of inhibiting or otherwise interfering, at least in part, with the binding of an antibody molecule, as defined herein, to a particular target.

For example, such a competitive antibody molecule may be capable of inhibiting the binding of an antibody molecule described herein by at least about 10%; for example, 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 inhibit the ability of an antibody described herein to interfere with or reduce binding to a specific target by at least about 10%, such as 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%.

Competitive binding can be determined by methods well known to those skilled in the art, such as enzyme immunoassay (ELISA).

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

It is well known that an antibody specifically binds or interacts with a specific target molecule or antigen. In other words, the antibody preferentially and selectively binds to its target, and not to a molecule that is not a target.

The targets of the antibodies of the present invention or of the antibodies used in accordance with the present invention are expressed on the surface of cells, i. they are a cell surface antigen that may include an epitope (also known in the context of this application as a cell surface epitope) for this antibody. Cell surface antigen and epitope are terms that can be easily understood by those skilled in immunology or cell biology.

By "cell surface antigen" in this application is meant that the surface cell antigen is located on the extracellular side of the cell membrane, but can be located on the extracellular side of the cell membrane only temporarily. By "temporarily located" in this application is meant that the surface cell antigen can be internalized into the cell or released from the extracellular side of the cell membrane into the extracellular space. The cell surface antigen can be released from the extracellular side of the cell membrane by cleavage, which can be mediated by a protease.

The cell surface antigen may be released from the extracellular side of the cell membrane by cleavage, which may be mediated by a protease. The term "temporarily bound" means that the cell surface antigen can be released from the extracellular side of the cell membrane into the extracellular space. The cell surface antigen may be released from the extracellular side of the cell membrane by cleavage, which may be mediated by a protease.

It is also contemplated herein that the cell surface antigen may be a peptide or a polypeptide or a carbohydrate or an oligosaccharide chain or a lipid and/or an epitope that is present on a protein or a glycoprotein or a lipoprotein.

Methods for assessing protein binding are known to those skilled in the art of biochemistry and immunology. It would be desirable if those skilled in the art could use these methods to assess binding of an antibody to a target and/or binding of the Fc region of an antibody to an Fc receptor, as well as to assess the relative strength or specificity or inhibition or reduction of these interactions or interference with these interactions. Examples of methods that can be used to assess protein binding are, for example, immunoassay, cell-to-cell interaction analysis using BIAcore systems, Western blotting, radioimmunoassay (RIA), and enzyme-linked immunosorbent assay (ELISA) (for a discussion of antibody specificity, see Fundamental Immunology Second Edition, Raven Press, New York, pages 332-336 (1989) (for a discussion of antibody specificity, see Fundamental Immunology, second edition, Raven Press, New York) (1989).

Accordingly, by "antibody molecule that specifically binds" or "antibody molecule specific for a target" in this application is meant that the antibody molecule specifically binds to the target, but does not bind to the non-target site, or binds to the non-target site (such as a site with lower affinity) more weakly than to the target.

Also included in the present application is the concept that an antibody specifically binds to a target at least two times stronger, or at least five 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 than with a site that is not target.

In addition, the present application includes the concept that an antibody specifically binds to a target if it binds to a target with a Kd of at least about 10-1 Kd, or at least about 10-2 Kd, or at least about 10-3 Kd, or at least about 10-4 Kd, or at least about 10-5 Kd, or at least about 10-6 Kd, or at least about 10-7 Kd, or at least about 10-8 Kd, or at least about 10-9 Kd, or at least about 10-10 Kd, or at least about 10-11 Kd, or at least about 10-12 Kd, or at least about 10-13 Kd, or at least about 10-14 Kd, or at least about 10-15 Kd.

As used herein, the term "immune cell depleting antibody molecule" or "immune cell deactivating antibody molecule" refers to an antibody molecule that, when administered to a patient, specifically binds to a target expressed on the surface of an immune cell, this binding resulting in the depletion or deactivation of the immune cell. In some embodiments of the invention, such a target is a target that is predominantly expressed on the tumor or in the tumor microenvironment.

To decide whether or not an antibody molecule is an antibody molecule depleting immune cell, in the concept of the present invention, an in vitro antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) assay can be applied. To decide if an antibody molecule is an immune cell molecule depleting an antibody molecule, the same assay will be performed in the presence of a depleting antibody and without a depleting antibody, which will show if the depleting antibody that is being tested is depleting.

An ADCC assay can be performed by labeling target cells with calcein AM (acetyl methyl ether) followed by the addition of diluted concentrations of antibody. The target cells are then cultured with human peripheral blood mononuclear cells (PBMC) at an effector:target (E:T) ratio of 50:1 for 4 hours at 37°C. The plate is centrifuged at a centrifugal acceleration of 400 g for 5 min to obtain a pellet of cells in the tube after centrifugation, and the supernatant is transferred to a white 96-well plate. The release of calcein was measured using a Varioskan instrument (Thermo Scientific) with an excitation wavelength of 485 nm and an emission wavelength of 530 nm. The percent maximum release is calculated as follows: % maximum release = (sample/triton treated) * 100.

ADCP analysis can be performed by labeling target cells with 5 mM carboxyfluorescein succinimidyl ether (CFSE) for 10 minutes at room temperature before washing in media containing fetal calf serum. CFSE-labeled targets are then opsonized with dilution concentrations of antibody before co-culture with bone marrow-derived macrophages (BMDM) at a ratio of 1:5 E:T in 96-well plates for 1 hour at 37°C. Bone marrow-derived macrophages (BMDM) are then labeled with anti-F4/80-allophycocyanin for 15 min at room temperature and washed twice with phosphate buffered saline (PBS). The plates are kept on ice, the wells are scraped to collect bone marrow-derived macrophages (BMDM), and phagocytosis is assessed by flow cytometry using the FACSCalibur (BD) analytical system to determine the percentage of F4/80+CFSE+ cells in the F4/80+ cell population.

You can also use the method described by Cleary et al. in J Immunol, April 12, 2017, 1601473.

In some embodiments, the antibody molecule that specifically binds FcyRIIb is a human antibody.

In some embodiments, the antibody molecule that specifically binds FcyRIIb is an antibody of human origin, i. originally a human antibody that has been modified as described in this application.

In some embodiments, the antibody molecule that specifically binds FcyRIIb is a humanized antibody, i. originally a non-human antibody that has been modified to increase its similarity to a human antibody. The humanized antibodies can be, for example, murine or llama antibodies.

In some embodiments, the antibody molecule that specifically binds FcyRIIb contains the following constant regions (CH and CL):

IgG1-CH [SEQ ID NO: 1]

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

IgG1-CL [SEQ ID NO: 2]

QPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS

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 Fcy receptors via its Fc region. As mentioned in this application, in some embodiments of the invention, it is preferable that the sequence of SEQ ID NO: 1 was aglycosylated by substitution N297Q, then IgG1-CH has the following sequence CH [SEQ ID NO: 195], with residue 297 Q marked in bold:

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY Q SRVVSVLTV LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

In some embodiments and/or examples, mouse antibody molecules are used. They can also be used to obtain surrogate antibodies Then they can include the following constant regions (CH and CL):

CH [SEQ ID NO: 196]

AKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDY STLRVVSALPIQHQ DWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK

CL [SEQ ID NO: 197]

QPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS

Thus, these constant regions (SEQ ID NO: 196 and SEQ ID NO: 197) are of murine origin. The sequence of SEQ ID NO: 196 contains the N297A mutation (in the above sequence, residue 297 A is in bold). This N297A mutation in the mouse sequence corresponds to the N297Q mutation in the human sequence.

In some embodiments, the antibody molecule that specifically binds FcyRIIb contains one or more of the following clone sequences:

Antibody clone: 1A01

1A01-VH [SEQ ID NO: 3]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMNWIRQTPGKGLEWVSLIGWDGGSTYYADSVKGRFTISRDNSENTLYLQMNSLRAEDTAVYYCARAYSGYELDYWGQGTLVTVSS

1A01-VL [SEQ ID NO: 27]

QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNAVNWYQQLPGTAPKLLIYDNNNRPSGVPDRFSSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNASIFGGGTKLTVLG

CDR complementarity-determining regions

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]

Antibody clone: 1B07

1B07-VH [SEQ ID NO: 4]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFTRYDGSNKYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARENIDAFDVWGQGTLVTVSS

1B07-VL [SEQ ID NO: 28]

QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNAVNWYQQLPGTAPKLLIYDNQQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCEAWDDRLFGPVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 1C04

1C04-VH [SEQ ID NO: 5]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSISDSGAGRYYADSVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTHDSGELLDAFDIWGQGTLVTVSS

1C04-VL [SEQ ID NO: 29]

QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNHVLWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGWVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 1E05

1E05-VH [SEQ ID NO: 6]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQVPGKGLEWVAVISYDGSNKNYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNFDNSGYAIPDAFDIWGQGTLVTVSS

1E05-VL [SEQ ID NO: 30]

QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNNSRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLGGPVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 2A09

2A09-VH [SEQ ID NO: 7]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVAYISRDADITHYPASVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTGFDYAGDDAFDIWGQGTLVTVSS

2A09-VL [SEQ ID NO: 31]

QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNAVNWYQQLPGTAPKLLIYGNSDRPSGVPDRFSSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGRWVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 2B08

2B08-VH [SEQ ID NO: 8]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMSWVRQAPGKGLEWVALIGHDGNNKYYLDSLEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARATDSGYDLLYWGQGTLVTVSS

2B08-VL [SEQ ID NO: 32]

QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNAVNWYQQLPGTAPKLLIYYDDLLPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCTTWDDSLSGVVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 2E8-VH

2E8-VH [SEQ ID NO: 9]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSAIGFSDDNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGDGSGWSFWGQGTLVTVSS

2E8-VL [SEQ ID NO: 33]

QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNAVNWYQQLPGTAPKLLIYDNNKRPSGVPDRFSSGSKSGTSASLAISGLRSEDEADYYCATWDDSLRGWVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 5C04

5C04-VH [SEQ ID NO: 10]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWRDAFDIWGQGTLVTVSS

5C04-VL [SEQ ID NO: 34]

QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSDNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLSGSWVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 5C05

5C05-VH [SEQ ID NO: 11]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARENFDAFDVWGQGTLVTVSS

5C05-VL [SEQ ID NO: 35]

QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGQVVFGGGTKLTVLG

Plot CDR

CDRH1: TYGMH [SEQ ID NO: 99]

CDRH2: VISYDGSNKYYADSVKG [SEQ ID NO: 100]

CDRH3: ENFDAFV [SEQ ID NO: 101]

CDRL1: TGSSSNIGAGYDVH [SEQ ID NO: 102]

CDRL2: SNSQRPS [SEQ ID NO: 103]

CDRL3: AAWDDSLNGQVV [SEQ ID NO: 104]

Antibody clone: 5D07

5D07-VH [SEQ ID NO: 12]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIAYDGSKKDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREYRDAFDIWGQGTLVTVSS

5D07-VL [SEQ ID NO: 36]

QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTTASLAISGLRSEDEADYYCAAWDDSVSGWMFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 5E12

5E12-VH [SEQ ID NO: 13]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGINKDYADSMKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARERKDAFDIWGQGTLVTVSS

5E12-VL [SEQ ID NO: 37]

QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDDSLNGLVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 5G08

5G08-VH [SEQ ID NO: 14]

EVQLLESGGGLVQPGGSLRLSCAASGFTFNNYGMHWVRQAPGKGLEWVAVISYDGSNRYYADSVKGRFTMSRDNSKNTLYLQMNSLRAEDTAVYYCARDRWNGMDVWGQGTLVTVSS

5G08-VL [SEQ ID NO: 38]

QSVLTQPPSASGTPGQRVTISCSGSSSNIGAGYDVHWYQQLPGTAPKLLIYANNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGPWVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 5H06

5H06-VH [SEQ ID NO: 15]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSDTAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDHSVIGAFDIWGQGTLVTVSS

5H06-VL [SEQ ID NO: 39]

QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYDNNKRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSSYAGSNNVVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 6A09

6A09-VH [SEQ ID NO: 16]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVTSYDGNTKYYANSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREDCGGDCFDYWGQGTLVTVSS

6A09-VL [SEQ ID NO: 40]

QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNEGVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 6B01

6B01-VH [SEQ ID NO: 17]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDQLGEAFDIWGQGTLVTVSS

6B01-VL [SEQ[SEQ ID NO: 41]

QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNNKRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDDSLSGPVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 6C11

6C11-VH [SEQ ID NO: 18]

EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSAISGSGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGDIDYFDYWGQGTLVTVSS

6C11-VL [SEQ ID NO:42]

QSVLTQPPSASGTPGQRVTISCTGSSSNFGAGYDVHWYQQLPGTAPKLLIYENNKRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGPVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 6C12

6C12-VH [SEQ ID NO: 19]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARERRDAFDIWGQGTLVTVSS

6C12-VL [SEQ ID NO: 43]

QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSDNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDSDTPVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 6D01

6D01-VH [SEQ ID NO: 20]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAMYYCARDHSAAGYFDYWGQGTLVTVSS

6D01-VL [SEQ ID NO:44]

QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYGNSIRPSGGPDRFSGSKSGTSASLAISGLRSEDEADYYCASWDDSLSSPVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 6G03

6G03-VH [SEQ ID NO: 21]

EVQLLESGGGLVQPGGSLRLSCAASGFTFGSYGMHWVRQAPGKGLEWVSGISWDSAIIDYAGSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDEAAAGAFDIWGQGTLVTVSS

6G03-VL [SEQ ID NO: 45]

QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNTDRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLSGPVVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 6G08

6G08-VH [SEQ ID NO: 22]

EVQLLESGGGLVQPGGSLRLSCAASGFTLSSYGISWVRQAPGKGLEWVSGISGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSVGAYANDAFDIWGQGTLVTVSS

6G08-VL [SEQ ID NO: 46]

QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGDTNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGPVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 6G11

6G11-VH [SEQ ID NO: 23]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWMAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELYDAFDIWGQGTLVTVSS

6G11-VL [SEQ ID NO:47]

QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYADDHRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCASWDDSQRAVIFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 6H08

6H08-VH [SEQ ID NO: 24]

EVQLLESGGGLVQPGGSLRLSCAASGFTFNNYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAREYKDAFDIWGQGTLVTVSS

6H08-VL [SEQ ID NO:48]

QSVLTQPPSASGTPGQRVTISCTGSSSNIGSNTVNWYQQLPGTAPKLLIYDNNKRPSGVPDRFSSGSKSGTSASLAISGLRSEDEADYYCQAWGTGIRVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 7C07

7C07-VH [SEQ ID NO: 25]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSQNTLYLQMNSLRAEDTAVYYCAREFGYIILDYWGQGTLVTVSS

7C07-VL [SEQ ID NO: 49]

QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYRDYERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCMAWDDSLSGVVFGGGTKLTVLG

Plots of CDRs

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]

Antibody clone: 4B02

4B02-VH [SEQ ID NO: 26]

EVQLLESGGGLVQPGGSLRLSCAASGFTFSNHGMHWVRQAPGKGLEWVAVISYDGTNKYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARETWDAFDVWGQGTLVTVSS

4B02-VL [SEQ ID NO: 50]

QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNNANWYQQLPGTAPKLLIYDNNKRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQAWDSSTVVFGGGTKLTVLG

Plots of CDRs

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]

In some embodiments, which are sometimes preferred embodiments of the invention, an antibody molecule that specifically binds FcyRIIb 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. CDRs of clone 6G11.

In some embodiments of the invention, which are sometimes preferred embodiments of the invention, the antibody molecule that specifically binds FcyRIIb contains 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. constant and variable regions of clone 6G11, the antibody molecule of which was further modified to reduce binding to Fcy receptors through its Fc region. In some embodiments, which are sometimes preferred embodiments of the invention, the antibody molecule that specifically binds FcyRIIb contains 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. constant and variable regions of clone 6G11, including the N297Q mutation.

In some embodiments, the immune cell that depletes or deactivates the antibody molecule is a human antibody molecule or an antibody molecule of human origin. In some such embodiments, the human antibody molecule or the human-derived antibody molecule is an IgG antibody. In some such embodiments, the human antibody molecule or the human-derived antibody molecule is an IgG1 or IgG2 antibody.

In some embodiments, the immune cell that depletes or deactivates the antibody molecule is a humanized antibody molecule.

In some embodiments of the invention, the immune cell that depletes or deactivates the antibody molecule is a chimeric antibody.

As mentioned above, an immune cell that depletes or deactivates an antibody must be able to bind to FcyR receptors.

The target that an immune cell binds to deplete or deactivate an antibody molecule according to the present invention can be selected from the group consisting of CTLA-4, 4-1BB, OX40, TNFR2, PD-L1, IL-2R and GITR.

In some embodiments of the invention, the target that the immune cell binds to deplete or deactivate the antibody molecule of the present invention is CTLA-4. CTLA-4 or CTLA4, which stands for cytotoxic T-lymphocyte-associated protein 4, is also known as CD152. It is a protein receptor that functions as a checkpoint of the immune response by down-regulating the immune response. CTLA4 is expressed constitutively in regulatory T cells, but is only activated in normal T cells after activation, a phenomenon that is particularly prominent in cancer. In some such embodiments, the immune cell depleting the antibody molecule is ipilimumab (such as ^Yervoy® manufactured by Bristol-Myers Squibb). In some such embodiments, the antibody depleting immune cell is tremelimumab (formerly ticilimumab and CP-675,206), which is a fully human anti-CTLA-4 monoclonal antibody formerly developed by Pfizer and now in clinical development by MedImmune.

In some embodiments of the present invention, at least one target is 4-1BB, which is also referred to as CD137 and as a member of the tumor necrosis factor receptor superfamily 9 (TNFRSF9). 4-1BB is expressed on regulatory T cells (Treg) after activation of CD4+ and CD8+ T cells, and its ligation is required for an optimal protective response of CD8-T cells against viruses and B-cell lymphoma in mice. Specific anti-4-1BB antibodies increase the proliferation and survival of antigen-stimulated T cells in vitro and, like anti-CD40 antibodies, anti-4-1BB mAbs promote antitumor immunity in preclinical cancer models that rely heavily on CD8 T cells. In some such embodiments, the antibody depleting immune cell is urelumab, an agonistic humanized IgG4 immunoglobulin monoclonal antibody developed by Bristol-Myers Squibb. In some such embodiments, the immune cell depleting the antibody molecule is utomilumab (also referred to as PF-05082566, PF-2566, and PF-5082566), a human agonist of the HuCAL mAb of the 4-1BB immune agonist target developed by Pfizer.

In some embodiments of the present invention, at least one target is OX40. OX40, also known as member 4 of the tumor necrosis factor receptor superfamily (TNFRSF4) and as CD134, is a secondary co-stimulatory immune checkpoint molecule of the immune response. In some such embodiments, the antibody depleting immune cell is MEDI6469 (9B12), MEDI0562, PF-04518600, INCAGN01949, BMS-986178, MOXR0916, GSK3174998, MEDI6383 (see, for example, Table 1 by Buchan et al., Blood 2 018 131: 39-48).

In some embodiments of the present invention, at least one target is TNFR-2. Tumor necrosis factor receptor 2 (TNFR-2 or TNFR2), also known as member 1B of the tumor necrosis factor receptor superfamily (TNFRSF1B) and CD120b, which is a membrane-bound receptor that binds tumor necrosis factor alpha (TNFα).

In some embodiments of the present invention, the target that the immune cell binds to deplete or deactivate the antibody molecule of the present invention is programmed death ligand 1 (PD-L1), also known as CD274 or the B7 homologue 1 (B7-H1).

In some embodiments of the present invention, at least one target is IL-2R. IL-2R is also known as CD25 and is highly expressed predominantly on regulatory T cells. In some embodiments of the present invention, at least one target is GITR.

In some embodiments of the present invention, at least one target is GITR. GITR is a member of TNFSFR and is also primarily expressed on regulatory T cells.

In some embodiments, the antibody molecule that specifically binds FcyRIIb and the immune cell that depletes or deactivates the antibody molecule are administered to the patient at the same time, meaning that they are either administered together at the same time or separately very close to each other in time.

In some embodiments, an antibody molecule that specifically binds FcyRIIb is administered to a patient prior to the introduction of an immune cell that depletes or deactivates the antibody molecule. Such sequential administration can be achieved by temporally separating the two antibodies. As an alternative or in combination with the first option, sequential administration can also be achieved by spatially separating two antibody molecules: an antibody molecule that specifically binds FcyRIIb is administered intratumorally so that it reaches the cancer site before the immune cell depletes the antibody molecule; and the immune cell is then administered systemically so that it reaches the cancer site after the antibody molecule that specifically binds FcyRIIb.

In some embodiments, an antibody-depleting immune cell is administered to a patient prior to administration of an antibody molecule that specifically binds FcyRIIb. Such sequential administration can be achieved as described above.

One of ordinary skill in the medical field may be aware that drugs can be modified with various additives, for example to change the rate at which the drug is absorbed into the body; and can be modified in various forms, for example, to provide a specific route of administration to the body.

Accordingly, the present application contemplates that the composition and/or antibody and/or drug of the present invention may be combined with an excipient and/or a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable diluent and/or an adjuvant.

The present application also contemplates that the composition and/or antibody and/or drug of the present invention may be suitable for parenteral administration, including aqueous and/or non-aqueous sterile injectable solutions that may contain antioxidants and/or buffers and/or bacteriostatics and/or solutes that render the formulation isotonic with the blood of the intended recipient; and/or aqueous and/or non-aqueous sterile suspensions, which may include suspending agents and/or thickeners. This composition and/or antibody and/or agent and/or drug of the present invention may be presented in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (i.e., lyophilized) state requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use.

Extemporaneous injection solutions and suspensions can be prepared from sterile powders and/or granules and/or tablets of the type previously described.

For parenteral administration to sick humans, the daily dose of an antibody molecule that specifically binds FcyRIIb and/or an immune cell that depletes or deactivates the antibody molecule is typically between 1 mg/kg and 20 mg/kg of the patient's body weight, and in some cases even up to 100 mg/kg of the patient's body weight; administered in a single dose or in divided doses. Lower doses may be used in special circumstances, such as long-term administration. In any case, the physician will determine the actual dosage that will be most appropriate for each individual patient, and which will vary with the age, weight, and response of the individual patient. The above doses are typical for the average case. Of course, there may be individual cases where higher or lower dosage ranges are justified, and such cases are within the scope of the present invention.

Typically, a composition and/or drug of the present invention contains an antibody molecule that specifically binds FcyRIIb and/or an antibody-depleting or deactivating immune cell at a concentration in the range of from about 2 mg/mL to 150 mg/mL, or from about 2 mg/mL to 200 mg/mL. In a preferred embodiment of the invention, the medicinal products and/or compositions of the present invention will contain an antibody molecule that specifically binds FcyRIIb and/or an immune cell molecule that depletes or deactivates the antibody at a concentration of 10 mg ml.

In general, in humans, oral or parenteral administration of a composition and/or antibody and/or agent and/or drug of the present invention is the preferred route of administration because it is the most convenient. For veterinary use, the composition and/or antibody and/or agent and/or medicament of the present invention is administered in a suitable acceptable dosage form in accordance with normal veterinary practice, and the veterinarian determines the dosage regimen and route of administration that will be most suitable for a particular animal. Thus, the present invention provides a pharmaceutical composition containing an amount of an antibody and/or an agent of the present invention effective for the treatment of various conditions (as described above and further below). It is preferred that the composition and/or antibody and/or agent and/or drug be adapted for delivery by administration selected from the group consisting of: intravenous (IV); subcutaneous (SC), intramuscular (IM), or intratumoral administration.

In some embodiments, either the first antibody molecule or the second antibody, or both, can be introduced using plasmids or viruses. Such plasmids then contain nucleotide sequences encoding either the first antibody molecule or the second antibody, or both. In some embodiments of the invention, nucleotide sequences encoding parts of sequences or complete sequences, or molecules of the first antibody, or the second antibody, or both, are integrated into the cell or the viral genome, or into the virion of the virus; such a cell or virus then acts as a delivery vehicle for either the first antibody molecule or the second antibody or both (or the delivery vehicle for the nucleotide sequence encoding either the first antibody molecule or the second antibody, or both). For example, in some embodiments of the invention, such a virus may be in the form of a therapeutic oncolytic virus containing nucleotide sequences encoding at least one of the antibody molecules described in this application. In some embodiments of the invention, such an oncolytic virus contains nucleotide sequences encoding a full-length human IgG antibody. Oncolytic viruses are known to those skilled in the art of medicine and virology.

The present invention also includes a composition and/or antibody and/or agent and/or drug containing pharmaceutically acceptable acidic or basic addition salts of the polypeptide-binding moieties of the present invention. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds useful in the present invention are acids which form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, in particular such as salts of 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)]. Pharmaceutically acceptable base addition salts can also be used to prepare pharmaceutically acceptable salt forms of the agents of the present invention. Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of the present agents that are acidic in nature are chemical bases that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, non-toxic base salts derived from pharmacologically acceptable cations such as alkali metal cations (eg potassium and sodium) and alkaline earth metal cations (eg calcium and magnesium). calcium and magnesium), ammonium, or water-soluble amine addition salts such as N-methylglucamine-(meglumine), as well as including lower alkanolammonium and other basic salts of pharmaceutically acceptable organic amines. These agents and/or polypeptide-binding moieties of the present invention may be lyophilized for storage and resuspended in a suitable vehicle prior to use. Any suitable lyophilization method (eg spray drying, cake drying) and/or resuspension methods can be used. Those skilled in the art will appreciate that lyophilization and resuspension can cause the body to lose varying degrees of antibody activity (e.g., with conventional immunoglobulins, IgM antibodies tend to lose activity more than IgG antibodies) and that application levels can be adjusted upwards to compensate for this. In one embodiment, the lyophilized (freeze-dried) polypeptide-binding group loses no more than about 20%, or no more than about 25%, or no more than about 30%, or no more than about 35%, or no more than about 40%, or no more than about 45%, or no more than about 50% of its activity (before lyophilization) upon rehydration.

The combination of an antibody molecule that specifically binds FcyRIIb and an immune cell that depletes or deactivates the antibody molecule can be used to treat cancer.

The term "patient" as used herein refers to an animal, including a human, who has been diagnosed with an FcyRIIb-negative cancer or a cancer that is considered likely to be an FcyRIIb-negative cancer and/or that exhibits symptoms of such cancer.

In this application, it is contemplated that the patient may or may not be a 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.

By "demonstrate" in this application is meant that the subject demonstrates a symptom of cancer and/or a diagnostic marker of cancer; and/or a symptom of cancer and/or a diagnostic marker of cancer can be measured and/or evaluated and/or quantified.

A medical professional will immediately understand what are the symptoms of cancer and diagnostic markers of cancer, as well as how to measure and/or evaluate and/or quantify whether there is a decrease or increase in the severity of cancer symptoms or a decrease or increase in diagnostic markers of cancer; and how these cancer symptoms and/or diagnostic markers of cancer can be used to predict the course of cancer.

Cancer treatment is often given as a course of treatment, that is, the drug is administered over a period of time. The length of the course of treatment will depend on a number of factors, which may include, among others, the type of drug being administered; the type of cancer being treated; the severity of the cancer being treated; age and health status of the patient.

By "during treatment" in this application is meant that the patient is currently undergoing treatment and/or receiving a drug, and/or receiving a course of drug.

In some embodiments, the FcyRIIb-negative cancer being treated according to the present invention is a solid cancer.

In some embodiments, the cancer is selected from the group consisting of carcinomas, sarcomas, and lymphomas.

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

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

The FcyRIIb-negative cancer is selected from the group consisting of melanoma, breast cancer, ovarian cancer, prostate cancer, metastatic hormone-refractory prostate cancer, colon cancer, lung cancer, small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC), non-small cell lung cancer, urothelial carcinoma, bladder cancer, kidney cancer, mesothelioma, Merkel cell carcinoma and head and neck cancer.

Each of the cancers described above is well known, and the symptoms and diagnostic markers of cancer are well documented, as are the drugs used to treat these cancers. Accordingly, the symptoms, diagnostic markers of cancer, and drugs used to treat the above types of cancer are known to those skilled in the medical arts.

The clinical definitions of diagnosis, prognosis, and progression of a large number of cancers are based on specific classifications known as cancer staging. These cancer staging systems operate to correlate a number of different diagnostic markers of cancer and symptoms of cancer to provide a diagnosis and/or prognosis and/or progression of the cancer. These cancer staging systems operate to correlate a number of different diagnostic markers of cancer and symptoms of cancer to provide a diagnosis and/or prognosis and/or progression of the cancer.

By "cancer staging" in this application is meant the staging of a cancer according to the Rai classification, which includes stage 0, stage I, stage II, stage III, and stage IV, and/or the Binet classification, which includes stage A, stage B, and stage C, and/or the Ann Arbor classification, which includes stage I, stage II, stage III, and stage IV.

It is known that cancer can cause abnormalities in cell morphology. These abnormalities often reoccur in certain types of cancer, which means that the study of these changes in morphology (also known as histological examination) can be used in the diagnosis or prognosis of cancer. Methods for imaging samples for studying cell morphology and preparing samples for imaging are well known in the art; for example, light microscopy or confocal microscopy.

By "histological examination" in this application is meant the presence of small mature lymphocytes and / or the presence of small mature lymphocytes with a narrow border of cytoplasm, the presence of small mature lymphocytes with a dense nucleus devoid of clearly visible nucleoli, and / or the presence of small mature lymphocytes with a narrow border of the cytoplasm, and / or with a dense nucleus devoid of clearly visible nucleoli, and / or the presence of a type egg cells and/or split cells and/or prolymphocytes.

It is well known that cancer is the result of mutations in a cell's DNA, which can cause the cell to escape cell death or multiply uncontrollably. Therefore, the study of these mutations (also known as cytogenetic study) can be a useful tool to assess the diagnosis and/or prognosis of cancer. An example of this is the deletion of the chromosomal location 13q14.1, which is characteristic of chronic lymphocytic leukemia. Methods for studying mutations in cells are well known in the art; for example, fluorescence in situ hybridization (FISH).

Under the "cytogenetic study" in this application refers to the study of DNA in the cell and, in particular, chromosomes. Cytogenetic testing can be used to detect changes in DNA that may be associated with the presence of refractory cancer and/or recurrent cancer. Such DNA changes may include: deletions in the long arm of chromosome 13 and/or deletions of the locus 13q14.1 of the chromosome and/or trisomy of chromosome 12 and/or deletions in the long arm of chromosome 12 and/or deletions in the long arm of chromosome 11 and/or deletion of 11q and/or deletions in the long arm of chromosome 6 and/or deletion of 6q and/or deletions in short m arm of chromosome 17, and/or deletion in 17p, and/or t(11:14) translocation, and/or translocation (q13:q32), 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 translocation (q13 :q32) and/or translocations (3:v) and/or translocations (8:14) and/or translocations (8:v) and/or translocations t(11:14) and (q13:q32).

Cancer patients are known to exhibit certain physical symptoms, which are often a result of the cancer's burden on the body. These symptoms often recur in the same cancer and may therefore be characteristic of the diagnosis and/or prognosis and/or progression of the disease. The medical professional must understand which physical symptoms are associated with which cancers, and how the evaluation of these physical systems may correlate with diagnosis and/or prognosis and/or disease progression. By "physical symptoms" in this application is meant hepatomegaly and/or splenomegaly.

Brief description of graphic materials

In the examples below, reference is made to the following figures:

fig. 1 shows a potential mechanism to explain why the present invention works. An immune cell that depletes or deactivates an antibody molecule, in this case an anti-CTLA-4 antibody, binds to a receptor present on an immune cell that suppresses the anti-cancer effect, in this case a regulatory T cell (Treg). The Fc region of the anti-CTLA-4 antibody binds to the active Fcy receptor, which in this case is present on the surface of the macrophage. In addition, an antibody molecule that specifically binds FcyRIIb binds to FcyRIIb present on the surface of the macrophage. Because this specific antibody has an Fc region with reduced binding to activating Fcy receptors, it does not bind to any of the activating Fcy receptors present on the macrophage, which are instead free to bind to the Fc region of the anti-CTLA-4 antibody.

Fig. 1A shows the use of only anti-CTLA-4 antibodies. The anti-CTLA-4 antibody binds to both activating and inhibitory Fcγ receptors and thereby activates them, resulting in weak activation and therefore a reduced effect compared to when the anti-CTLA-4 antibody only bound to activating Fcγ receptors.

Fig. 1B shows that the combination of an anti-CTLA-4 antibody and a wild-type (WT) FcγRIIb antibody results in a decrease in activation. In this case, the FcγRIIb antibody simultaneously blocks activating Fcγ receptors and activates inhibitory Fcγ receptors, which is the opposite of the desired effect according to the present invention.

Fig. 1C shows that the combination of an anti-CTLA-4 antibody and an aglycosylated FcγRIIb antibody of the present invention results in maximum activation. There is no blocking of Fcγ receptor activation and no activation of inhibitory Fcγ receptors leading to maximum deletion of the target. In the present application, the aglycosylated FcγRIIb antibody may be one of the Fc domain binding antibodies or otherwise have reduced binding to FcR receptors.

Fig. 2 shows that FcyRIIB antibodies with reduced Fc binding to activating Fc receptors, but not wild-type antibodies with preserved binding to activating Fc receptors, increase B cell depletion by CD20 mAb antibodies.

Fig. 2 A-B - CFSE+ hCD20+/- x mFcyRII-/- (target) and mFcyRII-/- (non-target) splenocytes were injected into hFcyRIIB+/- x mFcyRII-/- recipient mice. Mice received wild-type (WT) or therapeutic N297Q FcyRIIB mAb (6G11) (2 x 20 mg/kg) followed by rituximab (Rit) (0.2-2 mg/kg); the ratio of blood (A) and spleen (B) CFSE+ CD19+ cells was determined as before. Pooled data from at least two independent experiments. (FIG. 2C) CFSE+ hCD20+/- x mFcγRII-/- (target) and mFcyRII-/- (non-target) splenocytes were injected into hFcyRIIB+/- x mFcyRII-/- recipient mice. Mice received wild-type (WT) or therapeutic N297Q FcγRIIB mAb (6G11) (20mg/kg) followed by rituximab (Rit) (2mg/kg), and expression of activating mFcγR receptors was quantified on F4/80+ spleen effector cells with the indicated therapeutic mAb. (Fig. 2D-E). The ability of wild-type (WT) and specific therapeutic antibody N297Q (NQ) hFcγRIIB mAb (6G11; 10 μg/ml for 15 min) to induce phosphorylation of the immunoreceptor inhibitory tyrosine-containing motif (ITIM) hFcγRIIB (pFcγRIIB) on (Fig. 2D) bone marrow-derived mouse macrophages (BMDM) and (Fig. 2 E) isolated primary peripheral blood monocytes after cell culture to achieve a high density of their mass, respectively. α-Tubulin, GAPDH and hFcγRIIB were used as loading controls as indicated; representative spots are shown.

Fig. 3 shows that wild-type (WT) antibodies and therapeutic FcγR-null FcγRIIB mAbs can be combined for optimal target cell depletion.

CFSE+ hCD20+/- (target) and mFcγRII-/- (non-target) splenocytes were administered to hFcγRIIB+/- x mFcγRII-/- recipient mice (Balb/c mice). Mice received wild-type (WT) antibodies (2 x 10-20 mg/kg) or therapeutic F(ab')2 antibodies (2 x 20 mg/kg) mFcyRII (AT130-5) or wild-type (WT) antibodies (2 x 20 mg/kg) or therapeutic F(ab')2 antibodies (2 x 40 mg/kg) hFcyRIIB mAb (AT10) followed by rituxim ba (Rit) (0.2-2 mg/kg) as indicated on the x-axis; the ratio of CFSE+ to CD19+ splenic cells was determined as before. Data are pooled from 1-3 independent experiments. Each dot depicts the result of an individual mouse; average ratios are indicated by a horizontal line. Data are analyzed using one-way analysis of variance (ANOVA).

Fig. 4 shows an assessment of regulatory T cell (Treg) deletion with blockade of anti-IL2R mAb +/- FcyRIIB antibody with mutant Fc-inert-NA mAb. Figure 4A): 100 μg of AT130-2 NA administered intraperitoneally (ip) to female Balb/C mice. 100 μg PC61 was injected intraperitoneally after 6 hours. After 4 days, regulatory T cells (FoxP3+) were determined in blood, spleen and lymph nodes using the FACS analytical system. Mice were sacrificed and a single cell suspension was obtained from spleen, lymph nodes and blood, which were stained with antibodies against CD4, CD8 and B220 before intracellular staining with FoxP3 dye prior to analysis using the FACS canto analytical system. The number of leukocytes in each tissue was determined. Regulatory T cells (Treg) were defined as CD8-CD4+FoxP3+, and the number of regulatory T cells was calculated using the number of leukocytes. Figure 4B - as above, but with C57BL/6 mice. Figure 4C - CD8/Treg ratio calculated from FIG. 4 B).

Fig. 5 shows evaluation of Treg deletion blocked by anti-IL2R mAb +/- FcγRIIB with wild type (WT) or NA mutant mAb. The wild-type (WT) antibody AT130-2 does not appear to provide any improvement in deletion, while the NA variant provides an improvement in deletion. A) 100 μg of AT130-2 NA or mIgG1 WT AT130-2 was administered intraperitoneally to female Balb/C mice. After 6 hours, 100 μg of PC61 was administered intraperitoneally. Regulatory T cells (FoxP3+) in the spleen were determined by the FACS assay system after 4 days. Mice were sacrificed and a single cell suspension from the spleen was obtained, which was stained with antibodies against CD4, CD8 and B220 before intracellular staining with FoxP3 dye before analysis with the FACS canto assay system. The number of leukocytes in each tissue was determined. Regulatory T cells (Treg) were defined as CD8-CD4+FoxP3+; the number of regulatory T cells was calculated using the number of leukocytes. In the spleen of mice treated after 4 days with N297A in combination with PC61, significantly fewer regulatory T cells were observed compared with mice treated with wild-type antibodies mIgG1 AT130-2 (Student's t-test for one set, P = 0.044).

Fig. 6 shows combination therapy with anti-CTLA-4 blockade and FcγRIIB. Female BALB/c mice were subcutaneously injected with 5x105 CT26 cells. Mice were randomized into treatment groups when the tumor area (tumor width x tumor length) was approximately 100 mm2. The treatment was carried out on the 0th, 2nd, 4th and 11th day. Each day, mice received only anti-mouse CTLA4 hamster (9H10) antibodies at a dose of 200 µg ip in 200 µl of phosphate buffered saline (PBS). On day 0, mice receiving combination treatment received 100 μg AT130-2 N297A (anti-mouse CD32 antibody) ip in 200 μl PBS and 6 hours later 200 μg 9H10 ip in 200 μl PBS. On the 2nd, 4th and 11th day, the combination-treated mice received both antibodies (200 μg 9H10 and 100 μg AT130-2 NA) in a single 200 μl intraperitoneal injection. The width and length of the tumor were measured; mice were sacrificed when the tumor area (tumor length x tumor width) exceeded 400 mm ² . Fig. 6A) shows the treatment schedule. Group 1: No antibodies were administered; Group 2: anti-mCD32 (AT130-2 NA; 100 µg); Group 3: anti-CTLA-4 (9H10; 200 µg); Group 4: combination (PC61) 6 hours after AT130-2. It was allowed to install and treat tumors with their area of 100 mm2. An additional dose was given on the 12th day. Fig. 6B) shows the growth of individual tumors. Fig. 6C) shows mean tumor area +/- standard deviation (SD) or standard error of the mean (SEM). Fig. 6D) shows the survival rate of the animals. Fig. 6E) Combination of data from 2 separate experiments (n=10/group) demonstrating survival; the combination of 9H10 and AT130-2NK (NA combination) was also shown to be significantly more effective than 9H10 alone in prolonging survival (P=0.0179).

Fig. 7 shows combination therapy with anti-CTLA-4 antibodies and FcγRIIB blockade compared to therapy with wild type (WT) antibodies (referred to as M1 combination) and Fc-inert antibodies (referred to as NA combination) AT130-2 mAb. 5x105 CT26 cells were administered subcutaneously to female BALB/c mice. Mice were randomized to treatment groups when the tumor area (tumor width x tumor length) was approximately 100 mm2. The treatment was carried out on the 0th, 2nd, 4th and 11th day. On day 0, mice receiving combination treatment received 100 µg of AT130-2 N297A or AT130-2 mIgG1 (CD32 anti-mouse antibodies) in 200 µl of PBS ip, and 6 hours later received 200 µg of 9H10 in 200 µl of PBS ip. On days 2, 4, and 11, mice treated with combination treatment received both antibodies (200 μg 9H10 and 100 μg AT130-2 NA/mIgG1) in a single 200 μl intraperitoneal injection. Tumor width and length were measured and mice were sacrificed when the tumor area (length x width) exceeded 400 mm ² . Data are shown on the survival curve below N=11-12. The NA combination treatment group experienced significantly longer survival compared to mIgG1 combination treated mice (log-rank P=0.0460).

Fig. 8 shows combination therapy with blockade of anti-PD-L1 and FcγRIIB antibodies; to determine whether this effect depends on the NA format of the antibody, an experiment was performed using both the wild-type (WT) mIgG1 antibody and the NA format antibody. Fig. 8A) shows the growth of individual tumors in each group (one graph per group). The number indicates the number of surviving mice in each group. Fig. 8B) shows survival curves of mice.

Fig. 9 shows wild-type (top) and N297A (bottom) formats for binding of anti-mouse FcγRIIB mAb AT130-2 binding to FcγR receptors. Surface plasmon resonance (SPR) analysis of AT130-2 in any binding format to the indicated mouse FcγR receptors (100 nm) is shown.

Fig. 10 shows binding of wild-type 6G11 versus N297A 6G11 to Fc-gamma receptors (mouse and human). Surface plasmon resonance (SPR) analysis of the binding of native antibodies and N297A anti-huCD32b 6G11 hIgG1 antibodies to these low affinity human and mouse FcγR receptors is shown. Fig. 10 A and B) shows the results for the human FcγR receptor (100 nm). Figure 10 C and D shows the results for mouse FcγR (100 nm). Fig. 10 E and F) - shows results for human FcγR receptor (sequential incremental additions) - FcγRIIb and hCD64. Fig. 10 G and H) shows the results for the mouse FcγR receptor (100 nm), i.e. the same as in FIG. C and B), but scaled for a clearer view.

Examples

Specific, non-limiting examples will now be described that include certain aspects of the present invention. Two sets of surrogate antibodies must be used to enable investigation of the effect of FcγRIIB blockade in complex in vivo systems. The mouse equivalent of 6G11 is called AT130-2. In order to block the Fc region of a human antibody (hence to affect binding to FcγR receptors highly disrupted or neglected), amino acid N at position 297 is replaced by amino acid Q in the present application. 11. Briefly, the human 6G11 antibody corresponds to the surrogate mouse antibody AT1302-2, while 6G11-N297Q corresponds to AT130-3-N297A.

Another way to block the Fc region of an antibody (which is well known to those skilled in the art) would be to remove the Fc region and generate a Fab or Fab2 fragment.

Experimental Procedures

Animals

hCD20 Tg mice (transgenic) hFcγRIIB+/- and mFcγRIIB-/- (Beers et al., Blood 2008 Nov 15; 112(10): 4170-7; Roghanian et al., Cancer Cell 27, 473-488, April 13, 2015) with genotypes confirmed by polymerase chain reaction (PCR) and/or flow cytometry. Mice were bred and maintained at local facilities in accordance with guidance from the UK Home Office or the Swedish Ethics Committee.

Cell culture

Cell culturing was performed in RPMI enriched nutrient medium (RPMI 1640 medium containing 2 mM glutamine, 1 mM pyruvate, 100 IU/ml penicillin and streptomycin, and 10% FCS [Myoclone]) (GIBCO BRL, Paisley, Scotland). Mouse splenic B cells were purified by negative selection using MACS B cell isolation kits (Miltenyi Biotec, UK) and cultured in the same media. The cell lines were obtained from the European Collection of Authenticated Cell Cultures (ECACC) and maintained in antibiotic-free fortified RPMI.

Obtaining human macrophages of monocytic origin (MDM) and mouse macrophages of bone marrow origin (BMDM)

Human macrophages of monocytic origin (MDM) were differentiated from peripheral blood obtained either from the National Blood Service, Southampton General Hospital (Southampton, UK) or from blood centers at Halmstad Hospital or Skåne Teaching Hospital. Sweden. Briefly, CD14+ adherent monocytes were cultured in enriched RPMI medium containing 25-100 ng/mL recombinant human macrophage colony-stimulating factor with low endotoxicity (M-CSF, R&D Systems, USA, or in-house) as previously described (Roghanian et al., Cell Immunol. 2010; 265 (2): 120-6 ). Half of the culture medium was replaced with fresh M-CSF every 2 days until cell collection. Macrophages of monocytic origin (MDM) were harvested on day 7-10 of cultivation after a short incubation with cold PBS.

Bone marrow-derived mouse macrophages (BMDM) were derived from cells isolated from mouse femur and tibia bone marrow as previously reported (Williams et al., J Immunol. 2013 Oct 15; 191(8): 4130-40.). Briefly, bone marrow cells were cultured in RPMI enriched medium containing 20% medium conditioned with L929 cells (containing M-CSF). Cells were cultured at 37°C, in an atmosphere of 5% CO ₂ for 10-12 days before use. Macrophage differentiation was routinely confirmed by morphological examination and/or flow cytometry for CD11b and F4/80 expression.

Antibodies and reagents

Typically, mAb antibodies were obtained from hybridoma culture supernatant or stably transfected CHO-k1 cells (obtained from ECACC). F(ab') ₂ fragments were generated as previously described (Glennie et al., 1987). The hFcγRII mAb AT10 antibody has been described previously (Greenman et al., 1991). Anti-CTLA4 (9H10; Bio X Cell, USA), anti-IL2R (PC-61.5.3; Bio X Cell/in-house), anti-PDL-1 (10F.9G2 Bio X Cell, USA). Antibodies hFcγRII mAb 6G11 hIgG1 and N297Q were obtained by BioInvent (see Roghanian et al, Cancer Cell 27, 473-488, April 13, 2015). Antibodies MFcyRII mAb AT130-2 mIgG1, mIgG2a and mIgG1 N297A were self-produced. Antibody AT130-5 (Williams et al, Eur J Immunol. . 2012; 42(8): 2109-20, and Tutt et al., J Immunol 2015, 195 (11) 5503-5516) is a mouse anti-mouse FcyRII antibody similar to human antibody clone 6G11). Anti-hFcyRIIB antibodies (clone EP888Y; Abcam, UK), phosphorylated hFcyRIIB antibodies (clone EP926Y; Origene, USA), GAPDH (Abcam, UK), and α-tubulin (Cell Signaling, USA) were used for immunoblotting. For immunophenotyping of peripheral blood mononuclear cells (PBMCs), PE-labeled FcyRIIB mAb was used using a Zenon labeling kit (molecular probes) in combination with anti-CD3-FITC, anti-CD19-PerCP-Cy5.5 and anti-CD56-APC antibodies (antibodies obtained from Biolegend).

flow cytometry

The fluorescently conjugated mAbs were purchased from BD Biosciences, eBiosciences, Biolegend, AbD Serotec (all from the UK) or made in-house. Flow cytometry was performed as previously described (Tutt et al., 1998) with samples evaluated on the FACScan, FACSCalibur, or FACSCanto II analytical systems, with data analyzed using CellQuest Pro, FACSDiva (all software from BD Biosciences, UK) or FCS Express (from De Novo Software, CA, USA) software.

Western blotting

As previously described (Roghanian et al, Cancer Cell 27, 473-488, April 13, 2015).

Immunotherapy in vivo

Adoptive Transference: As previously detailed (Beers et al., Blood. 2010 Jun 24; 115 (25): 5191-201).

B cell depletion: Mice were intravenously injected with hCD20 or hFcyRIIB mAb, alone or in combination, and leukocytes evaluated as before (Beers et al., Blood. 2010 Jun 24;115(25):5191-201). 2010 Jun 24; 115 (25): 5191-201).

CT26 cells

CT26 cells were stored in Dulbecco's Complete Eagle's Medium (DMEM) and harvested with trypsin-EDTA solution. Cells were washed, resuspended in PBS and adjusted to 5x10 ⁶ cells/ml using a hemocytometer. 100 μl of the cell suspension (5 x 10 ⁵ cells) was injected subcutaneously into BALB/c mice (bred in-house from the original breed obtained from Charles River, UK). Tumors were allowed to be placed and measured 3 times per week until randomization and treatment. Tumors were considered terminal when their area (length x width) exceeded 400 mm ² .

Cells MC38

MC38 cells were stored in complete DMEM and harvested with trypsin-EDTA solution. Cells were washed, resuspended in PBS and adjusted to 5 x 106 cells/ml using a hemocytometer. C56/Bl6 mice (obtained from Taconic, Denmark) were injected subcutaneously with 100 μl of the cell suspension (5 x 10 ⁵ cells). Tumors were allowed to be identified and measured prior to randomization and treatment. Treatment was started with a tumor area of 50-100 mm ² and then the tumors were measured 2 times a week. The treatment was carried out 4 times with an interval between treatment sessions of 3-4 days; the dose of anti-PD-L1 was set at 10 mg/kg, and the dose of both variants of AT130-2 was set at 20 mg/kg. Tumors were considered terminal when their area exceeded 2000 mm ² .

Statistical analysis

To compare the experimental groups, analysis was carried out using the Wilcoxon signed rank test, paired t-test or Student's t-test for one sample, Kaplan-Meier curves were obtained and analyzed using the logarithmic rank test. One- or two-way analysis of variance (ANOVA) was used for in vivo adaptive transfer analysis containing >2 groups.

Chi-square test was used to determine differences in OR and CR. Statistical analysis was performed using GraphPadPrism software (version 5 or 6). Asterisks indicate significance as follows: *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001 unless otherwise noted.

results

B Cell Depletion Efficiency Depends on Antibody Format FcγRIIB mAb

FcγRIIB antibodies are expressed on both target B cells and effector monocytes/macrophages, making interpretation difficult when FcγRIIB mAbs contribute to a deeper deletion of target cells. To further explore this, the present application took advantage of the various available strains of hFcγRIIB Tg and KO mice to provide systems in which either the target cell or the effector or both can be targeted to the FcγRIIB mAb. In assays where hCD20+/- targets lacking hFcγRIIB were adoptively transferred into hFcγRIIB+/- x mFcγRIIB-/- recipients, treatment with FcyR-null alone and wild-type (WT) FcγRIIB mAb did not have the expected effect on B-cell deletion (Fig. 2A). In combination with rituximab, the FcγR-null FcγRIIB mAb potentiated the depletion of both circulating target cells (Fig. 2A) and tissue resident (Fig. 2B) target cells, while the wild-type (WT) FcγRIIB mAb abolished the deletion. This shows that when the normal monoclonal antibody FcγRIIB is used, the deletion of target cells by the second antibody is disrupted, which was very unexpected for the inventors. When assessing the expression of FcγR receptors on splenic macrophages of F4/80+ treated mice, it was apparent that mFcγRIV detection (Fig. 2C) was less with wild-type (WT) antibodies but not with FcγR-null FcγRIIB mAb, which may partly explain the inhibitory effects of wild-type (WT) FcγRIIB mAb. This shows that the normal IgG monoclonal antibody FcγRIIB worsens the deletion by blocking the FcγRIV activating receptor.

This so-called "scorpion effect" (reviewed by Hogarth) occurs when a functional cell-surface Fc domain that binds an antibody mAb occupies the Fc-binding cleft of an FcγR receptor expressed on the same cell and is therefore not seen with an FcγR-null FcγRIIB mAb. This has been described previously and explains a possible overinterpretation of the relative importance of individual FcγRs when they are blocked by an anti-FcγR mAb with a functional Fc domain, such as the FcγRIV mAb 9E9 (Tipton et al, Blood 2015 125:1901-1909).

In addition to physical blockade, this "scorpion effect" also has the potential to provide cross-linking and activation of the FcγR receptor. Since the ITIM-containing FcγRIIB receptor is the only FcγR inhibitory receptor on effector cells, its activation can help inhibit the function of effector cells (Dahal et al., Immunol Rev. 2015 nov; 268 (1): 104-22), this application was evaluated T) or antibodies FcγR-NULL FcγRIIB MAB. Earlier in this application, it was shown that on B cells (which express only FcyRIIB), treatment with a wild 6G11 WT antibody antagonist or an NQ mAb antibody does not activate FcyRIIB (Roghanian et al, Cancer Cell 27, 473-488, April 13, 2015). However, treatment with wild-type (WT) antibodies, but not with FcγR-null FcγRIIB mAbs, resulted in FcγRIIB-ITIM phosphorylation in both those treated with human monocyte-derived macrophages (MDM) (Fig. 2D) and bone marrow-derived mouse macrophages hFcγRIIB+/- x mFcγRIIB-/- (Fig. 2E), providing evidence for this phenomenon. in our system and pointing out that effector activation may not be optimal when using the wild type WT FcγRIIB mAb. This indicates that the normal FcyRIIB mAb activates inhibitory signals in immune effector cells. In view of this observation with the above observations considering the optimal FcγRIIB mAb format for deletion of target cells, the present application further investigates how an optimal deletion can be obtained.

Wild-type (WT) antibodies and FcγR-null hFcyRIIB mAbs can be combined for optimal depletion of target cells

The present application further investigates the efficacy of different forms of hFcγRIIB and mFcγRII mAb antibodies in the presence or absence of rituximab in a system in which mFcγRIIB was expressed only on target B cells and hFcγRIIB was expressed only on effector cells. This system allowed for a simultaneous targeting and targeting analysis of FcγRIIB limited to targets and effectors. Initially, this application investigated the effect on antibody mAb binding FcγRIIB only on the target. Treatment of mice with suboptimal doses of rituximab alone resulted in minimal depletion of target B cells (FIG. 3). Treatment of mice with optimal doses of WT mFcγRII mAb alone (targeting FcγRIIB present only on targets) resulted in approximately 50% depletion of target cells. Co-administration of the wild type WT mFcyRII mAb with rituximab resulted in profound depletion (about 75% of resident spleen B cells), while the addition of the Fc-null F(ab') ₂ mFcγRII mAb had no effect either when administered alone or when administered together with rituximab. This demonstrates that a normal FcγRIIB mAb can be used to achieve deletion of a target expressing FcγRIIB in the absence of FcγRIIB on effectors.

We subsequently investigated the targeting of FcγRIIB specifically on effector cells; treatment of mice with wild type (WT) antibodies or F(ab') ₂ hFcγRIIB antibodies (targeting FcγRIIB only on effectors) did not result in B cell deletion as expected. However, the combination of rituximab and wild-type (WT) antibodies or F(ab') ₂ hFcγRIIB resulted in increased target cell depletion compared to rituximab treatment alone. An even greater deletion was observed when the WT mFcγRII mAb was used to target B cells and F(ab') ₂ hFcyRIIB was used to target effectors. In contrast, treatment with WT mFcγRIIB mAb along with WT hFcγRIIB mAb suppressed depletion (FIG. 3). This shows that normal blocking of the FcγRIIB mAb interferes with target depletion. Fc-modified Fab2 mAb was used to block effectors.

In a further study of these combinations, when the WT hFcγRIIB mAb was used to block hFcyRIIB effector cells, the depletion from the combination of rituximab and the wild-type WT mFcγRII mAb was only about 30%. Much deeper depletion was observed when rituximab and the WT mFcγRII mAb, both of which opsonize target B cells, were combined with the Fc-null F(ab') ₂ hFcγRIIB mAb, which blocks hFcγRIIB effector cells resulting in approximately 90% depletion of target cells (Figure 3).

Optimal formats for enhancing the deletion of regulatory T cells (Treg) by blocking FcgRIIB with mAb

The next step was to evaluate whether the ability to enhance target cell deletion by blocking FcgRIIB could be transferred to other cellular targets such as regulatory T cells (Treg). This is similar to the example above, but using IL2R to deplete regulatory T cells (Treg). To address this, Balb/c mice were intraperitoneally injected with 100 μg of an Fc-inert anti-FcγRIIb mAb antibody (AT130-2 mIgG1 NA, Fig. 9). Subsequently, 100 μg of anti-IL2R (PC61) was administered intraperitoneally 6 hours later to delete FoxP3+ regulatory T cells. Then, after 4 days, they were evaluated in the blood, spleen and lymph nodes using the FACS analytical system. AT130-2 NA has been shown to improve deletion of regulatory T cells, especially in the spleen (Fig. 4A). To address the issue of reproducibility of this effect, this experiment was repeated in C57BL/6 mice. Again, AT130-2 NA was seen to improve deletion of regulatory T cells in B6 mice, especially in the spleen and lymph nodes (Fig. 4B), resulting in higher CD8:Treg ratios in the blood, spleen, and lymph nodes (Fig. 4C). This blood ratio was significantly higher with the NA combination than with PC61 alone (PC61 versus combination, P=0.0218). To confirm the previous findings, the ability of the WT AT130-2 wild-type mutant, compared with the AT130-2 NA mutant having an inert Fc region, to improve IL2R mAb-mediated deletion of regulatory T cells was then evaluated. The WT AT130-2 variant did not give any increase in deletion, while the NA variant increased the deletion (*Student's t-test for one sample, P=0.044) (FIG. 5). Thus, this shows that the normal FcγRIIb blocking mAb does not enhance depletion.

mAb-mediated blockade of FcgRIIB enhances CTLA-4 immunotherapy

Again, this is the same concept as above, but using another target antibody highly expressed on tumor-associated regulatory T cells (CTLA-4) leading to anti-tumor immunity. Thus, to see if this approach could enhance cancer immunotherapy, CT26 cells were injected subcutaneously into female BALB/C mice. Mice were randomized into treatment groups when the tumor area (tumor width x length) was approximately 100 mm ² . Mice were injected with 200 μg of 9H10 antibody (hamster anti-mouse CTLA4 antibody) intraperitoneally in 200 μl of PBS on days 0, 2, 4 and 11. On day 0, the combination treated mice received 100 μg of AT130-2 N297A. Tumor width and length were measured and mice were sacrificed when the tumor area (length x tumor width) exceeded 400 mm ² (FIG. 6A). In FIG. 6B shows the growth of individual tumors in each group, and FIG. 6C shows the median area (+/- standard error of the mean (SEM) or standard deviation (SD)). The survival curve for these mice is shown in Fig. 6D; the survival curve from the second experiment, in which the NA combination was treated, is shown in FIG. 6E, the difference in survival between mice treated with the NA combination compared to mice treated with 9H10 alone was statistically significant (log-rank test P 0.0179). Finally, to decide whether this effect depends on the NA format of the antibody, the experiment was repeated with WT mIgG1 antibodies (wild type) and compared to the NA format as before. The NA variant was not significantly different from the 9H10-only group, and the combination with NA was significantly more effective than the combination with WT mAb (log-rank P = 0.0460) (Fig. 7) This shows that the combination with wild-type WT Ab, i.e. normal glycosylated mAb, is ineffective and even worsens the desired therapeutic effect.

mAb-mediated blockade of FcγRIIB enhances PD-L1 immunotherapy

As with CTLA4, it is believed that the effect of antibodies targeting PD-L1 depends on the activation of FcγR receptors. However, a distinct form of CTLA-4, PD-L1, is expressed on a variety of cells, primarily myeloid cells and cancer cells. To determine whether the combination of PD-L1 antibody with FcγRIIB blockade enhances cancer immunotherapy, MC38 cells were injected subcutaneously into female C57/Bl6 mice. Mice were randomized into treatment groups when the tumor area (tumor width x tumor length) was approximately 100 mm ² . Mice received 10 mg/kg 9H10 antibody (hamster anti-mouse CTLA4 antibody) ip in 200 μl PBS on days 0, 2, 4 and 11. On day 0, mice receiving the combination received 100 μg of AT130-2 N297A or WT AT130-2. Produced by measuring the width and length of the tumors and killed mice when the area of the tumor exceeded 2000 mm ² . In FIG. 8A shows the growth of individual tumors in each group. The number indicates the number of surviving mice in each group. In FIG. 8B shows mouse survival curves. To decide whether this effect depends on the NA format of the antibody, the experiment was carried out using both WT mIgG1 wild-type antibodies and NA format antibodies, as before. The NA variant was more effective than the combination with the WT mAb and resulted in better mouse survival (FIG. 8B). This shows that the most effective combination for PD-L1 antibodies targeting primarily cancer cells and monocytes/macrophages/myeloid suppressor cells is the aglycosylated NA-format.

Taken together, the above data show that blockade of FcyRIIB as a means to increase the therapeutic efficacy of other antibodies is broad and applicable to antibodies against various targets (CD20, CD25, CTLA4 and PD-L1) expressed on various cell types (B cells, regulatory T cells and myeloid cells).

Comparison of binding of WT 6G11 and N297A 6G11 to Fc-gamma receptors (mouse and human)

Surface plasmon resonance (SPR) analysis was performed using a BIAcore T200 system (GE Healthcare). Samples were run at 25 ^° C. in HBS-EP+ buffer at a rate of 30 ml/min. Data was analyzed using BiaEvaluation software. The control flow cell response was automatically subtracted prior to data analysis. For comparison of Fc-gamma receptor (FcγR) binding, wild-type antibody 6g11 WT or 6G11 N297Q hIgG1 was immobilized at pH 5 on a CM5 sensor chip at the amino group; recombinant human and mouse FcγR (100 nM) were injected (R&D Systems) through both surfaces for 180 seconds. Alternatively, various concentrations of FcγR were added sequentially ranging from 0-500 nM and the responses were measured. The results are shown in FIG. 10 A-H.

Claims (1038)

1. Combination application a first antibody molecule, or antigen-binding fragment thereof, that specifically binds FcγRIIb via its Fab region, and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, and a second antibody molecule that specifically binds to a receptor present on an immune cell, wherein the immune cell is an immune cell that suppresses anti-cancer immunity, in which the second antibody molecule has an Fc region that binds to at least one activating Fcγ receptor, wherein binding of the second antibody molecule to the receptor on the immune cell causes depletion and/or deactivation of that immune cell; in the treatment of FcγRIIb-negative cancer in a patient. 2. Use according to claim 1, wherein the first antibody, or antigen-binding fragment thereof, does not have an Fc region. 3. Use according to claim 1 or 2, wherein the anti-cancer immune suppressing immune cell is a regulatory T cell (Treg). 4. Use according to claim 1 or 2, wherein the anti-cancer immune-suppressing immune cell is a myeloid cell. 5. Use according to claim 4, wherein the myeloid cell is a tumor-associated macrophage. 6. Application according to any one of paragraphs. 1-5, wherein the FcγRIIb-negative cancer is a solid cancer. 7. Use according to claim 6, wherein the solid cancer is selected from the group consisting of: carcinoma; sarcomas and lymphomas. 8. Use according to claim 6 or 7, wherein the solid cancer is selected from the group consisting of: melanoma, breast cancer, prostate cancer, colon cancer, lung cancer, bladder cancer, kidney cancer, mesothelioma, Merkel cell carcinoma and head and neck cancer. 9. Application according to any one of paragraphs. 1-8, wherein the first antibody molecule or antigen-binding fragment thereof is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin. 10. Application according to any one of paragraphs. 1-9, wherein the first antibody molecule or antigen-binding fragment thereof is a monoclonal antibody molecule or an antibody molecule of monoclonal origin. 11. Application according to any one of paragraphs. 1-10, wherein the first antibody molecule or antigen-binding fragment thereof is selected from the group consisting of: full length antibody, chimeric antibody, single chain antibody, Fab fragment, (Fab') ₂ fragment, Fab' fragment, Fv fragment, and scFv fragment. 12. Application according to any one of paragraphs. 1-11, wherein the first antibody molecule or antigen-binding fragment thereof is a human IgG antibody molecule having an aglycosylated Fc region or a human IgG antibody molecule having an aglycosylated Fc region. 13. Use according to claim 12, wherein the IgG antibody molecule is an IgG1 or IgG2 antibody molecule. 14. Use according to claim 13, wherein the IgG antibody molecule is an aglycosylated human IgG1 antibody, or an aglycosylated humanized mouse antibody, or an aglycosylated humanized llama hcIgG antibody, or an aglycosylated chimerized mouse IgG. 15. Use according to claim 14, wherein the first antibody molecule or its antigen-binding fragment has been aglycosylated by changing the amino acid at position 297. 16. Use according to claim 15, wherein the first antibody molecule or antigen-binding fragment thereof has been aglycosylated via the N297Q substitution. 17. Application according to any one of paragraphs. 1-16, wherein the first antibody molecule or antigen-binding fragment thereof contains a variable heavy chain (VH) containing 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 and 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 (viiSEQ 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 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 and SEQ ID NO: 190 and SEQ ID NO: 191. 18. Application according to any one of paragraphs. 1-17, wherein the first antibody molecule or antigen-binding fragment thereof contains a variable light chain (VL) containing 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 and 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 and SEQ ID NO: 193 and SEQ ID NO: 194. 19. Application according to any one of paragraphs. 1-18, wherein the first antibody molecule or antigen-binding fragment thereof 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. 20. Application according to any one of paragraphs. 1-19, wherein the first antibody molecule or antigen-binding fragment thereof 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. 21. Application according to any one of paragraphs. 1-20, wherein the molecule of the first antibody or antigen-binding fragment contains 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. 22. Application according to any one of paragraphs. 1-21, wherein the molecule of the first antibody or antigen-binding fragment contains the following amino acid sequences: (i) SEQ ID NO: 3 and SEQ ID NO: 27; or (ii) SEQ IS NO: 4 and SEQ ID NO: 28; or (iii) SEQ IS 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. 23. Application according to any one of paragraphs. 1-16, wherein the first antibody molecule, or antigen-binding fragment thereof, is an antibody molecule, or antigen-binding fragment thereof, capable of competing for binding to FcγRIIb with an antibody molecule that: (a) contains a variable heavy chain (VH) containing 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 and 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 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 and SEQ ID NO: 190 and SEQ ID NO: 191; And contains a variable light chain (VL) containing 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 and 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 and SEQ ID NO: 193 and SEQ ID NO: 194; or (b) contains 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, and a variable light chain (VL) 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, or (c) contains 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. 24. Application according to any one of paragraphs. 1-23, wherein the second antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and a human-derived antibody molecule. 25. Application according to any one of paragraphs. 1-24, wherein the second antibody molecule is a human IgG antibody. 26. Application according to any one of paragraphs. 1-25, wherein the second antibody molecule specifically binds to a receptor selected from the group consisting of: CTLA-4; 4-1BB; OX40; TNFR2; PD-L1; Il-2R and GITR. 27. Use according to claim 26, wherein the second antibody molecule specifically binds to CTLA-4. 28. Use according to claim 26, wherein the second antibody molecule specifically binds to PD-L1. 29. Pharmaceutical composition containing: (i) a first antibody molecule, or antigen-binding fragment thereof, that specifically binds FcγRIIb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; And (ii) a second antibody molecule that specifically binds to a receptor present on an immune cell, wherein the immune cell is an immune cell that suppresses anti-cancer immunity, wherein the second antibody molecule has an Fc region that binds to at least one activating Fcγ receptor, wherein binding of the second antibody to that receptor on the immune cell causes depletion and/or inactivation of that immune cell; for use in the treatment of FcγRIIb-negative cancer in a patient. 30. A pharmaceutical composition for use according to claim 29, wherein the first antibody or antigen-binding fragment does not have an Fc region. 31. A pharmaceutical composition for use according to claim 29 or 30, wherein the immune cell that suppresses anti-cancer immunity is a regulatory T cell (Treg). 32. A pharmaceutical composition for use according to claim 29 or 30, wherein the anti-cancer immune suppressing immune cell is a myeloid cell. 33. A pharmaceutical composition for use according to claim 32, wherein the myeloid cell is a tumor-associated macrophage. 34. Pharmaceutical composition for use according to any one of paragraphs. 29-33, wherein the FcγRIIb negative cancer is a solid cancer. 35. A pharmaceutical composition for use according to claim 34, wherein the solid cancer is selected from the group consisting of: carcinomas, sarcomas, and lymphomas. 36. A pharmaceutical composition for use according to claim 34 or 35, wherein the solid cancer is selected from the group consisting of: melanoma, breast cancer, prostate cancer, colon cancer, lung cancer, bladder cancer, kidney cancer, mesothelioma, Merkel cell carcinoma, and head and neck cancer. 37. Pharmaceutical composition for use according to any one of paragraphs. 29-36, wherein the first antibody molecule or antigen-binding fragment thereof is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and a human-derived antibody molecule. 38. Pharmaceutical composition for use according to any one of paragraphs. 29-37, wherein the first antibody molecule or antigen-binding fragment thereof is a monoclonal antibody molecule or an antibody molecule of monoclonal origin. 39. Pharmaceutical composition for use according to any one of paragraphs. 29-38, wherein the first antibody molecule or antigen-binding fragment thereof is selected from the group consisting of: full length antibody, chimeric antibody, single chain antibody, Fab fragment, (Fab') ₂ fragment, Fab' fragment, Fv fragment, and scFv fragment. 40. Pharmaceutical composition for use according to any one of paragraphs. 29-39, wherein the first antibody molecule or antigen-binding fragment thereof is a human IgG antibody molecule having an aglycosylated Fc region or a human IgG antibody molecule having an aglycosylated Fc region. 41. A pharmaceutical composition for use according to claim 40, wherein the IgG antibody molecule is an IgG1 or IgG2 antibody molecule. 42. A pharmaceutical composition for use according to claim 41, wherein the IgG antibody molecule is an aglycosylated human IgG1 antibody, or an aglycosylated humanized mouse antibody, or an aglycosylated humanized llama hcIgG antibody, or an aglycosylated chimerized mouse IgG. 43. Pharmaceutical composition for use according to claim 42, where the first antibody molecule or its antigen-binding fragment has been aglycosylated by replacing the amino acid at position 297. 44. A pharmaceutical composition for use according to claim 43, wherein the first antibody molecule or antigen-binding fragment thereof has been aglycosylated by replacing N297Q. 45. Pharmaceutical composition for use according to any one of paragraphs. 29-44, wherein the first antibody molecule or antigen-binding fragment thereof contains a variable heavy chain (VH) containing 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 and 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 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 and SEQ ID NO: 190 and SEQ ID NO: 191. 46. Pharmaceutical composition for use according to any one of paragraphs. 29-45, wherein the first antibody molecule or antigen-binding fragment thereof contains a variable light chain (VL) containing 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 and 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 and SEQ ID NO: 193 and SEQ ID NO: 194. 47. Pharmaceutical composition for use according to any one of paragraphs. 29-46, wherein the first antibody molecule or antigen-binding fragment thereof 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. 48. Pharmaceutical composition for use according to any one of paragraphs. 29-47, wherein the first antibody molecule or antigen-binding fragment thereof 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. 49. Pharmaceutical composition for use according to any one of paragraphs. 29-48, wherein the first antibody molecule or antigen-binding fragment thereof contains 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. 50. Pharmaceutical composition for use according to any one of paragraphs. 29-49, wherein the molecule of the first antibody or antigen-binding fragment contains the following amino acid sequences: (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. 51. Pharmaceutical composition for use according to any one of paragraphs. 29-44, wherein the first antibody molecule or antigen-binding fragment thereof is an antibody molecule or antigen-binding fragment capable of competing for binding to FcγRIIb with an antibody molecule that: (a) contains a variable heavy chain (VH) containing 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 and 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 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 and SEQ ID NO: 190 and SEQ ID NO: 191; And contains a variable light chain (VL) containing 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 and 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 and SEQ ID NO: 193 and SEQ ID NO: 194; or (b) contains 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, and 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; or (c) contains 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. 52. Pharmaceutical composition for use according to any one of paragraphs. 29-51, wherein the second antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and a human-derived antibody molecule. 53. Pharmaceutical composition for use according to any one of paragraphs. 29-52, wherein the second antibody molecule is a human IgG antibody. 54. Pharmaceutical composition for use according to any one of paragraphs. 29-53, wherein the second antibody molecule specifically binds to a receptor selected from the group consisting of: CTLA-4; 4-1BB; OX40; TNFR2; PD-L1; Il-2R and GITR. 55. A pharmaceutical composition for use according to claim 54, wherein the second antibody molecule specifically binds to CTLA-4. 56. A pharmaceutical composition for use according to claim 54, wherein the second antibody molecule specifically binds to PD-L1. 57. A kit for use in the treatment of FcγRIIb-negative cancer, containing: (i) a first antibody molecule, or antigen-binding fragment thereof, that specifically binds FcγRIIb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; And (ii) a second antibody molecule that specifically binds to a receptor present on an immune cell, wherein the immune cell is an immune cell that suppresses anti-cancer immunity, wherein the second antibody molecule has an Fc region that binds to at least one activating Fcγ receptor, wherein binding of the second antibody molecule to the receptor on the immune cell causes depletion and/or inactivation of the immune cell. 58. A kit for use according to claim 57, wherein the first antibody or antigen-binding fragment thereof does not have an Fc region. 59. The kit for use according to claim 57 or 58, wherein the immune cell that suppresses anti-cancer immunity is a regulatory T cell (Treg). 60. The kit for use according to claim 57 or 58, wherein the cancer suppressing immune cell is a myeloid cell. 61. The kit for use according to claim 60, wherein the myeloid cell is a tumor-associated macrophage. 62. Set for use according to any one of paragraphs. 57-61, wherein the FcγRIIb-negative cancer is a solid cancer. 63. Set for use according to claim 62, in which solid cancer is selected from the group consisting of: carcinoma; sarcomas and lymphomas. 64. The kit for use according to claim 62 or 63, wherein the solid cancer is selected from the group consisting of: melanoma, breast cancer, prostate cancer, colon cancer, lung cancer, bladder cancer, kidney cancer, mesothelioma, Merkel cell carcinoma, and head and neck cancer. 65. Set for use according to any one of paragraphs. 57-64, wherein the first antibody molecule or antigen-binding fragment thereof is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and a human-derived antibody molecule. 66. Set for use according to any one of paragraphs. 57-65, wherein the first antibody molecule or antigen-binding fragment thereof is a monoclonal antibody molecule or an antibody molecule of monoclonal origin. 67. Set for use according to any one of paragraphs. 57-66, wherein the first antibody molecule or antigen-binding fragment thereof is selected from the group consisting of: full length antibody, chimeric antibody, single chain antibody, Fab fragment, (Fab') ₂ fragment, Fab' fragment, Fv fragment, and scFv fragment. 68. Set for use according to any one of paragraphs. 57-67, wherein the first antibody molecule or antigen-binding fragment thereof is a human IgG antibody molecule having an aglycosylated Fc region or a human IgG antibody molecule having an aglycosylated Fc region. 69. A kit for use according to claim 68, wherein the IgG antibody molecule is an IgG1 or IgG2 antibody molecule. 70. A kit for use according to claim 69, wherein the IgG antibody molecule is an aglycosylated human IgG1 antibody, or an aglycosylated humanized mouse antibody, or an aglycosylated humanized llama hcIgG antibody, or an aglycosylated chimerized mouse IgG. 71. A kit for use according to claim 70, where the first antibody molecule or its antigen-binding fragment has been aglycosylated by replacing the amino acid at position 297. 72. The kit for use according to claim 71, wherein the first antibody molecule or antigen-binding fragment thereof has been aglycosylated by replacing N297Q. 73. Set for use according to any one of paragraphs. 57-72, wherein the first antibody molecule or antigen-binding fragment thereof contains a variable heavy chain (VH) containing 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 and 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 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 and SEQ ID NO: 190 and SEQ ID NO: 191. 74. Set for use according to any one of paragraphs. 57-73, wherein the first antibody molecule or antigen-binding fragment thereof contains a variable light chain (VL) containing 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 and 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 and SEQ ID NO: 193 and SEQ ID NO: 194. 75. Set for use according to any one of paragraphs. 57-74, wherein the first antibody molecule or antigen-binding fragment thereof 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. 76. Set for use according to any one of paragraphs. 57-75, wherein the first antibody molecule or antigen-binding fragment thereof 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. 77. Set for use according to any one of paragraphs. 57-76, wherein the molecule of the first antibody or antigen-binding fragment contains 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. 78. Set for use according to any one of paragraphs. 57-77, wherein the molecule of the first antibody or antigen-binding fragment contains the following amino acid sequences: (i) SEQ ID NO: 3 and SEQ ID NO: 27; or (ii) SEQ IS NO: 4 and SEQ ID NO: 28; or (iii) SEQ IS 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. 79. Set for use according to any one of paragraphs. 57-72, wherein the first antibody molecule, or antigen-binding fragment thereof, is an antibody molecule, or antigen-binding fragment thereof, capable of competing for binding to FcγRIIb with an antibody molecule that: (a) contains a variable heavy chain (VH) containing 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 and 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 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 and SEQ ID NO: 190 and SEQ ID NO: 191; And variable light chain (VL) containing 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 and 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 and SEQ ID NO: 193 and SEQ ID NO: 194; or (b) contains 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, and contains 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; or (c) contains 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. 80. Set for use according to any one of paragraphs. 57-79, wherein the second antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and a human-derived antibody molecule. 81. Set for use according to any one of paragraphs. 57-80, wherein the second antibody molecule is a human IgG antibody. 82. Set for use according to any one of paragraphs. 57-81, wherein the second antibody molecule specifically binds to a receptor selected from the group consisting of: CTLA-4; 4-1BB; OX40; TNFR2; PD-L1; Il-2R and GITR. 83. A kit for use according to claim 82, wherein the second antibody molecule specifically binds to CTLA-4. 84. A kit for use according to claim 82, wherein the second antibody molecule specifically binds to PD-L1. 85. Application (i) a first antibody molecule, or an antigen-binding fragment thereof, that specifically binds FcγRIIb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; And (ii) a second antibody molecule that specifically binds to a receptor present on an immune cell, wherein the immune cell is an immune cell that suppresses anti-cancer immunity, wherein the second antibody molecule has an Fc region that binds to at least one activating Fcγ receptor, wherein binding of the second antibody to that receptor on the immune cell causes depletion and/or inactivation of that immune cell; in the manufacture of a medicinal product for use in the treatment of FcγRIIb-negative cancer in a patient. 86. The use of claim 85, wherein the first antibody, or antigen-binding fragment thereof, does not have an Fc region. 87. Use according to claim 85 or 86, wherein the immune cell suppressing anti-cancer immunity is a regulatory T cell (Treg). 88. Use according to claim 85 or 86, wherein the immune cell suppressing anti-cancer immunity is a myeloid cell. 89. The use of claim 88, wherein the myeloid cell is a tumor-associated macrophage. 90. Application according to any one of paragraphs. 85-89, wherein the FcγRIIb-negative cancer is a solid cancer. 91. Use according to claim 90, in which solid cancer is selected from the group consisting of: carcinoma; sarcomas and lymphomas. 92. The use of claim 90 or 91 wherein the solid cancer is selected from the group consisting of: melanoma, breast cancer, prostate cancer, colon cancer, lung cancer, bladder cancer, kidney cancer, mesothelioma, Merkel cell carcinoma, and head and neck cancer. 93. Application according to any one of paragraphs. 85-92, wherein the first antibody molecule or antigen-binding fragment thereof is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and a human-derived antibody molecule. 94. Application according to any one of paragraphs. 85-93, wherein the first antibody molecule or antigen-binding fragment thereof is a monoclonal antibody molecule or an antibody molecule of monoclonal origin. 95. Application according to any one of paragraphs. 85-94, wherein the first antibody molecule or antigen-binding fragment thereof is selected from the group consisting of: full length antibody, chimeric antibody, single chain antibody, Fab fragment, (Fab') ₂ fragment, Fab' fragment, Fv fragment, and scFv fragment. 96. Application according to any one of paragraphs. 85-95, wherein the first antibody molecule or antigen-binding fragment thereof is a human IgG antibody molecule having an aglycosylated Fc region or a human IgG antibody molecule having an aglycosylated Fc region. 97. Use according to claim 96, wherein the IgG antibody molecule is an IgG1 or IgG2 antibody molecule. 98. Use according to claim 97, wherein the IgG antibody molecule is an aglycosylated human IgG1 antibody, or an aglycosylated humanized mouse antibody, or an aglycosylated humanized llama hcIgG antibody, or an aglycosylated chimerized mouse IgG. 99. Use according to claim 98, where the first antibody molecule or its antigen-binding fragment has been aglycosylated by changing the amino acid at position 297. 100. The use of claim 99, wherein the first antibody molecule or antigen-binding fragment thereof has been aglycosylated via the N297Q substitution. 101. Application according to any one of paragraphs. 85-100, wherein the first antibody molecule or antigen-binding fragment thereof contains a variable heavy chain (VH) containing 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 and 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 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 and SEQ ID NO: 190 and SEQ ID NO: 191. 102. Application according to any one of paragraphs. 85-101, wherein the first antibody molecule or antigen-binding fragment thereof contains a variable light chain (VL) containing 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 and 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 and SEQ ID NO: 193 and SEQ ID NO: 194. 103. Application according to any one of paragraphs. 85-102, wherein the first antibody molecule or antigen-binding fragment thereof 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. 104. Application according to any one of paragraphs. 85-103, wherein the first antibody molecule or antigen-binding fragment thereof 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. 105. Application according to any one of paragraphs. 85-104, wherein the molecule of the first antibody or antigen-binding fragment contains 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. 106. Application according to any one of paragraphs. 85-105, wherein the molecule of the first antibody or antigen-binding fragment contains the following amino acid sequences: (i) SEQ ID NO: 3 and SEQ ID NO: 27; or (ii) SEQ IS NO: 4 and SEQ ID NO: 28; or (iii) SEQ IS 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. 107. Application according to any one of paragraphs. 85-100, wherein the first antibody molecule, or antigen-binding fragment thereof, is an antibody molecule, or antigen-binding fragment thereof, capable of competing for binding to FcγRIIb with an antibody molecule that: (a) contains a variable heavy chain (VH) containing 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 and 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 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 and SEQ ID NO: 190 and SEQ ID NO: 191, and contains a variable light chain (VL) containing 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 and 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 and SEQ ID NO: 193 and SEQ ID NO: 194; or (b) contains 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, and contains 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; or (c) contains 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. 108. Application according to any one of paragraphs. 85-107, wherein the second antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and a human-derived antibody molecule. 109. Application according to any one of paragraphs. 85-108, wherein the second antibody molecule is a human IgG antibody. 110. Application according to any one of paragraphs. 85-109, wherein the second antibody molecule specifically binds to a receptor selected from the group consisting of: CTLA-4; 4-1BB; OX40; TNFR2; PD-L1; Il-2R and GITR. 111. The use of claim 110, wherein the second antibody molecule specifically binds to CTLA-4. 112. The use of claim 110, wherein the second antibody molecule specifically binds to PD-L1. 113. A method for treating FcγRIIb-negative cancer in a patient, comprising administering: (i) a first antibody molecule, or antigen-binding fragment thereof, that specifically binds FcγRIIb via its Fab region and which lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; And (ii) a second antibody molecule that specifically binds to a receptor present on an immune cell, wherein the immune cell is an immune cell that suppresses anti-cancer immunity, wherein the second antibody molecule has an Fc region that is capable of activating at least one activating Fcγ receptor, wherein binding of the second antibody to that receptor on the immune cell causes depletion and/or deactivation of that immune cell. 114. The method of claim 113, wherein the first antibody or antigen-binding fragment thereof lacks an Fc region. 115. The method of claim 113 or 114, wherein the immune cell that suppresses anti-cancer immunity is a regulatory T cell (Treg). 116. The method according to claim 113 or 114, wherein the immune cell that suppresses anti-cancer immunity is a myeloid cell. 117. The method of claim 116 wherein the myeloid cell is a tumor-associated macrophage. 118. The method according to any one of paragraphs. 113-117, wherein the FcγRIIb negative cancer is a solid cancer. 119. The method according to p. 118, in which solid cancer is selected from the group consisting of: carcinoma; sarcomas and lymphomas. 120. The method of claim 118 or 119, wherein the solid cancer is selected from the group consisting of: melanoma, breast cancer, prostate cancer, colon cancer, lung cancer, bladder cancer, kidney cancer, mesothelioma, Merkel cell carcinoma, and head and neck cancer. 121. The method according to any one of paragraphs. 113-120, wherein the first antibody molecule or antigen-binding fragment thereof is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and a human-derived antibody molecule. 122. The method according to any one of paragraphs. 113-121, wherein the first antibody molecule or antigen-binding fragment thereof is a monoclonal antibody molecule or an antibody molecule of monoclonal origin. 123. The method according to any one of paragraphs. 113-122, wherein the first antibody molecule or antigen-binding fragment thereof is selected from the group consisting of: full length antibody, chimeric antibody, single chain antibody, Fab fragment, (Fab') ₂ fragment, Fab' fragment, Fv fragment, and scFv fragment. 124. The method according to any one of paragraphs. 113-123, wherein the first antibody molecule or antigen-binding fragment thereof is a human IgG antibody molecule having an aglycosylated Fc region or a human IgG antibody molecule having an aglycosylated Fc region. 125. The method of claim 124, wherein the IgG antibody molecule is an IgG1 or IgG2 antibody molecule. 126. The method of claim 125, wherein the IgG antibody molecule is an aglycosylated human IgG1 antibody, or an aglycosylated humanized mouse antibody, or an aglycosylated humanized llama hcIgG antibody, or an aglycosylated chimerized mouse IgG. 127. The method of claim 126, wherein the first antibody molecule or its antigen-binding fragment has been aglycosylated by replacing the amino acid at position 297. 128. The method of claim 127, wherein the first antibody molecule or antigen-binding fragment thereof has been aglycosylated by replacing N297Q. 129. The method according to any one of paragraphs. 113-128, wherein the first antibody molecule or antigen-binding fragment thereof contains a variable heavy chain (VH) containing 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 and 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 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 and SEQ ID NO: 190 and SEQ ID NO: 191. 130. The method according to any one of paragraphs. 113-129, wherein the first antibody molecule or antigen-binding fragment thereof contains a variable light chain (VL) containing 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 and 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 and SEQ ID NO: 193 and SEQ ID NO: 194. 131. The method according to any one of paragraphs. 113-130, wherein the first antibody molecule or antigen-binding fragment thereof 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. 132. The method according to any one of paragraphs. 113-131, wherein the first antibody molecule or antigen-binding fragment thereof 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. 133. Sosob according to any one of paragraphs. 113-132, wherein the molecule of the first antibody or antigen-binding fragment contains 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. 134. The method according to any one of paragraphs. 113-133, wherein the molecule of the first antibody or antigen-binding fragment contains the following amino acid sequences: (i) SEQ ID NO: 3 and SEQ ID NO: 27; or (ii) SEQ IS NO: 4 and SEQ ID NO: 28; or (iii) SEQ IS 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. 135. The method according to any one of paragraphs. 113-128, wherein the first antibody molecule, or antigen-binding fragment thereof, is an antibody molecule, or antigen-binding fragment thereof, capable of competing for binding to FcγRIIb with an antibody molecule that: (a) contains a variable heavy chain (VH) containing 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 and 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 (viiSEQ 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 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 and SEQ ID NO: 190 and SEQ ID NO: 191, and contains a variable light chain (VL) containing 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 and 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 and SEQ ID NO: 193 and SEQ ID NO: 194; or (b) contains 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, and contains 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, or (c) contains 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, or (d) contains the following amino acid sequences: (i) SEQ ID NO: 3 and SEQ ID NO: 27; or (ii) SEQ IS NO: 4 and SEQ ID NO: 28; or (iii) SEQ IS 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. 136. The method according to any one of paragraphs. 113-135, wherein the second antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and a human-derived antibody molecule. 137. The method according to any one of paragraphs. 113-136, wherein the second antibody molecule is a human IgG antibody. 138. The method according to any one of paragraphs. 113-137, wherein the second antibody molecule specifically binds to a receptor selected from the group consisting of: CTLA-4; 4-1BB; OX40; TNFR2; PD-L1; Il-2R and GITR. 139. The method of claim 138, wherein the second antibody molecule specifically binds to CTLA-4. 140. The method of claim 138, wherein the second antibody molecule specifically binds to PD-L1.

Images