Improvement of antibody tolerance associated with intravenous administration

Abstract

The present invention generally relates to therapeutic systems and combinations for use in antibody dosing regimens, as well as their uses. Also described herein is a model for predicting whether a therapeutic antibody that binds to a human target is associated with tolerability problems associated with intravenous administration, and / or whether pretreatment, changing the route of administration, or modifying the antibody can prevent tolerability problems associated with intravenous administration of a therapeutic antibody to humans. The model involves administering the antibody intravenously or intraperitoneally to mice and observing the mice immediately after administration for any transient manifestations of isolated macroscopic symptoms and reduced activity. The model may also involve administering a pretreatment in combination with administration of the antibody, administering the therapeutic antibody by a route of administration other than intravenous or intraperitoneal administration, or administering a modified form of the antibody to the mice, and observing the mice immediately after such administration for any transient manifestations of isolated macroscopic symptoms and reduced activity, and comparing this to the transient manifestations of isolated macroscopic symptoms and reduced activity following intravenous or intraperitoneal administration of an unmodified antibody without pretreatment.

Description

[Technical Field]

[0001] The present invention generally relates to combinations, uses, methods, and kits for use in therapeutic systems, drug regimens, and for improving the tolerability of antibody molecules that specifically bind to FcyRllb in a target. The present invention also relates to methods or models that can be used to predict whether a therapeutic antibody molecule that specifically binds to a human target is associated with a tolerability issue associated with intravenous administration to a human, and / or whether prophylactic or therapeutic measures, changes in the route of administration, and / or modifications of the therapeutic antibody molecule can prevent or mitigate a tolerability issue associated with intravenous administration of a therapeutic antibody molecule that specifically binds to a human target to a human. [Background technology]

[0002] Therapeutic antibodies constitute a well-proven class of drugs approved for the treatment of a variety of diseases, including cancer, inflammatory diseases, autoimmune diseases, and infectious diseases.

[0003] Monoclonal antibody therapies, particularly those used in cancer therapy, can be administered by intravenous infusion, allowing for high immediate drug exposure that can be maintained through repeated dosing. However, in many cases, patients or subjects may experience adverse reactions to the infusion of therapeutic antibodies, known as infusion-related reactions ("IRRs").

[0004] IRRs can be experienced by subjects during the infusion of therapeutic antibodies ("monophasal" reactions) and / or within a few hours of infusion ("biphasic" or "delayed" reactions), and these include hypersensitivity reactions and cytokine release syndrome ("CRS"). According to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, published by the U.S. Department of Health and Human Services on November 27, 2017, the severity of adverse events such as IRRs is classified into different grades from 1 (lowest severity) to 5 (highest severity).

[0005] Common internal respiratory reactions (IRRs) include, but are not limited to, respiratory conditions such as nasal congestion, cough, allergic rhinitis, throat irritation, and dyspnea, as well as non-respiratory conditions such as chills and nausea. IRRs often occur with the first dose administered to the subject, but they can also occur after second or subsequent doses. While IRRs are often mild, more severe IRRs can occur and, if not properly managed, can pose a fatal risk. IRRs can affect any organ system in the body.

[0006] Severe CRS can represent life-threatening adverse events and require rapid and aggressive treatment. Reducing tumor burden, limiting the dose of therapies administered, and premedication with steroids, as well as the use of anti-cytokine therapy, reduced the incidence of severe CRS.

[0007] Tolerance issues may vary between different therapeutic antibodies and between subjects with different frequencies, durations, severity, and characteristics.

[0008] Conventional management of hypersensitivity reactions such as IRRs includes temporary interruption of infusion, reduction of infusion rate, and / or treatment with antihistamines, antipyretics, and / or corticosteroids, or, in severe cases, interruption / cessation of infusion. In such severe cases, cautious reintroduction of infusion at a slower rate with an acceptable increase may be considered. Pretreatment with antipyretics and / or antihistamines may prevent reactions during subsequent infusions.

[0009] Corticosteroids are often used to prevent or suppress infusion-related reactions (IRRs) and associated toxicities seen with therapeutic antibodies. The corticosteroid regimen, i.e., the type, dose, and timing of administration of the corticosteroid, depends on both the therapeutic antibody used and the indication. Rituxan (rituximab) is a CD20-targeted cytolytic antibody commonly used in both CD20-positive B-cell lymphomas (non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL)), as well as in chronic inflammatory disorders such as rheumatoid arthritis (RA). In the case of NHL and CLL, corticosteroids are often used to reduce the risk of IRRs, and are then administered 30 minutes before the first rituximab cycle, and only in subsequent cycles if a severe infusion-related adverse event is experienced during the first cycle. In the case of NHL, corticosteroids (i.e., prednisone) are also used as part of combination therapy (i.e., rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)). In the case of RA, corticosteroids are recommended 30 minutes before each infusion. When administering another CD20-targeting antibody, Gazyva (obinutuzumab), corticosteroid premedication is recommended before the first treatment cycle and before the next treatment cycle in patients who have experienced a grade 3 IRR in a previous infusion, or whose lymphocyte count is >25×10 before the next treatment. 9 Recommended only for patients with / L. In the case of Gazyva, corticosteroid premedication should be administered at least one hour before antibody infusion. A third example of a therapeutic antibody in which corticosteroids are used to reduce the risk of IRR is CD38-targeted anti-Darzalex (daratumumab), indicated for the treatment of patients with multiple myeloma. In this case, corticosteroids are recommended before and after all infusions, 1-3 hours before infusion, and for 2 days after infusion.

[0010] WO2020 / 047389 describes drug administration strategies and regimens for therapeutic proteins, such as antibodies (e.g., bispecific antibodies targeting T cells), that reduce the prevalence and severity of cytokine release syndrome or infusion-related reactions in patients receiving immunotherapy, wherein (i) a primary dose (D1) fraction of the therapeutic protein is administered in the first week of the drug regimen, the primary dose comprising 10 mg or less of the therapeutic protein, the first dose fraction (F1D1) comprising 40% to 60% of the total primary dose, and administered to the subject on day 1 of the first week, and the second dose fraction (F2D1) comprising the remaining 40% to 60% of the total primary dose, and F1D1 (ii) administering a secondary dose (D2) fraction of the therapeutic protein to the subject 12 to 96 hours after administration, wherein the secondary dose is less than half of the maximum weekly dose of the therapeutic protein, with a first dose fraction (F1D2) comprising 40% to 60% of the total secondary dose, and a second dose fraction (F2D2) comprising the remaining 40% to 60% of the total secondary dose, and F2D2 being administered to the subject 12 to 96 hours after the administration of F1D2 during the second week of the drug regimen, and (iii) administering the maximum weekly dose of the therapeutic protein as a single dose to the subject in the following week of the drug regimen. Fractionated dosing is not ideal because, in the worst case, administering at a suboptimal dose may result in no clinical benefit from the intended therapeutic treatment or may induce disease progression, thus limiting the therapeutic benefit.

[0011] WO2020 / 037024 refers to the use of additional therapeutic agents such as antihistamines, acetaminophen, or corticosteroids to prevent or reduce the severity of adverse events, such as infusion-related reactions, in the treatment of ovarian cancer, peritoneal cancer, or fallopian tube cancer, using monomethyl auristatin or its functional analogs or derivatives, or anti-tissue factor antibodies or their antigen-binding fragments conjugated to functional derivatives.

[0012] Management of toxicities associated with immunotherapy is a difficult clinical problem. There is a great need for methods that reduce, suppress, or overcome tolerance issues associated with intravenous administration of different antibodies. However, the heterogeneity in the nature and frequency of tolerance issues associated with antibodies targeting different antigens, as well as insufficient molecular and cellular understanding of the underlying mechanisms, means that a large number of different approaches have been developed, and the efficacy of each approach can vary greatly depending on the type of therapeutic antibody for which it is used.

[0013] The above shows that intravenous administration of antibodies targeting different antigens is often associated with tolerance issues. Such tolerance issues can vary between different therapeutic antibodies, and between patients with different frequencies, durations, severities, and natures of conditions.

[0014] Accordingly, methods for reducing, suppressing, or overcoming different tolerance issues associated with intravenous (IV) administration of different antibodies targeting the same antigen (e.g., anti-CD20 antibody rituximab compared with obinutuzumab) or different antigens (e.g., anti-CD38 antibody compared with anti-CD20 antibody) differ greatly, and include administration of different agents (e.g., corticosteroids or antihistamines) immediately before, concurrently with, and / or immediately after intravenous administration of the therapeutic antibody.

[0015] There is great need and value for methods that enable prediction of whether tolerance issues are likely to occur in association with intravenous administration of an antibody targeting a different antigen, and, equally importantly, methods that enable discovery of means useful for preventing, suppressing, or overcoming tolerance issues associated with intravenous administration of an antibody targeting a given antigen. Preclinical methods that enable such prediction and screening at relatively low cost and higher throughput compared to the human clinical setting in the early stages of therapeutic antibody development are of outstanding importance. Summary of the Invention Problem to be Solved by the Invention

[0016] Against this background, the present inventors have developed a surprisingly advantageous approach for administering antibody molecules that specifically bind to FcyRIIb in a subject. As demonstrated in the accompanying examples, the approach of the present inventors maintains the therapeutic efficacy of such antibodies while reducing and / or preventing IRR associated with the administration of such antibodies. The approach of the present inventors comprises administering several separate doses of the antibody, including an initial sub-maximal therapeutic dose of the antibody, and performing the administration of the antibody after a corticosteroid has been administered to the subject. Accordingly, the approach of the present inventors provides an improved regimen for the administration of such antibodies, which is carried out to reduce and / or prevent tolerance issues in the subject.

[0017] In addition, the present inventors have developed a method or model that can be used to predict whether a therapeutic antibody molecule that specifically binds to a human target is associated with tolerance problems related to intravenous administration to humans, and / or to predict whether prophylactic or therapeutic treatment, modification of the administration route, and / or modification of the therapeutic antibody molecule can prevent or alleviate tolerance problems related to intravenous administration to humans of a therapeutic antibody molecule that specifically binds to a human target. [Means for Solving the Problems]

[0018] First to fifth aspects of the present invention In a first aspect, the present invention provides a therapeutic system for use in improving the tolerability of an antibody molecule that specifically binds to FcyRIIb in a subject, the therapeutic system comprising: (i) an antibody molecule that specifically binds to FcyRIIb, wherein the antibody molecule is administered to the subject as at least a first dose and a second dose; and (ii) a corticosteroid, wherein the first dose of the antibody molecule is lower than the maximum therapeutically effective dose of the antibody molecule, and the corticosteroid is administered to the subject prior to the first dose of the antibody molecule.

[0019] In a second aspect, the present invention provides a combination of an antibody molecule and a corticosteroid for use in a drug regimen to improve the tolerance of an antibody molecule that specifically binds to FcyRllb in a subject, wherein the drug regimen comprises the following steps: (i) The step of administering a corticosteroid before administering the first dose of the antibody molecule, (ii) The step of administering a first dose of an antibody molecule that specifically binds to FcyRllb, which is lower than the maximum therapeutic effective dose, (iii) a step of administering a second dose (and preferably at least a second dose) of an antibody molecule that specifically binds to FcyRllb, wherein a first dose of the antibody molecule is administered before the second dose.

[0020] In a third aspect, the present invention is (i) an antibody molecule that specifically binds to FcyRllb, (ii) Provide the use of corticosteroids, In the manufacture of a pharmaceutical product for improving the tolerability of an antibody molecule that specifically binds to FcyRllb in a subject, the pharmaceutical product comprises at least a first dose and a second dose of the antibody molecule, wherein the first dose of the antibody molecule is lower than the maximum therapeutically effective dose of the antibody molecule, and a corticosteroid is administered before the first dose of the antibody molecule.

[0021] In a fourth aspect, the present invention provides a method for improving the tolerance of an antibody molecule that specifically binds to FcyRllb in a target, (i) Before administering the first dose of the antibody molecule, administer a corticosteroid, (ii) Administering a first dose of an antibody molecule that specifically binds to FcyRllb, which is lower than the maximum therapeutic dose. (iii) Administering a second dose (and preferably at least a second dose) of an antibody molecule that specifically binds to FcyRllb, wherein the second dose is administered before the first dose of the antibody molecule.

[0022] To our surprise, we found that a combination of a certain dose of corticosteroid, followed by a first dose of an antibody molecule that specifically binds to FcyRllb at a dose lower than the maximum therapeutic dose, followed by a second dose of the antibody molecule, leads to a remarkable improvement in the tolerance of the antibody molecule that specifically binds to FcyRllb.

[0023] Antibody molecules are well known to those skilled in the art of immunology and molecular biology. Typically, an antibody comprises two heavy chains (H) and two light chains (L). In this specification, this complete antibody molecule is sometimes referred to as a full-size antibody or full-length antibody. The heavy chain of an antibody comprises one variable domain (VH) and three constant domains (CH1, CH2, and CH3), and the light chain of the antibody molecule comprises one variable domain (VL) and one constant domain (CL). V The variable domains (collectively referred to as heavy chain regions) bind to the antibody's target or antigen. Each variable domain contains three loops called complementarity-determining regions (CDRs), which are involved in target binding. The constant domains do not directly participate in the antibody's binding to the antigen but exhibit various effector functions. Depending on the amino acid sequence of the constant regions of their heavy chains, antibodies or immunoglobulins can be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM. In humans, some of these are further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, and IgG4, as well as IgA1 and IgA2.

[0024] Another part of the antibody is the Fc region (also known as the fragment crystallizable domain), which contains two constant domains in each of the antibody's heavy chains. As referred to herein, the Fc region is involved in the interaction between the antibody and the Fc receptor.

[0025] As used herein, the term antibody molecule includes full-length antibodies or full-size antibodies, as well as functional fragments of full-length antibodies and derivatives of such antibody molecules.

[0026] A functional fragment of a full-size antibody has the same antigen-binding characteristics as the corresponding full-size antibody and contains either the same variable domain (i.e., the VH and VL sequences) and / or the same CDR sequence as the corresponding full-size antibody. The fact that the functional fragment has the same antigen-binding characteristics as the corresponding full-size antibody means that it binds to the same target epitope as the full-size antibody. Such a functional fragment may correspond to the Fv portion of the full-size antibody. Alternatively, such a fragment may be a monovalent antigen-binding fragment without an Fc portion, such as Fab (also represented as F(ab)), or a bivalent antigen-binding fragment containing two antigen-binding Fab portions linked together by a disulfide bond, such as F(ab')2 or F(ab') (i.e., a monovalent variant of F(ab')2). Such a fragment may also be a single-chain variable fragment (scFv).

[0027] Functional fragments do not always contain all six CDRs of the corresponding full-size antibody. It is understood that molecules containing three or fewer CDR regions (in some cases, only a single CDR or a portion thereof) can retain the antigen-binding activity of the antibody derived from that CDR. For example, Gao et al., 1994, J. Biol. Chem., 269:32389-93, describe how the entire VL chain (containing all three CDRs) has high affinity for its substrate.

[0028] Molecules containing two CDR regions are described, for example, in Vaughan & Sollazzo 2001, Combinatorial Chemistry & High Throughput Screening, 4:417-430. On page 418 (right column-3 (Inventors' Strategy for Design)), a minibody containing only H1 and H2 CDR hypervariable regions scattered within a framework region is described. The minibody is described as being capable of binding to a target. Pessi et al., 1993, Nature, 362:367-9 and Bianchi et al., 1994, J.Mol.Biol., 236:649-59, referenced by Vaughan & Sollazzo, describe the H1 and H2 minibodies and their properties in more detail. Qiu et al., 2007, Nature Biotechnology, 25:921-9 shows that a molecule consisting of two bound CDRs is capable of binding to an antigen. Quiocho 1993, Nature, 362:293-4 provides an overview of the "mini-body" technology. Ladner 2007, Nature Biotechnology, 25:875-7 comments that molecules containing two CDRs can retain antigen-binding activity.

[0029] Antibody molecules containing a single CDR region are described, for example, in Laune et al., 1997, JBC, 272:30937-44. Here, it is demonstrated that various hexapeptides derived from the CDR exhibit antigen-binding activity, and it is noted that synthetic peptides from a complete single CDR exhibit potent binding activity. Monnet et al., 1999, JBC, 274:3789-96, shows that various 12-mer peptides and related framework regions possess antigen-binding activity, and comments that CDR3-like peptides alone can bind to antigens. Heap et al., 2005, J.Gen.Virol., 86:1791-1800, reports that "microantibodies" (molecules containing a single CDR) can bind to antigens, and demonstrates that cyclic peptides from anti-HIV antibodies possess antigen-binding activity and function. Nicaise et al., 2004, Protein Science, 13:1882-91, demonstrated that a single CDR can confer antigen-binding activity and affinity to its lysozyme antigen.

[0030] Therefore, antibody molecules with five, four, or three or fewer CDRs can retain the antigen-binding properties of the full-length antibodies from which they are derived.

[0031] The antibody molecule may be a derivative of a full-length antibody or a fragment of such an antibody. If a derivative is used, it should have the same antigen-binding characteristics as the corresponding full-length antibody, in the sense that it binds to the same target epitope as the full-length antibody.

[0032] Therefore, as used herein, the term “antibody molecule” includes all types of antibody molecules, as well as their functional fragments and derivatives, including monoclonal antibodies, polyclonal antibodies, synthetic antibodies, recombinant antibodies, multispecific antibodies, bispecific antibodies, human antibodies, antibodies of human origin, humanized antibodies, chimeric antibodies, single-chain antibodies, single-chain Fv(scFv), Fab fragments, F(ab')2 fragments, F(ab') fragments, disulfide-bonded Fv(sdFv), antibody heavy chains, antibody light chains, homodimers of antibody heavy chains, homodimers of antibody light chains, heterodimers of antibody heavy chains, heterodimers of antibody light chains, and antigen-binding functional fragments of such homodimers and heterodimers.

[0033] Furthermore, as used herein, the term “antibody molecule” includes all classes of antibody molecules and functional fragments, including (unless otherwise specified) IgG, IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgD, and IgE.

[0034] As outlined above, different types and forms of antibody molecules are included in the present invention and will be known to those skilled in the art of immunology. Antibodies used for therapeutic purposes are often modified with additional components that alter the properties of the antibody molecule.

[0035] Accordingly, the inventors include that the antibody molecule of the present invention or the 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) includes a detectable portion and / or a cytotoxic portion.

[0036] A "detectable portion" includes one or more components from the group consisting of enzymes, radioactive atoms, fluorescent portions, chemiluminescent portions, and bioluminescent portions. The detectable portion makes it possible to visualize the antibody molecule in vitro and / or in vivo and / or ex vivo.

[0037] The "cytotoxic portion" includes radioactive portions and / or enzymes, where the enzymes are caspases and / or toxins, and the toxins are bacterial toxins or venoms, and the cytotoxic portion is capable of inducing cell lysis.

[0038] The inventors further include that the antibody molecule may be in an isolated and / or purified form and / or may be PEGylated. PEGylation is a method of adding a polyethylene glycol polymer to a molecule such as an antibody molecule or derivative in order to modify its behavior, for example, by increasing its hydrodynamic size and preventing renal clearance, thereby extending its half-life.

[0039] As discussed above, antibody CDRs bind to antibody targets. The amino acid assignments to each CDR described herein follow the definitions of Kabat EA et al. 1991, In “Sequences of Proteins of Immunological Interest,” Fifth Edition, NIH Publication No. 91-3242, pp. xv-xvii.

[0040] As those skilled in the art will recognize, other methods exist for assigning amino acids to each CDR. For example, the International ImMunoGeneTics information system (IMGT®) (http: / / www.imgt.org / and Lefranc and Lefranc, “The Immunoglobulin FactsBook,” published by Academic Press, 2001).

[0041] In some embodiments, the antibody molecule specifically binds to FcyRllb. Fc receptors are well known in the art as membrane proteins found on the cell surface of immune effector cells such as macrophages. The name derives from their binding specificity to the Fc region of antibodies, which is the usual way in which antibodies bind to receptors. However, certain antibodies can also bind to Fc receptors via the complementarity-determining region ("CDR") sequence of the antibody, if the antibody specifically binds to one or more Fc receptors.

[0042] A subgroup of Fc receptors includes Fcγ receptors (Fc-γ receptors, FcγR) that are specific to IgG antibodies. There are two types of Fcγ receptors: activated Fcγ receptors (also expressed as activated Fcγ receptors) and inhibitory Fcγ receptors. Activated and inhibitory receptors transmit their signals via immunoreceptor-activated 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 are activated Fcγ receptors. FcγRIIIb is a GPI-binding receptor expressed on neutrophils. Although it lacks an ITAM motif, it is considered activating due to its ability to cross-link lipid rafts and associate with other receptors. In mice, the activating receptors are FcγRI, FcγRIII, and FcγRIV.

[0043] It is well known that antibodies regulate immune cell activity through their interaction with Fcγ receptors. Specifically, how antibody-immune complexes regulate immune cell activation is determined by the relative involvement of activating and inhibitory Fcγ receptors. Different antibody isotypes bind to activating and inhibitory Fcγ receptors with different affinities, resulting in different A:I ratios (activation:inhibition ratio) (Nimmerjahn et al; Science. 2005 Dec 2; 310(5753): 1510-2).

[0044] By binding to inhibitory Fcγ receptors, antibodies can inhibit, block, and / or downregulate effector cell function.

[0045] Antibodies can activate the function of effector cells by binding to activated Fcγ receptors, thereby inducing mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), cytokine release, and / or antibody-dependent endocytosis, and in the case of neutrophils, netosis (i.e., activation and release of NETs (neutrophil extracellular traps)). Antibodies that bind to activated Fcγ receptors can also lead to increases in specific activation markers such as CD40, MHCII, CD38, CD80, and / or CD86.

[0046] The antibody molecule according to the present invention, which specifically binds to FcγRIIb, binds to or interacts with this Fcγ receptor via the Fab region of the antibody, that is, via the antigen-binding region on the antibody that binds to the antigen, which consists of one constant domain and one variable domain in each of the heavy and light chains. In particular, it binds to FcγRIIb present on immune effector cells (especially FcγRIIb present on the surface of immune effector cells).

[0047] In some preferred embodiments, the antibody molecule according to the present invention, which specifically binds to FcγRIIb, can also bind to Fcγ receptors via its Fc region. In some embodiments, these are activated Fcγ receptors or inhibitory Fcγ receptors. In some preferred embodiments, the antibody molecule may be an IgG1, IgG2, IgG3, or IgG4 type antibody molecule.

[0048] In some other embodiments, an antibody molecule that specifically binds to FcγRIIb may be manipulated to enhance its binding to the Fcγ receptor via its Fc region (e.g., via defucosylation).

[0049] In some other embodiments, the antibody molecule according to the present invention has reduced or impaired binding to the Fcγ receptor via its Fc region. It is well known that deglycosylation of the antibody, specifically at position 297 (e.g., one of the following mutations: N297A, N297Q, or N297G), impairs the binding of both human IgG and mouse IgG to FcγR. The antibody molecule may also exhibit reduced or impaired binding if it lacks an Fc region. Furthermore, impaired or inactivated FcγR binding means that the modified format does not bind to FcγR at all, or does not bind to FcγR more strongly than the unmodified antibody.

[0050] "Reduced binding to the Fcγ receptor" (also referred to as "reduced affinity binding") means that the antibody molecule has reduced Fc-mediated binding to the Fcγ receptor; in other words, the Fc region of the antibody molecule that specifically binds to FcγRIIb binds to the activated Fcγ receptor with lower affinity than the Fc region of normal human IgG1. Reduced binding can be evaluated using techniques such as surface plasmon resonance. In this context, "normal IgG1" refers to conventionally produced IgG1 with a non-mutated Fc region that is not produced in a way that alters its glycosylation. Rituximab produced in CHO cells can be used as a criterion for this "normal IgG1" without any modification (Tipton et al, Blood 2015 125:1901-1909; rituximab is described, for example, in EP0605442). Human IgG2 and human IgG4 are examples of antibody isotypes that bind with reduced affinity to the Fcγ receptor compared to human IgG1. Therefore, antibodies based on human IgG2 and IgG4 exhibit "reduced binding to the Fcγ receptor" within the scope of this term.

[0051] In some other embodiments, the antibody molecule according to the present invention may lack an Fc region (and therefore cannot bind to the Fcγ receptor via an Fc region). Such fragments have been discussed above and include Fv, Fab (also represented as F(ab)), F(ab')2, F(ab'), or scFv. The antibody molecule according to the present invention may be a bispecific antibody fragment specific to FcgRIIB and additional FcgR, e.g., scFv, Fab, or Fab'2.

[0052] The therapeutic antibody molecule may be an antibody molecule described in WO2012 / 022985, WO2015 / 173384, and / or WO2019 / 13805. In some embodiments, it is an antibody having the CDR sequences (SEQ ID NOs. 83-88) described in WO2012 / 022985. In some embodiments, it is an antibody having VH of SEQ ID NOs. 12 and VL of SEQ ID NOs. 25, as described in WO2012 / 022985.

[0053] In some embodiments, it is the antibody described in WO2012 / 022985, having VH of SEQ ID NO: 12, VL of SEQ ID NO: 25, CH of SEQ ID NO: 1, and CL of SEQ ID NO: 2 (corresponding to the antibody disclosed herein, which includes a light chain having SEQ ID NO: 1 and a heavy chain having SEQ ID NO: 2). In some preferred embodiments, the antibody molecule of the present invention has the light chain of SEQ ID NO: 1. In some further embodiments, the antibody molecule of the present invention has the heavy chain of SEQ ID NO: 2. Light chain: QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYADDHRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCASWDDSQRAVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS(Sequence ID 1) Heavy chain: EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWMAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELYDAFDIWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(Sequence ID 2)

[0054] In some embodiments, the antibody molecule of the present invention has a light chain of SEQ ID NO: 1 and a heavy chain of SEQ ID NO: 2 (this antibody is represented as BI-1206).

[0055] As described above, in some embodiments of the present invention, the antibody molecule may have reduced or impaired binding to the Fcγ receptor via its Fc region. In this case, the therapeutic antibody molecule is an Fc receptor binding antibody, and the modified form is an antibody that has the same Fv variable sequence but in which FcγR binding is impaired or inactivated compared to the therapeutic antibody molecule.

[0056] In some embodiments, the therapeutic antibody is an anti-FcγRIIB antibody that binds to the Fc receptor, and in some such cases, the modified form is an antibody in which the anti-FcγRIIB antibody has the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 195.

[0057] In the modified form of BI-1206, the glycosylation site at N297 (marked in bold in the above SEQ ID NO: 2) is mutated to Q (marked in bold below) (i.e., the N297Q mutation), resulting in the following heavy chain. EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWMAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELYDAFDIWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(Sequence ID 195)

[0058] The CDR region of the light chain of SEQ ID NO: 1 and the CDR region of the heavy chain of SEQ ID NO: 2 or 195 are shown below. [Table 1]

[0059] Therefore, in some embodiments, the antibody molecule of the present invention includes one or more of the CDR sequences of SEQ ID NOs: 196-201. For example, the antibody molecule includes two or more, three or more, four or more, five or more, or all six of the CDR sequences of SEQ ID NOs: 196-201. For example, the antibody molecule may include one or more, two or more, or three light chain CDR regions (i.e., SEQ ID NOs: 199, 200, and 201), and / or one or more, two or more, or three heavy chain CDR regions (i.e., SEQ ID NOs: 196, 197, and 198).

[0060] Preferably, the antibody molecule of the present invention includes the following constant regions (CH and CL). IgG1-CH[SEQ ID NO: 202]: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK λ-CL[SEQ ID NO: 203]: QPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS

[0061] Therefore, in a preferred embodiment, the antibody molecule of the present invention is - The light chain of SEQ ID NO: 1, the heavy chain of SEQ ID NO: 2, and the steady regions of SEQ ID NOs: 202 and 203, or -Includes the light chain of SEQ ID NO: 1, the heavy chain of SEQ ID NO: 195, and the constant regions of SEQ ID NOs: 202 and 203.

[0062] In alternative embodiments, the antibody molecule that specifically binds to FcγRIIb is the antibody described in the published PCT patent applications WO2012 / 022985, WO2015 / 173384, and / or WO2019 / 138005.

[0063] Antibodies that specifically bind to FcγRIIb may contain one or more sequences from the following clones: Antibody clone: ​​1A01 1A01-VH[Sequence ID 3] EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMNWIRQTPGKGLEWVSLIGWDGGSTYYADSVKGRFTISRDNSENTLYLQMNSLRAEDTAVYYCARAYSGYELDYWGQGTLVTVSS 1A01-VL[Sequence ID 27] QSVLTQPPSASGTPGQRVTISSCSGSSSNIGNNAVNWYQQLPGTAPKLLIYDNNNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNASIFGGGTKLTVLG CDR area CDRH1:DYYMN[Sequence ID 51] CDRH2:LIGWDGGSTYYADSVKG[Sequence ID 52] CDRH3:AYSGYELDY[SEQ ID NO: 53] CDRL1:SGSSSNIGNNAVN[Sequence ID 54] CDRL2:DNNNRPS[SEQ ID NO: 55] CDRL3:AAWDDSLNASI[Sequence ID 56]

[0064] Antibody clone: ​​1B07 1B07-VH[Sequence ID 4] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFTRYDGSNKYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARENIDAFDVWGQGTLVTVSS 1B07-VL[Sequence ID 28] QSVLTQPPSASGTPGQRVTISSCSGSSSNIGNNAVNWYQQLPGTAPKLLIYDNQQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCEAWDDRLFGPVFGGGTKLTVLG CDR area CDRH1:SYGMH[SEQ ID NO: 57] CDRH2:FTRYDGSNKYYADSVRG[Sequence ID 58] CDRH3:ENIDAFDV[Sequence ID 59] CDRL1:SGSSSNIGNNAVN[Sequence ID 60] CDRL2:DNQQRPS[Sequence ID 61] CDRL3:WDDRLFGPV[Sequence ID 62]

[0065] Antibody clone: ​​1C04 1C04-VH[SEQ ID NO: 5] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSISDSGAGRYYADSVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTHDSGELLDAFDIWGQGTLVTVSS 1C04-VL[Sequence ID 29] QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNHVLWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGWVFGGGTKLTVLG CDR area CDRH1:SYAMS[SEQ ID NO: 63] CDRH2:SISDSGAGRYYADSVEG[SEQ ID NO: 64] CDRH3:THDSGELLDAFDI[SEQ ID NO: 65] CDRL1:SGSSSNIGSNHVL[Sequence ID 66] CDRL2:GNSNRPS[Sequence ID 67] CDRL3:AAWDDSLNGWV[Sequence ID 68]

[0066] Antibody clone: ​​1E05 1E05-VH[Sequence ID 6] EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQVPGKGLEWVAVISYDGSNKNYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNFDNSGYAIPDAFDIWGQGTLVTVSS 1E05-VL[Sequence ID 30] QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNNSRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLGGPVFGGGTKLTVLG CDR area CDRH1:TYAMN[Sequence ID:69] CDRH2:VISYDGSNKNYVDSVKG[Sequence ID 70] CDRH3:NFDNSGYAIPDAFDI[SEQ ID NO: 71] CDRL1:TGSSSNIGAGYDVH[Sequence ID 72] CDRL2:DNNSRPS[Sequence ID 73] CDRL3:AAWDDSLGGPV[Sequence ID 74]

[0067] Antibody clone: ​​2A09 2A09-VH[Sequence ID 7] EVQLLESGGGLVQPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVAYISRDADITHYPASVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTGFDYAGDDAFDIWGQGTLVTVSS 2A09-VL[Sequence ID 31] QSVLTQPPSASGTPGQRVTISSCSGSSSNIGSNAVNWYQQLPGTAPKLLIYGNSDRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGRWVFGGGTKLTVLG CDR area CDRH1:NAWMS[SEQ ID NO: 75] CDRH2:YISRDADITHYPASVKG[Sequence ID 76] CDRH3:GFDYAGDDAFDI[SEQ ID NO: 77] CDRL1:SGSSSNIGSNAVN[Sequence ID 78] CDRL2:GNSDRPS[Sequence ID 79] CDRL3:AAWDDSLNGRWV[Sequence ID 80]

[0068] Antibody clone: ​​2B08 2B08-VH[Sequence ID 8] EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMSWVRQAPGKGLEWVALIGHDGNNKYYLDSLEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARATDSGYDLLYWGQGTLVTVSS 2B08-VL[Sequence ID 32] QSVLTQPPSASGTPGQRVTISSCSGSSSNIGNNAVNWYQQLPGTAPKLLIYYDDLLPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCTTWDDSLSGVVFGGGTKLTVLG CDR area CDRH1:DYYMS[SEQ ID NO: 81] CDRH2:LIGHDGNNKYYLDSLEG[Sequence ID 82] CDRH3:ATDSGYDLLY[SEQ ID NO: 83] CDRL1:SGSSSNIGNNAVN[Sequence ID 84] CDRL2:YDDLLPS[Sequence ID 85] CDRL3:TTWDDSLSGVV[Sequence ID 86]

[0069] Antibody clone: ​​2E08 2E08-VH[Sequence ID 9] EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSAIGFSDDNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGDGSGWSFWGQGTLVTVSS 2E08-VL[Sequence ID 33] QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNAVNWYQQLPGTAPKLLIYDNNKRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDDSLRGWVFGGGTKLTVLG CDR area CDRH1:DYYMS[SEQ ID NO: 87] CDRH2:AIGFSDDNTYYADSVKG[Sequence ID 88] CDRH3:GDGSGWSF[Sequence ID 89] CDRL1:SGSSSNIGNNAVN[Sequence ID 90] CDRL2:DNNKRPS[Sequence ID 91] CDRL3:ATWDDSLRGWV[Sequence ID 92]

[0070] Antibody clone: ​​5C04 5C04-VH[Sequence ID 10] EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWRDAFDIWGQGTLVTVSS 5C04-VL[Sequence ID 34] QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSDNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLSGSWVFGGGTKLTVLG CDR area CDRH1:NYGMH[SEQ ID NO: 93] CDRH2:VISYDGSNKYYADSVKG[Sequence ID 94] CDRH3:WRDAFDI[SEQ ID NO: 95] CDRL1:TGSSSNIGAGYDVH[Sequence ID 96] CDRL2:SDNQRPS[Sequence ID 97] CDRL3:AAWDDSLSGSWV[Sequence ID 98]

[0071] Antibody clone: ​​5C05 5C05-VH[Sequence ID 11] EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYGMHVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARENFDAFDVWGQGTLVTVSS 5C05-VL[SEQ ID NO: 35] QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGQVVFGGGTKLTVLG CDR area CDRH1:TYGMH[SEQ ID NO: 99] CDRH2:VISYDGSNKYYADSVKG[Sequence ID 100] CDRH3:ENFDAFDV[SEQ ID NO: 101] CDRL1:TGSSSNIGAGYDVH[Sequence ID 102] CDRL2:SNSQRPS[Sequence ID 103] CDRL3:AAWDDSLNGQVV[Sequence ID 104]

[0072] Antibody clone: ​​5D07 5D07-VH[Sequence ID 12] EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIAYDGSKKDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREYRDAFDIWGQGTLVTVSS 5D07-VL[Sequence ID 36] QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTTASLAISGLRSEDEADYYCAAWDDSVSGWMFGGGTKLTVLG CDR area CDRH1:TYGMH[SEQ ID NO: 105] CDRH2:VIAYDGSKKDYADSVKG[Sequence ID 106] CDRH3:EYRDAFDI[SEQ ID NO: 107] CDRL1:TGSSSNIGAGYDVH[Sequence ID 108] CDRL2:GNSNRPS[Sequence ID 109] CDRL3:AAWDDSVSGWM[Sequence ID 110]

[0073] Antibody clone: ​​5E12 5E12-VH[Sequence ID 13] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGINKDYADSMKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARERKDAFDIWGQGTLVTVSS 5E12-VL[Sequence ID 37] QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDDSLNGLVFGGGTKLTVLG CDR area CDRH1:SYGMH[SEQ ID NO: 111] CDRH2:VISYDGINKDYADSMKG[SEQ ID NO: 112] CDRH3:ERKDAFDI[SEQ ID NO: 113] CDRL1:TGSSSNIGAGYDVH[Sequence ID 114] CDRL2:SNNQRPS[Sequence ID 115] CDRL3:ATWDDSLNGLV[Sequence ID 116]

[0074] Antibody clone: ​​5G08 5G08-VH[Sequence ID 14] EVQLLESGGGLVQPGGSLRLSCAASGFTFNNYGMHWVRQAPGKGLEWVAVISYDGSNRYYADSVKGRFTMSRDNSKNTLYLQMNSLRAEDTAVYYCARDRWNGMDVWGQGTLVTVSS 5G08-VL[Sequence ID 38] QSVLTQPPSASGTPGQRVTISCSGSSSNIGAGYDVHWYQQLPGTAPKLLIYANNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGPWVFGGGTKLTVLG CDR area CDRH1:NYGMH[Sequence ID:117] CDRH2:VISYDGSNRYYADSVKG[Sequence ID 118] CDRH3:DRWNGMDV[Sequence ID 119] CDRL1:SGSSSNIGAGYDVH[Sequence ID 120] CDRL2:ANNQRPS[Sequence ID 121] CDRL3:AAWDDSLNGPWV[Sequence ID 122]

[0075] Antibody clone: ​​5H06 5H06-VH[Sequence ID 15] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSDTAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDHSVIGAFDIWGQGTLVTVSS 5H06-VL[Sequence ID 39] QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYDNNKRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSSYAGSNNVVFGGGTKLTVLG CDR area CDRH1:SYGMH[SEQ ID NO: 123] CDRH2:VISYDGSDTAYADSVKG[Sequence ID 124] CDRH3:DHSVIGAFDI[SEQ ID NO: 125] CDRL1:SGSSSNIGSNTVN[Sequence ID 126] CDRL2:DNNKRPS[Sequence ID 127] CDRL3:SSYAGSNNVV[Sequence ID 128]

[0076] Antibody clone: ​​6A09 6A09-VH[Sequence ID 16] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVTSYDGNTKYYANSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREDCGGDCFDYWGQGTLVTVSS 6A09-VL[Sequence ID 40] QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNEGVFGGGTKLTVLG CDR area CDRH1:SYGMH[SEQ ID NO: 129] CDRH2:VTSYDGNTKYYANSVKG[Sequence ID 130] CDRH3:EDCGGDCFDY[Sequence ID 131] CDRL1:TGSSSNIGAGYDVH[Sequence ID 132] CDRL2:GNSNRPS[Sequence ID 133] CDRL3:AAWDDSLNEGV[Sequence ID 134]

[0077] Antibody clone: ​​6B01 6B01-VH[Sequence ID 17] EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDQLGEAFDIWGQGTLVTVSS 6B01-VL[Sequence ID 41] QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYDNNKRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDDSLSGPVFGGGTKLTVLG CDR area CDRH1:NYGMH[SEQ ID NO: 135] CDRH2:VISYDGSNKYYADSVKG[Sequence ID 136] CDRH3:DQLGEAFDI[Sequence ID 137] CDRL1:TGSSSNIGAGYDVH[Sequence ID 138] CDRL2:DNNKRPS[Sequence ID 139] CDRL3:ATWDDSLSGPV[Sequence ID 140]

[0078] Antibody clone: ​​6C11 6C11-VH[Sequence ID 18] EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSAISGSGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGDIDYFDYWGQGTLVTVSS 6C11-VL[Sequence ID 42] QSVLTQPPSASGTPGQRVTISCTGSSSNFGAGYDVHWYQQLPGTAPKLLIYENNKRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGPVFGGGTKLTVLG CDR area CDRH1:DYGMS[SEQ ID NO: 141] CDRH2:AISGSGSSTYYADSVKG[Sequence ID 142] CDRH3:GDIDYFDY[SEQ ID NO: 143] CDRL1:TGSSSNFGAGYDVH[Sequence ID 144] CDRL2:ENNKRPS[SEQ ID NO: 145] CDRL3:AAWDDSLNGPV[Sequence ID 146]

[0079] Antibody clone: ​​6C12 6C12-VH[Sequence ID 19] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARERRDAFDIWGQGTLVTVSS 6C12-VL[Sequence ID 43] QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSDNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDSDTPVFGGGTKLTVLG CDR area CDRH1:SYGMH[SEQ ID NO: 147] CDRH2:VISYDGSNKYYADSVKG[Sequence ID 148] CDRH3:ERRDAFDI[SEQ ID NO: 149] CDRL1:TGSSSNIGAGYDVH[Sequence ID 150] CDRL2:SDNQRPS[Sequence ID 151] CDRL3:ATWDSDTPV[Sequence ID 152]

[0080] Antibody clone: ​​6D01 6D01-VH[Sequence ID 20] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAMYYCARDHSAAGYFDYWGQGTLVTVSS 6D01-VL[Sequence ID:44] QSVLTQPPSASGTPGQRVTISSCSGSSSNIGSNTVNWYQQLPGTAPKLLIYGNSIRPSGGPDRFSGSKSGTSASLAISGLRSEDEADYYCASWDDSLSSPVFGGGTKLTVLG CDR area CDRH1:SYGMH[SEQ ID NO: 153] CDRH2:VISYDGSNKYYADSVKG[Sequence ID 154] CDRH3:DHSAAGYFDY[SEQ ID NO: 155] CDRL1:SGSSSNIGSNTVN[Sequence ID 156] CDRL2:GNSIRPS[Sequence ID 157] CDRL3:ASWDDSLSSPV[Sequence ID 158]

[0081] Antibody clone: ​​6G03 6G03-VH[Sequence ID 21] EVQLLESGGGLVQPGGSLRLSCAASGFTFGSYGMHWVRQAPGKGLEWVSGISWDSAIIDYAGSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDEAAAGAFDIWGQGTLVTVSS 6G03-VL[Sequence ID:45] QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNTDRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLSGPVVFGGGTKLTVLG CDR area CDRH1:SYGMH[SEQ ID NO: 159] CDRH2:GISWDSAIIDYAGSVKG[Sequence ID 160] CDRH3:DEAAAGAFDI[Sequence ID 161] CDRL1:TGSSSNIGAGYDVH[Sequence ID 162] CDRL2:GNTDRPS[Sequence ID 163] CDRL3:AAWDDSLSGPVV[Sequence ID 164]

[0082] Antibody clone: ​​6G08 6G08-VH[Sequence ID 22] EVQLLESGGGLVQPGGSLRLSCAASGFTLSSYGISWVRQAPGKGLEWVSGISGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSVGAYANDAFDIWGQGTLVTVSS 6G08-VL[Sequence ID:46] QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGDTNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGPVFGGGTKLTVLG CDR area CDRH1:SYGIS[Sequence ID 165] CDRH2:GISGSGGNTYYADSVKG[Sequence ID 166] CDRH3:SVGAYANDAFDI[SEQ ID NO: 167] CDRL1:TGSSSNIGAGYDVH[Sequence ID 168] CDRL2:GDTNRPS[Sequence ID 169] CDRL3:AAWDDSLNGPV[Sequence ID 170]

[0083] Antibody clone: ​​6G11 6G11-VH[Sequence ID 23] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWMAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELYDAFDIWGQGTLVTVSS 6G11-VL[Sequence ID:47] QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYADDHRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCASWDDSQRAVIFGGGTKLTVLG CDR area CDRH1:SYGMH[SEQ ID NO: 171] CDRH2:VISYDGSNKYYADSVKG[Sequence ID 172] CDRH3:ELYDAFDI[SEQ ID NO: 173] CDRL1:TGSSSNIGAGYDVH[Sequence ID 174] CDRL2:ADDHRPS[Sequence ID 175] CDRL3:ASWDDSQRAVI[SEQ ID NO: 176]

[0084] Antibody clone: ​​6H08 6H08-VH[Sequence ID 24] EVQLLESGGGLVQPGGSLRLSCAASGFTFNNYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAREYKDAFDIWGQGTLVTVSS 6H08-VL[Sequence ID 48] QSVLTQPPSASGTPGQRVTISCTGSSNIGSNTVNWYQQLPGTAPKLLIYDNNKRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQAWGTGIRVFGGGTKLTVLG CDR area CDRH1:NYGMH[SEQ ID NO: 177] CDRH2:VISYDGSNKYYAD SVKG[SEQ ID NO: 178] CDRH3:EYKDAFDI[SEQ ID NO: 179] CDRL1:TGSSSNIGSNTVN[Sequence ID 180] CDRL2:DNNKRPS[Sequence ID 181] CDRL3:QAWGTGIRV[Sequence ID 182]

[0085] Antibody clone: ​​7C07 7C07-VH[SEQ ID NO: 25] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSQNTLYLQMNSLRAEDTAVYYCAREFGYIILDYWGQGTLVTVSS 7C07-VL[SEQ ID NO: 49] QSVLTQPPSASGTPGQRVTISSCSGSSSNIGSNTVNWYQQLPGTAPKLLIYRDYERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCMAWDDSLSGVVFGGGTKLTVLG CDR area CDRH1:SYGMH[SEQ ID NO: 183] CDRH2:VISYDGSNKYYADSVKG[Sequence ID 184] CDRH3:EFGYIILDY[Sequence ID 185] CDRL1:SGSSSNIGSNTVN[Sequence ID 186] CDRL2:RDYERPS[Sequence ID 187] CDRL3:MAWDDSLSGVV[Sequence ID 188]

[0086] Antibody clone: ​​4B02 4B02-VH[Sequence ID 26] EVQLLESGGGLVQPGGSLRLSCAASGFTFSNHGMHWVRQAPGKGLEWVAVISYDGTNKYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARETWDAFDVWGQGTLVTVSS 4B02-VL[Sequence ID 50] QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNNANWYQQLPGTAPKLLIYDNNKRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQAWDSSTVVFGGGTKLTVLG CDR area CDRH1:NHGMH [Sequence ID 189] CDRH2:VISYDGTNKYYADSVRG[Sequence ID 190] CDRH3:ETWDAFDV[Sequence ID 191] CDRL1:SGSSSNIGSNNAN[Sequence ID 192] CDRL2:DNNKRPS[Sequence ID 193] CDRL3:QAWDSSTVV[Sequence ID 194]

[0087] In some embodiments, the antibody molecule that specifically binds to FcγRIIb is a human antibody.

[0088] In some embodiments, the antibody molecule that specifically binds to FcγRIIb is a human-derived antibody, i.e., an originally human antibody modified as described herein.

[0089] In some embodiments, the antibody molecule that specifically binds to FcγRIIb is a humanized antibody, i.e., an originally non-human antibody modified to increase its similarity to a human antibody. The humanized antibody may be, for example, a mouse antibody or a llama antibody.

[0090] As discussed above, the first antibody may be a monoclonal antibody or an antibody molecule of monoclonal origin.

[0091] It is well known that antibodies specifically bind to or interact with defined target molecules or antigens. In other words, antibodies preferentially and selectively bind to their targets and do not bind to molecules that are not their targets.

[0092] Methods for assessing protein binding are known to those skilled in the art of biochemistry and immunology. Those skilled in the art will understand that those methods can be used to assess the binding of an antibody to a target and / or the binding of the Fc region of an antibody to an Fc receptor, as well as the relative strength, specificity, inhibition, prevention or reduction of those interactions. Examples of methods that can be used to assess protein binding include, for example, immunoassays, BIAcore, Western blot, radioimmunoassay (RIA), and enzyme-linked immunosorbent assay (ELISA) (see Fundamental Immunology Second Edition, Raven Press, New York at pages 332-336 (1989) for a discussion of antibody specificity).

[0093] Accordingly, the expression "antibody molecule that specifically binds" includes that the antibody molecule specifically binds to a target, but does not bind to non-targets, or binds non-targets more weakly (e.g., with a lower affinity) than the target.

[0094] It also includes the meaning that an antibody specifically binds to a target at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least about 1000-fold more strongly than it binds to non-targets.

[0095] In addition, an antibody binds to a target with at least about 10 -1 K d , or at least about 10 -2 K d , or at least about 10 -3 K d , or at least about 10 -4 K d , or at least about 10 -5 K d , or at least about 10 -6 K d , or at least about 10 -7 K d, or at least about 10 -8 K d , or at least about 10 -9 K d , or at least about 10 -10 K d , or at least about 10 -11 K d , or at least about 10 -12 K d , or at least about 10 -13 K d , or at least about 10 -14 K d , or at least about 10 -15 K d K d When referring to binding, it implies that the antibody specifically binds to the target.

[0096] As discussed above, the systems, combinations, methods, or uses of the present invention are for improving the tolerability of antibody molecules that specifically bind to FcyRllb in a subject. It is well known that the administration of therapeutic antibodies may be associated with tolerability issues. In some embodiments, these issues may be associated with the intravenous administration of the antibody.

[0097] As used herein, the term “tolerability” refers to the degree to which the adverse effects of a therapeutic agent can be tolerated by the subject. “Adverse effects” include any effects caused directly or indirectly by the therapeutic agent that are not the desired therapeutic effect, or any other beneficial effects directly or indirectly caused by the therapeutic agent.

[0098] "Improved tolerability" includes preventing or mitigating tolerability issues associated with the administration of antibody molecules. By another definition, it includes reducing or preventing adverse effects associated with the administration of antibody molecules.

[0099] As used herein, the term “tolerance issues” encompasses different types of adverse effects that may occur in connection with the administration of antibody molecules to humans (particularly intravenous administration). These may include, for example, infusion-related reactions (IRRs), cytokine release syndrome, thrombocytopenia, hepatotoxicity (e.g., elevated liver enzymes), fever, hypotension, and / or cutaneous toxicity (including rashes such as convulsions). Here, these different tolerance issues are defined in the manner defined in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (issued by the U.S. Department of Health and Human Services on November 27, 2017), as further described below.

[0100] Tolerance issues can vary in grade (i.e., severity) depending on the individual experiencing them. They may cause discomfort, or they may lead to serious problems that prevent continued treatment with the therapeutic antibody molecule. In worse cases, tolerance issues can even lead to death.

[0101] The tolerability issues that can be predicted, prevented, and / or mitigated as described herein are related to the intravenous administration of therapeutic antibody molecules to a subject, i.e., adverse events that occur immediately after administration of the therapeutic antibody molecule (e.g., within minutes to a maximum of a few hours or within 24 hours of administration of the therapeutic antibody molecule to the subject). In many cases, the first tolerability issue is observed within 30 minutes.

[0102] In some preferred embodiments, improving the tolerability of antibodies that specifically bind to FcγRllb with respect to IRR is of particular interest. In some embodiments, these antibodies may cause, or are more likely to cause, IRR of varying severity in human subjects. Therefore, preventing or mitigating such IRR is advantageous because they improve the subject's experience and allow therapeutic antibodies to be administered for longer periods and at higher doses before treatment needs to be discontinued due to tolerability issues (if this is necessary).

[0103] In some cases, it may be particularly important to prevent thrombocytopenia and / or hepatotoxicity.

[0104] Any IRR that can be prevented or mitigated as described herein, and / or predicted by the methods described herein, may be any IRR. In CTCAE version 5.0, an adverse event referred to as “injection-related reaction” is used for a disorder characterized by an adverse reaction to the injection of a pharmacological or biological substance, belonging to the group of “injury, poisoning, and procedural complications.” The five grades identified in CTCAE are as follows: 1) Mild, transient reactions do not warrant discontinuation of infusion or intervention. 2) Discontinuation of treatment or infusion is indicated, but prophylactic medication administered within 24 hours is indicated, provided that the patient responds quickly to symptomatic treatment (e.g., antihistamines, NSAIDs, narcotics, intravenous solutions). 3) Indications for hospitalization due to prolonged duration (e.g., failure to respond promptly to symptomatic medication and / or short-term interruption of infusion), recurrence of symptoms after initial improvement, or clinical complications. 4) Life-threatening consequences, requiring emergency intervention. 5) Death.

[0105] Based on the classification criteria described above, those skilled in the art will be able to identify infusion-related reactions in a subject after administration of an antibody molecule as defined herein, for example, by observing the subject for symptoms of IRR. These may include, in some embodiments, pruritus, urticaria, fever / chills, sweating, bronchospasm, nausea, muscle pain, and cardiovascular collapse.

[0106] In some preferred embodiments, the IRR associated with the antibody molecules described herein is reduced or completely prevented by the drug regimen described herein.

[0107] In CTCAE version 5.0, the adverse event referred to as "cytokine release syndrome" is used to describe disorders characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and / or hypoxia caused by the release of cytokines belonging to the "immune system disorder" group. The five grades identified in CTCAE are as follows: 1) Fever regardless of the presence or absence of systemic symptoms 2) Hypotension that reacts to liquids, hypoxia that reacts to <40% O2 3) Hypotension managed with a single vasopressor, hypoxia requiring ≥40% oxygen saturation. 4) The result is life-threatening, and emergency intervention is indicated. 5)Death

[0108] In CTCAE version 5.0, the adverse event described as "decreased platelet count" (i.e., thrombocytopenia) is used for clinical laboratory findings indicating a decrease in platelet count in blood samples belonging to the "investigation" group. The five grades identified by CTCAE are as follows: 1) <LLN~75,000 / mm3;<LLN~75.0×10e9 / L 2)<75,000~50,000 / mm3;<75.0~50.0×10e9 / L 3)<50,000~25,000 / mm3;<50.0~25.0×10e9 / L 4) <25,000 / mm3; <25.0 × 10⁹ / L 5)-

[0109] Furthermore, associated toxicity may be hepatic adverse events or hepatotoxicity. Examples of such toxicity include elevated levels of one or both of the two enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Similar to thrombocytopenia, the adverse events described as “increased aspartate aminotransferase” and “increased alanine aminotransferase” in CTCAE version 5.0 belong to the “investigation” group. Elevated AST or ALT are findings based on clinical laboratory results indicating increased levels of AST (or SGOT) and ALT (or SGPT) in blood samples, respectively. For both elevated AST and elevated ALT, the five grades identified in CTCAE are as follows: 1) > ULN ~ 3.0 × ULN (if baseline was normal), 1.5 ~ 3.0 × baseline (if baseline was abnormal) 2) >3.0~5.0 × ULN (if baseline was normal), >3.0~5.0 × baseline (if baseline was abnormal) 3) >5.0-20.0 × ULN (if baseline was normal), >5.0-20.0 × baseline (if baseline was abnormal) 4) >20.0 × ULN (if baseline was normal), >20.0 × baseline (if baseline was abnormal) 5)-.

[0110] In CTCAE version 5.0, the adverse event referred to as "fever" is used for disorders characterized by an increase in body temperature exceeding the upper limit of normal, belonging to the "systemic disorder and administration site conditions" group. The five grades identified in CTCAE are as follows: 1) 38.0~39.0℃ 2) >39.0~40.0℃ 3) >40.0℃ (within 24 hours) 4) >40.0℃ (over 24 hours) 5) Death.

[0111] In CTCAE version 5.0, the adverse event referred to as "hypotension" is used to describe disorders belonging to the "vascular disorders" category, characterized by blood pressure below the normal range expected for an individual in a given environment. The five grades identified in CTCAE are as follows: 1) Asymptomatic; intervention is not indicated. 2) Non-emergency medical intervention is applicable. 3) Medical intervention is indicated, and hospitalization is indicated. 4) Life-threatening consequences and situations requiring emergency intervention 5) Death.

[0112] In CTCAE version 5.0, the adverse event referred to as "urticaria" is used to describe a disorder characterized by itchy skin lesions with pale, distinctly red edges, belonging to the group of "skin and subcutaneous tissue disorders." The five grades identified in CTCAE are as follows: 1) Urticaria-like lesions covering <10% of BSA are indicated for local intervention. 2) Urticaria-like lesions covering 10-30% of BSA; oral intervention is indicated. 3) Urticaria-like lesions covering >30% of BSA are indicated for IV intervention. 4)- 5)-.

[0113] In some other embodiments, improved tolerability is associated with a reduction or prevention of adverse effects observed during antibody administration. These effects may, in some embodiments, be directly or indirectly caused by antibody administration.

[0114] In some embodiments, the aforementioned tolerability issues and / or adverse effects cause changes in several subject observations outside of normal levels. In some embodiments, these observations include one or more of the following: body temperature, platelet count, blood levels of liver enzymes (e.g., alanine aminotransferase (ALAT) and / or aspartate aminotransferase (ASAT)), and blood levels of cytokines (e.g., IL-6, TNF-α, IL-8, IFN-γ, MIP-1β, IL-10, IL-4, IL-1b, IL-2, IL-12).

[0115] The normal level for each of the above measurements is typically defined as follows: ●Body temperature: 36.1℃~37.9℃. ●Platelet count: 145 x 10 per liter 9 ~400×10 9 . ● ALAT blood levels: 0-1.09 μKat / L, 16-63 U / L. ● ASAT blood levels: 0-0.759 μKat / L, 15-37 U / L. ● Blood IL-6 levels: 0.16~27.2 pg / ml, median 0.47 pg / ml.

[0116] In some embodiments, the systems, combinations, methods, or uses of the present invention reduce changes in each of the above parameters. “Reduced changes” means that when the therapeutic system or drug regimen of the present invention is used, the degree of change in each of the above measurements is less than when a single dose equivalent to the sum of the first and second doses (in mg) of the antibody molecule as defined herein is administered. Preferably, these changes are reduced to an acceptable level.

[0117] "Acceptable level" means that the above measurement remains within the normal range defined above after treatment with a second dose of the antibody molecule. In some embodiments, the above measurement remains within the normal range defined above after administration of a second dose of the antibody molecule. In some other embodiments, "acceptable level" includes the reduction of the clinical grading of the IRR (as defined in the art and defined herein using the CTCAE scale) to at least Grade 2. In some preferred embodiments, the grading of the IRR is reduced to Grade 1. As discussed herein, those skilled in the art will recognize the method of grading the IRR according to the CTCAE scale.

[0118] In some preferred embodiments, these values ​​remain within normal levels or change within acceptable levels for at least 24 hours after administration of a second dose of the antibody molecule.

[0119] As discussed above, the present invention provides a system, combination, method, or use in which a corticosteroid is administered to a subject prior to a first dose of an antibody molecule. Corticosteroids are a well-known class of steroid hormones used in a wide variety of clinical applications.

[0120] As shown in Example 1, corticosteroids have been found to remarkably provide protection against infusion-related reactions associated with the administration of the therapeutic antibody of the present invention. As also shown in Example 2, other compounds previously used clinically to treat IRRs did not provide protection (or merely provided an additive effect). These other compounds that have been commonly used to treat IRRs include, but are not limited to, antihistamines (e.g., H1 and H2 blockers), anti-PAFs, anti-IL-6Rs, and leukotriene receptor antagonists (e.g., montelukast). Since none of these other commonly used therapies provided similar protection, this makes the protective effect of corticosteroids alone remarkable in the context of the present invention.

[0121] In preferred embodiments of the system, combination, method, or use of the present invention, the corticosteroid is administered to the subject 10 minutes to 48 hours prior to the administration of a first dose of an antibody molecule that specifically binds to FcyRllb. More preferably, the corticosteroid is administered to the subject 10 minutes to 24 hours prior to the administration of a first dose of an antibody molecule that specifically binds to FcyRllb.

[0122] Therefore, in embodiments of the present invention, the corticosteroid is administered for approximately 10 minutes, or approximately 20 minutes, or approximately 30 minutes, or approximately 40 minutes, or approximately 50 minutes, or approximately 1 hour, or approximately 2 hours, or approximately 3 hours, or approximately 4 hours, or approximately 5 hours, or approximately 6 hours, or approximately 7 hours, or approximately 8 hours, or approximately 9 hours, or approximately 10 hours, or approximately 11 hours, or approximately 12 hours, or approximately 13 hours, or approximately 14 hours, or approximately 15 hours, or approximately 16 hours, or approximately 17 hours, or approximately 18 hours, or approximately 19 hours, or approximately 20 minutes of the first dose of the antibody molecule that specifically binds to FcγRIIb. It is administered at a time approximately 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, or 48 hours prior to the scheduled time.

[0123] In embodiments of the present invention, corticosteroids may be administered in multiple doses prior to a first dose of an antibody molecule that specifically binds to FcγRIIb. For example, corticosteroids may be administered in two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or more than twelve doses prior to a first dose of an antibody molecule that specifically binds to FcγRIIb.

[0124] In some additional or alternative embodiments, if multiple doses of corticosteroids are administered, the corticosteroids may be administered both before and after the first dose of the antibody molecule that specifically binds to FcγRIIb (but before the second dose of the antibody that specifically binds to FcγRIIb). At least one dose of corticosteroid is administered before the first dose of the antibody molecule, but any subsequent doses of corticosteroids described may be administered after the first dose of the antibody molecule and may be distributed between the antibody doses in any order.

[0125] In these embodiments, corticosteroid administration prior to the second dose of the antibody that specifically binds to FcγRIIb is approximately 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours prior to the second dose of the antibody molecule that specifically binds to FcyRllb. This could be approximately 19 hours, or approximately 20 hours, or approximately 21 hours, or approximately 22 hours, or approximately 23 hours, or approximately 24 hours, or approximately 25 hours, or approximately 26 hours, or approximately 27 hours, or approximately 28 hours, or approximately 29 hours, or approximately 30 hours, or approximately 31 hours, or approximately 32 hours, or approximately 33 hours, or approximately 34 hours, or approximately 35 hours, or approximately 36 hours, or approximately 37 hours, or approximately 38 hours, or approximately 39 hours, or approximately 40 hours, or approximately 41 hours, or approximately 42 hours, or approximately 43 hours, or approximately 44 hours, or approximately 45 hours, or approximately 46 hours, or approximately 47 hours, or approximately 48 hours prior.

[0126] Preferably, the corticosteroid is administered as a first and second dose, prior to the first dose of the antibody that specifically binds to FcγRIIb. Preferably, when the corticosteroid is administered as a first and second dose, the first dose of the corticosteroid is administered 16 to 48 hours before the first dose of the antibody molecule that specifically binds to FcyRllb, and the second dose of the corticosteroid is administered 10 minutes to 2 hours before the first dose of the antibody molecule that specifically binds to FcyRllb.

[0127] In such embodiments of the present invention, the first dose of the corticosteroid is given at any point between 16 and 48 hours prior to the first dose of the antibody molecule, for example, about 16 hours, or about 17 hours, or about 18 hours, or about 19 hours, or about 20 hours, or about 21 hours, or about 22 hours, or about 23 hours, or about 24 hours, or about 25 hours, or about 26 hours, or about 27 hours prior to the first dose of the antibody molecule that specifically binds to FcyRllb. It may be administered at a time of approximately 28 hours, or approximately 29 hours, or approximately 30 hours, or approximately 31 hours, or approximately 32 hours, or approximately 33 hours, or approximately 34 hours, or approximately 35 hours, or approximately 36 hours, or approximately 37 hours, or approximately 38 hours, or approximately 39 hours, or approximately 40 hours, or approximately 41 hours, or approximately 42 hours, or approximately 43 hours, or approximately 44 hours, or approximately 45 hours, or approximately 46 hours, or approximately 47 hours, or approximately 48 hours prior to the first dose of the antibody molecule. It will also be understood that in such embodiments of the present invention, the second dose of the corticosteroid may be administered at any time between 10 minutes and 2 hours prior to the first dose of the antibody molecule that specifically binds to FcyRllb, for example, at approximately 10 minutes, or approximately 20 minutes, or approximately 30 minutes, or approximately 40 minutes, or approximately 50 minutes, or approximately 1 hour, or approximately 2 hours prior to the first dose of the antibody molecule that specifically binds to FcyRllb.

[0128] In a further preferred embodiment of the present invention, an additional dose of corticosteroid is administered before a second dose of an antibody molecule that specifically binds to FcyRllb. Thus, in such an embodiment, the additional dose of corticosteroid is administered after the first dose of the antibody molecule but before the second dose of the antibody molecule. Preferably, one or more additional doses of corticosteroid are administered, for example, one additional dose, or two additional doses, or three additional doses, or four additional doses, or five additional doses, or six additional doses, or seven additional doses, or eight additional doses, or nine additional doses, or ten additional doses, or eleven additional doses, or twelve or more additional doses.

[0129] Preferably, the additional dose of corticosteroid is administered 16 to 48 hours before the second dose of the antibody molecule that specifically binds to FcyRllb. Thus, in such embodiments of the present invention, the additional dose of corticosteroid is administered at any point 16 to 48 hours before the second dose of the antibody molecule, for example, about 16 hours, or about 17 hours, or about 18 hours, or about 19 hours, or about 20 hours, or about 21 hours, or about 22 hours, or about 23 hours, or about 24 hours, or about 25 hours, or about 26 hours, or Administration may also be possible at approximately 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, or 48 hours prior to the scheduled time.

[0130] In some embodiments, the drug regimens described herein can be repeated as many times as needed in a particular patient. For example, this drug regimen can be used each time an antibody molecule that specifically binds to FcyRllb is administered to the patient. In some embodiments, the exact form of the drug regimen (with respect to time and dosage) may vary between repeated administrations to the patient. The advantage of repeatedly using the drug regimens described herein is that it ensures improved tolerability (e.g., reduced injection-related reactions) is achieved with each administration of the antibody that specifically binds to FcyRllb.

[0131] The corticosteroid of the present invention may be administered in doses of 0.5 to 20 mg. In preferred embodiments of the present invention, the corticosteroid is administered in doses of about 4 mg to about 20 mg, for example, in doses of about 12 mg to about 20 mg, or in doses of about 4 mg to about 12 mg. For example, the corticosteroid is administered in doses of about 4 mg or more, for example, about 5 mg or more, or about 6 mg or more, or about 7 mg or more, or about 8 mg or more, or about 9 mg or more, or about 10 mg or more, or about 11 mg or more, or about 12 mg or more, or about 13 mg or more, or about 14 mg or more, or about 15 mg or more, or about 16 mg or more, or about 17 mg or more, or about 18 mg or more, or about 19 mg or more, or about 20 mg or more.

[0132] In some preferred embodiments, the corticosteroid is dexamethasone. In some additional or alternative embodiments, the corticosteroid is betamethasone. In some embodiments, a combination of dexamethasone and betamethasone is used. Those skilled in the art will understand that other corticosteroids, for example, one or more of the following, are intended by the present invention: cortisone, hydrocortisone, prednisone, prednisolone, triamcinolone, and methylprednisolone, or combinations thereof.

[0133] In some embodiments, when the corticosteroid is dexamethasone, the dose of dexamethasone is 0.5 mg to 20 mg. In some embodiments, when dexamethasone is used, the dose of dexamethasone is about 4 mg or more, for example, about 4 to 20 mg in preferred embodiments. In some embodiments, the dose of dexamethasone is about 12 mg or more, for example, about 12 to 20 mg. In some embodiments, the dose of dexamethasone is about 4 to 12 mg. In particularly preferred embodiments, the dose of dexamethasone is about about 12 mg or about 20 mg.

[0134] In particularly preferred embodiments of the present invention, a first dose and a second dose of the corticosteroid dexamethasone are administered. More preferably, in these embodiments of the present invention, when dexamethasone is used, the first dose is about 4 to 20 mg and / or the second dose is about 4 to 25 mg, or the first dose is about 4 to 20 mg and the second dose is about 4 to 25 mg, or the first dose is about 10 to 12 mg and / or the second dose is about 20 mg, or the first dose is about 10 to 12 mg and the second dose is about 20 mg.

[0135] In some embodiments, when the corticosteroid is betamethasone, the dose of betamethasone is 0.5 mg to 20 mg. In some embodiments, when betamethasone is used, the dose of betamethasone is about 3.2 mg or more, for example, about 4 mg or more, for example, about 3.2 to 16 mg, or about 4 to 20 mg. In some embodiments, the dose of betamethasone is about 12 mg or more, for example, about 12 to 20 mg. In some embodiments, the dose of betamethasone is about 4 to 12 mg. In a particularly preferred embodiment, the dose of betamethasone is about about 12 mg or about 20 mg.

[0136] In particularly preferred embodiments of the present invention, a first dose and a second dose of betamethasone, a corticosteroid, are administered. More preferably, in these embodiments of the present invention, when betamethasone is used, the first dose is about 3.2 to 16 mg and / or the second dose is about 3.2 to 20 mg, or the first dose is about 3.2 to 16 mg and the second dose is about 3.2 to 20 mg, or the first dose is about 8 to 9.6 mg and / or the second dose is about 16 mg.

[0137] Those skilled in the art will understand that, in addition to those described herein, other corticosteroids are known in the art. They will also understand that any corticosteroid can be used in the present invention because corticosteroids function in a similar manner.

[0138] As discussed above, the present invention provides a system, combination, method, or use in which an antibody molecule that specifically binds to FcyRllb is administered to a subject in at least a first dose and a second dose.

[0139] In a preferred embodiment of the present invention, a first dose of an antibody molecule that specifically binds to FcyRllb is administered about 1 to about 24 hours before a second dose of the antibody molecule that specifically binds to FcyRllb. Therefore, in such an embodiment of the present invention, the first dose of the antibody molecule is administered at any point about 1 to about 24 hours before a second dose of the antibody molecule, for example, about 1 hour, or about 2 hours, or about 3 hours, or about 4 hours, or about 5 hours, or about 6 hours, or about 7 hours, or about 8 hours, or about 9 hours, or about 10 hours, or about 11 hours, or about 12 hours, or about 13 hours, or about 14 hours, or about 15 hours, or about 16 hours, or about 17 hours, or about 18 hours, or about 19 hours, or about 20 hours, or about 21 hours, or about 22 hours, or about 23 hours, or about 24 hours before a second dose of an antibody molecule that specifically binds to FcγRllb.

[0140] Most preferably, in the embodiments of the present invention, a first dose of an antibody molecule that specifically binds to FcyRllb is administered about 1 hour before a second dose of an antibody molecule that specifically binds to FcyRllb, or about 24 hours before a second dose of an antibody molecule that specifically binds to FcyRllb.

[0141] In another embodiment, a first dose of an antibody molecule that specifically binds to FcyRllb is administered approximately 24 to 48 hours before a second dose of the antibody molecule that specifically binds to FcyRllb. Therefore, in such embodiments of the present invention, the first dose of the antibody molecule is administered at any point in time about 24 to 48 hours before the second dose of the antibody molecule, for example, about 24 hours, or about 25 hours, or about 26 hours, or about 27 hours, or about 28 hours, or about 29 hours, or about 30 hours, or about 31 hours, or about 32 hours, or about 33 hours, or about 34 hours, or about 35 hours, or about 36 hours, or about 37 hours, or about 38 hours, or about 39 hours, or about 40 hours, or about 41 hours, or about 42 hours, or about 43 hours, or about 44 hours, or about 45 hours, or about 46 hours, or about 47 hours, or about 48 hours before the second dose of the antibody molecule that specifically binds to FcyRllb.

[0142] As discussed above, the present invention provides a system, combination, method, or use in which a first dose of the antibody molecule is lower than the maximum therapeutically effective dose of the antibody molecule.

[0143] Those skilled in the art will recognize that for approved antibody therapies, a specific dose (typically expressed in mg / kg) is recommended for use in a particular patient group or subject with a particular type of cancer. Often, the recommended dose is indicated on the label or prescribing information of the approved antibody therapy. The recommended dose may be calculated for a specific subject, based on factors such as the type of cancer, the stage of the cancer, their weight, Body Mass Index (BMI), and other factors.

[0144] Those skilled in the art will understand that the recommended dose varies depending on the identity of the antibody molecule. If the antibody molecule is not labeled or described in the formulation information, a method for determining the recommended dose using techniques well known in the art will be obvious to those skilled in the art.

[0145] The "recommended dose" is typically referred to as the "approved dose," "maximum tolerable dose (MTD)," or "therapeutic effective dose" of an antibody molecule. MTD is a well-known term in drug discovery and refers to the highest dose of a drug that can be used with acceptable tolerance levels.

[0146] "Therapeutic effective dose" means any dose that would be considered therapeutically active (i.e., a dose that produces the desired therapeutic effect in a subject, as defined herein).

[0147] The "maximum therapeutic dose" refers to the (minimum) dose that achieves maximum therapeutic activity without considering tolerability (this may be suboptimal or unacceptable if there is no appropriate dosage scale to mitigate adverse effects). This would be the ideal dose that a person skilled in the art would attempt to use when administering an antibody molecule to a target that needs it.

[0148] "Therapeutically active" includes cases where the dose produces the desired therapeutic effect in the subject. "Therapeutic effect" includes all effects directly or indirectly resulting from the use of the treatment in question. This may be a measurable therapeutic effect, such as a reduction in tumor volume or tumor size (which may be determined, for example, by a CT scan), or the effectiveness of the therapeutic antibody or treatment. In other cases, this may be a more subjective effect, such as a reduction in the severity of symptoms reported by the subject. Measuring therapeutic effects in subjects in response to the administration of therapeutic antibodies is well known in the art. Furthermore, the survival level of a subject or group of subjects over a given period is an alternative read of therapeutic effect.

[0149] This invention is based on the inventors' remarkable discovery that administering a corticosteroid to a subject, followed by administering an antibody molecule in at least a first and a second dose (the first dose being lower than the "maximum therapeutic dose" of the antibody), improves the tolerance of the antibody molecule that specifically binds to FcγRIIb in the subject. In other words, the first dose of the antibody molecule is a near-maximum therapeutic dose (i.e., a dose lower than the maximum therapeutic dose of the antibody).

[0150] In a preferred embodiment of the present invention, the first dose of the antibody molecule that specifically binds to FcyRllb is lower than the maximum tolerable therapeutic dose. As discussed above, the maximum tolerable therapeutic dose is the highest dose of the available drug that is considered tolerable (i.e., one that does not result in an untolerable level of toxicity or side effect in the patient, and this may be lower than the maximum therapeutic effective dose). This differs from the maximum therapeutic effective dose in that the dose must be tolerable in the patient. The level of side effect / toxicity tolerable by a particular patient depends on factors such as the stage or severity of the disease.

[0151] Improving drug tolerance and the therapeutic window is important not only for treating severely ill patients with cancer, for example, but also for use in patients with non-life-threatening conditions such as autoimmune diseases or infectious diseases where even moderate or mild side effects are unacceptable.

[0152] In some other cases, doses lower than the maximum therapeutically effective dose or the maximum tolerable therapeutic dose are lower than the minimum dose considered therapeutically effective (i.e., the minimum effective dose). In other words, the first dose of an antibody molecule may not be therapeutically effective when administered alone as a single dose.

[0153] In some cases, the initial dose of an antibody is lower than the maximum feasible dose. In some cases, practical considerations such as formulation limitations may restrict the maximum dose that can be administered. The highest such dose, taking such factors into account, is called the maximum feasible dose.

[0154] In some other cases, a dose lower than the tolerable therapeutic dose is lower than the recommended tolerable therapeutic dose. In some embodiments, this may include the recommended dose for the indication as stated on the drug label.

[0155] In general, how a particular acceptable therapeutic dose is defined for any given antibody using dose escalation studies during clinical trials will be obvious to those skilled in the art. An acceptable therapeutic dose for an antibody not yet approved may be based on the acceptable therapeutic doses of similar antibodies that are approved or have undergone extensive clinical trials.

[0156] In a preferred embodiment of the present invention, the first dose of the antibody molecule that specifically binds to FcyRllb is at least 50% lower than the maximum therapeutic dose. For example, the first dose of the antibody molecule is at least 60% lower, or at least 70% lower, or at least 80% lower, or at least 90% lower than the maximum therapeutic dose.

[0157] In one embodiment of the present invention, an antibody molecule that specifically binds to FcγRIIb is administered in a first dose that results in a high receptor saturation of FcγRIIb, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, near 100%, or 100%. Methods for measuring receptor saturation are well known to those skilled in the art.

[0158] Preferably, high receptor saturation can be maintained for a longer period, at least temporarily. Temporary receptor saturation means that the indicated saturation is maintained for at least 15 minutes, preferably 1 to 6 hours, and most preferably until the second antibody dose. As discussed herein, the time between the first and second doses of the antibody molecule can vary from about 1 hour to about 48 hours.

[0159] As discussed herein, the dose of an antibody molecule is expressed based on the body weight of the subject to whom it is administered, and is typically expressed in milligrams of antibody molecules per kilogram of body weight of the subject.

[0160] In a preferred embodiment of the present invention, the first dose of the antibody molecule that specifically binds to FcyRllb is administered in a dose of about 0.2 mg / kg to about 0.6 mg / kg, for example, about 0.3 mg / kg to about 0.5 mg / kg. Therefore, it will be understood that the first dose of the antibody molecule may be administered in a dose of about 0.2 mg / kg, or about 0.3 mg / kg, or about 0.4 mg / kg, or about 0.5 mg / kg, or about 0.6 mg / kg.

[0161] It will be understood that, depending on the body weight of the subject to whom the antibody molecule is administered, the first dose of the antibody molecule that specifically binds to FcyRllb may be administered in doses of approximately 10 mg to approximately 20 mg. In other embodiments, the first dose of the antibody may be administered in doses of approximately 20 mg to approximately 40 mg or more, for example, approximately 20 mg to 30 mg, or approximately 30 mg to 40 mg, or approximately 40 mg to 50 mg, or approximately 50 mg to 60 mg, or approximately 60 mg to 70 mg or more. Therefore, it will be understood that the first dose of the antibody molecule may be administered in doses of approximately 10 mg, approximately 20 mg, or approximately 25 mg, or approximately 30 mg, or approximately 35 mg, or approximately 40 mg, or approximately 45 mg, or approximately 50 mg, or approximately 55 mg, or approximately 60 mg, or approximately 65 mg, or approximately 70 mg or more.

[0162] In one embodiment of the present invention, an antibody molecule that specifically binds to FcγRIIb is administered at a dose that results in a high receptor saturation of the FcγRIb receptor, such as at least 50% receptor saturation, or at least 60% receptor saturation, or at least 70% receptor saturation, or at least 80% receptor saturation, or at least 90% receptor saturation, or at least 95% receptor saturation, or at least 96% receptor saturation, or at least 97% receptor saturation, or at least 98% receptor saturation, or at least 99% receptor saturation, or near 100% receptor saturation, or 100% receptor saturation. Methods for measuring receptor saturation are well known to those skilled in the art.

[0163] Transient receptor saturation means that the indicated saturation is maintained for at least 15 minutes, preferably 1 to 6 hours, and most preferably persists until the administration of a second antibody.

[0164] As discussed above, the present invention provides a system, combination, method, or use in which a second dose of an antibody molecule that specifically binds to FcγRIIb is administered to a subject.

[0165] Preferably, the second dose of the antibody molecule that specifically binds to FcyRllb is a therapeutically effective dose. In some embodiments, the second dose of the antibody molecule may be the maximum therapeutically effective dose as defined herein.

[0166] More preferably, the second dose of the antibody molecule that specifically binds to FcyRllb is the maximum feasible therapeutic dose.

[0167] More preferably, the second dose of the antibody molecule that specifically binds to FcyRllb is lower than the therapeutically effective dose.

[0168] In some embodiments, the second dose of the antibody molecule is higher than the first dose of the antibody molecule. In alternative embodiments, the second dose of the antibody molecule is lower than the first dose of the antibody molecule.

[0169] In some embodiments, the total amount of antibody that specifically binds to FcyRIIb administered between the first dose and the second dose is from about 30 mg to about 3000 mg. In some embodiments, the total dose of antibody that specifically binds to FcyRIIb administered between the first dose and the second dose is from about 0.3 mg / kg to about 20 mg / kg. In some other embodiments, the total dose between the first antibody dose and the second antibody dose is a dose that results in, at least temporarily, a high receptor saturation of FcγRIIb receptor, for example, at least 90% receptor saturation. In some preferred embodiments, this high receptor saturation persists for a total duration ranging from about 1 hour to about 4 weeks.

[0170] Those skilled in the art will understand that the second dose of the antibody molecule that specifically binds to FcyRIIb can be adjusted based on the amount of the first dose of the administered antibody molecule.

[0171] In some preferred embodiments, the second dose of the antibody molecule that specifically binds to FcγRIIb receptor is administered at a dose of from about 0.1 mg / kg to about 19.8 mg / kg.

[0172] It will be understood that, depending on the body weight of the subject to whom the antibody molecule is administered, the second dose of the antibody molecule that specifically binds to FcyRIIb can be administered at a dose of from about 20 mg to about 2900 mg.

[0173] In a preferred embodiment of the present invention, a further additional dose of the antibody molecule that specifically binds to FcyRIIb is administered to the subject after the second dose of the antibody molecule that specifically binds to FcyRIIb.

[0174] In a preferred embodiment, a further additional dose of an antibody molecule that specifically binds to FcγRIIb is also administered according to the dosing regimen disclosed herein. For example, this dosing regimen can be used each time an antibody molecule that specifically binds to FcγRIIb is administered to a patient. In some embodiments, the exact form of the dosing regimen (in terms of timing and dosage) may vary between repeated administrations to a patient. The advantage of repeated use of the dosing regimen described herein is that it ensures improved tolerability (e.g., reduction of infusion-related reactions) with each administration of an antibody that specifically binds to FcγRIIb. In some other embodiments, the further additional dose of the antibody molecule is administered at the maximum therapeutically effective dose as defined herein. Typically, repeated doses will be of a similar amount to the previously administered dose. For example, - if the previously administered antibody dose is 1.3 mg / kg (e.g., 0.3 mg / kg (first dose) + 1 mg / kg (second dose)), the subsequent additional dose will also be 1.3 mg / kg, - if the previously administered antibody dose is 2.5 mg / kg (e.g., 0.5 mg / kg (first dose) + 2 mg / kg (second dose)), the subsequent additional dose will also be 2.5 mg / kg, - if the previously administered antibody dose is 3.3 mg / kg (0.3 mg / kg (first dose) + 3 mg / kg (second dose)), the subsequent additional dose will also be 3.3 mg / kg, - if the previously administered antibody dose is 5.4 mg / kg (e.g., 0.4 mg / kg (first dose) + 5 mg / kg (second dose)), the subsequent additional dose will also be 5.4 mg / kg, - if the previously administered antibody dose is 10.5 mg / kg (e.g., 0.5 mg / kg (first dose) + 10 mg / kg (second dose)), the subsequent additional dose will also be 10.5 mg / kg.

[0175] However, as those skilled in the art will understand, repeated dosing can also utilize higher or lower total doses, as guided by patient tolerance. Similar flat-dosing-based or receptor-occupancy-inducing dosing regimens can be used.

[0176] It will be understood that antibody molecules that specifically bind to FcγRIIb are particularly useful when administered together with certain therapeutic antibodies (especially those used to treat cancer or inflammatory diseases).

[0177] It is well known that many therapeutic antibodies exert their therapeutic effects by mobilizing innate effector systems such as cytotoxic cells (e.g., macrophages) and enzymes (e.g., complement), and then stimulating the elimination of cancer and other undesirable cells by targeting cells to which the therapeutic antibody binds. For example, type I anti-CD20 monoclonal antibodies (e.g., rituximab, the current market leader) function by binding to the CD20 molecule on the surface of B cells and causing deletion of these target B cells. They do this by mobilizing and activating effector cells, which then interact with the Fc domain of the therapeutic antibody via Fcγ (i.e., Fc-γ) receptors expressed on the surface of these effector cells.

[0178] The effectiveness of such therapeutic antibodies (e.g., those against antigens such as CD20) is known to be determined by their interaction with inhibitory FcγRIIb (also known as CD32, CD32B, CD32B1, CD32B2, FcRII, FcγRII, or FcRIIB, and including them). FcγRIIB can reduce therapeutic efficacy and promote cancer resistance through several mechanisms, either acting cis (i.e., against cells targeted by the therapeutic antibody) or trans (i.e., against adjacent effector cells that associate via their Fcγ receptors in binding to the constant domain of the antibody coated on the surface of the antibody's target cell). For example, this interaction can lead to internalization (interaction) of the therapeutic antibody by the target cell, thus eliminating its ability to interact with the effector cell Fc receptor. Drugs that bind to FcγRIIb on target cells (e.g., antibody molecules that specifically bind to FcγRIIb) are known to block this internalization and enhance the activity of the therapeutic antibody.

[0179] Therefore, in a particularly preferred embodiment, the present invention provides a system, combination, use, or method further comprising the administration of one or more therapeutic antibodies for the treatment of cancer or inflammatory disease in a subject.

[0180] Preferably, one or more therapeutic antibodies are selected from the following group: - One or more anti-PD1 antibodies (e.g., pembrolizumab, nivolumab, semiprimab, camrelizumab, dostallimab, and / or their biosimilars), -One or more anti-CD20 antibodies (e.g., rituximab, obinutuzumab, ofatumumab, and / or their biosimilars; e.g., discussed in Roghanian et al., Cancer Cell, 2015, 27:473-488), - One or more anti-CD19 antibodies (e.g., roncustuximab tesirin), - One or more anti-CD40 antibodies (e.g., CP-870, 893), - One or more anti-CD38 antibodies (e.g., those described in Vaughan et al., Blood, 2014, 123:669-677, or daratumumab or a biosimilar of daratumumab), - One or more anti-Her2 antibodies (e.g., trastuzumab or a biosimilar of trastuzumab), - One or more anti-EGFR antibodies (e.g., cetuximab or a biosimilar of cetuximab).

[0181] Preferably, the therapeutic antibody is one or more selected from the group including rituximab, pembrolizumab, nivolumab, semiprimab, camrelizumab, dostallimab, obinutuzumab, ofatumumab, and their biosimilars or equivalents.

[0182] It should be understood that the respective doses and dosing regimens of the therapeutic antibodies discussed and intended herein depend on the approved doses / regimens of these therapeutic antibodies and vary depending on the indication (e.g., type / stage of cancer) and subject (e.g., BMI or age).

[0183] For example, in some embodiments, the therapeutic antibody may be rituximab, and its dose and administration regimen may be as defined on the FDA label (see https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2010 / 103705s5311lbl.pdf). As described herein, the dose may be as follows: ● Non-Hodgkin lymphoma (NHL): 375 mg / m2 administered once a week for 4 to 8 weeks. ●Chronic lymphocytic leukemia (CLL): 375 mg / m2 on the day before starting FC chemotherapy, followed by 500 mg / m2 on day 1 of cycles 2-6 (every 28 days). ● Rheumatoid arthritis (RA): Administer 1000 mg twice by injection at two-week intervals.

[0184] In another embodiment, the therapeutic antibody may be pembrolizumab, and its dose and administration regimen may be as defined on the FDA label (see https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2019 / 125514s040lbl.pdf). As described herein, the dose may be as follows: ● Melanoma: 200mg every 3 weeks, ● Non-small cell lung cancer (NSCLC): 200 mg every 3 weeks. ● Head and neck squamous cell carcinoma (HNSCC): 200 mg every 3 weeks, ● Classical Hodgkin lymphoma (cHL) or primary mediastinal large B-cell lymphoma (PMBCL): 200 mg every 3 weeks for adults, 2 mg / kg (maximum 200 mg) every 3 weeks for children. ●Urothelial carcinoma: 200 mg every 3 weeks, ● Microsatellite instability-high (MSI-H) cancer: 200 mg every 3 weeks for adults, 2 mg / kg (maximum 200 mg) every 3 weeks for children. ● Stomach cancer: 200 mg every 3 weeks, ● Cervical cancer: 200mg every 3 weeks. ● Hepatocellular carcinoma (HCC): 200 mg every 3 weeks. ● Merkel cell carcinoma (MCC): 200 mg every 3 weeks for adults, and 2 mg / kg (maximum 200 mg) every 3 weeks for children.

[0185] The term “subject” (as used herein interchangeably with “patient”) includes any animal, including humans, that requires treatment with an antibody molecule specifically bound to FcyRllb. Subjects or patients may be mammals or non-mammals. Preferably, subjects are mammals such as horses, or cattle, or sheep, or pigs, or camels, or dogs, or cats. Most preferably, mammalian patients are humans.

[0186] Preferably, the subject is a subject diagnosed as having cancer or an inflammatory disease, a subject identified as having a high likelihood of having cancer or an inflammatory disease, and / or a subject exhibiting symptoms of cancer or an inflammatory disease.

[0187] In another preferred embodiment, the subject is a subject diagnosed as having an infectious disease, a subject identified as having a high likelihood of having an infectious disease, and / or a subject exhibiting symptoms of an infectious disease. Infectious diseases include diseases caused by bacteria, fungi, parasites or viruses that are transmissible from person to person (either directly or indirectly).

[0188] In some other embodiments, the subject has cancer, and / or an inflammatory disease, and / or an infectious disease, and the dosing regimen described herein is used in combination with administration of a vaccine intended to enhance a humoral or cellular response to treat and / or prevent said cancer or disease.

[0189] The term "exhibiting" includes that the subject presents cancer symptoms and / or cancer diagnostic markers, and / or that cancer symptoms and / or cancer diagnostic markers can be measured, and / or assessed, and / or quantified. It will be readily apparent to a person skilled in the medical art what cancer symptoms and cancer diagnostic markers are, how to measure and / or assess and / or quantify whether there is a decrease or increase in the severity of cancer symptoms or a decrease or increase in cancer diagnostic markers, and how to form a prognosis for cancer using cancer symptoms and / or cancer diagnostic markers.

[0190] In some embodiments, the cancer is FcyRIIb-positive cancer. In other embodiments, the cancer is FcγRIIb-negative cancer.

[0191] "FcγRIIb-positive cancer" includes any cancer that expresses FcγRIIb, even if at varying levels. FcγRIIb expression is most prominent in chronic lymphocytic leukemia and mantle cell lymphoma, moderate in diffuse large B-cell lymphoma, and least prominent in follicular lymphoma. However, in some cases, subjects with cancers that generally express low levels of FcγRIIb (e.g., follicular lymphoma) may have very high levels of FcγRIIb expression.

[0192] "FcγRIIb-negative cancer" includes any cancer that does not present any FcγRIIb receptor. This can be tested using anti-FcγRIIB-specific antibodies in a variety of ways, including immunohistochemistry and flow cytometry, as described in Tutt et al, J Immunol, 2015, 195(11)5503-5516.

[0193] In some preferred 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 cell carcinoma, poorly differentiated 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.

[0194] In some preferred embodiments, the cancer is selected from the group of cancers indicated on the label of an approved therapeutic antibody to be administered co-administered with the anti-FcgRIIB antibody. Co-administration means the antibody used as part of the anti-FcgRIIB antibody, which may be administered before, simultaneously with, or after the anti-FcgRIIB antibody.

[0195] In some preferred embodiments, the disease is selected from the group of diseases indicated on the label of an approved therapeutic antibody to be administered co-administered with an anti-FcgRIIB antibody. Co-administration means an antibody used as part of the anti-FcgRIIB antibody, which may be administered before, simultaneously with, or after the anti-FcgRIIB antibody.

[0196] Cancer may be selected from a group that includes melanoma, breast cancer, ovarian cancer, cervical cancer, prostate cancer, metastatic hormone-refractory prostate cancer, colorectal cancer, lung cancer, small cell lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer, urothelial carcinoma, bladder cancer, kidney cancer, mesothelioma, Merkel cell carcinoma, head and neck cancer, and pancreatic cancer.

[0197] Preferably, the cancer is selected from the group of B-cell cancers, such as chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma.

[0198] Each of the aforementioned cancers is well known, and its symptoms and cancer diagnostic markers are well described, as are the therapeutic agents used to treat them. Therefore, the symptoms, cancer diagnostic markers, and therapeutic agents used to treat the aforementioned types of cancer will be known to those skilled in the medical field.

[0199] The diagnosis, prognosis, and clinical definition of progression for numerous cancers depend on specific classifications known as staging. These staging systems work by matching several different cancer diagnostic markers and cancer symptoms to provide an overview of the diagnosis, and / or prognosis, and / or progression of cancer. How to assess the diagnosis, and / or prognosis, and / or progression of cancer using staging systems, and which cancer diagnostic markers and cancer symptoms should be used to do so, will be known to those skilled in the field of oncology.

[0200] "Cancer staging" includes Rai's staging classification, which includes stages 0, I, II, III, and IV, and / or Binet's staging classification, which includes stages A, B, and C, and / or Ann Arbour's staging classification, which includes stages I, II, III, and IV.

[0201] Cancer is known to cause abnormalities in the morphology of cells. These abnormalities often occur reproducibly in certain cancers, meaning that examination of these morphological changes (also known as histological examination) can be used in the diagnosis or prognosis of cancer. Techniques for visualizing and preparing samples for visualization, such as optical microscopy or confocal microscopy, are well known in the art.

[0202] "Histological examination" includes the presence of small mature lymphocytes, and / or small mature lymphocytes with narrow cytoplasmic boundaries, small mature lymphocytes with dense nuclei lacking identifiable nucleoli, and / or small mature lymphocytes with narrow cytoplasmic boundaries and dense nuclei lacking identifiable nucleoli, and / or atypical cells, and / or cleaved cells, and / or prolymphocytes.

[0203] It is well known that cancer is the result of mutations in the DNA of cells, which can cause cells to avoid cell death or to proliferate uncontrollably. Therefore, testing for these mutations (also known as cytogenetic testing) can be a useful tool for evaluating the diagnosis and / or prognosis of cancer. An example of this is a deletion at chromosomal position 13q14.1, which is characteristic of chronic lymphocytic leukemia. Techniques for testing for cellular mutations, such as fluorescence insight hybridization (FISH), are well known in this field.

[0204] "Cytogenetic testing" includes the examination of DNA in cells (particularly chromosomes). Cytogenetic testing can be used to identify DNA changes that may be associated with the presence of refractory and / or recurrent cancer. Such include: deletion of the long arm of chromosome 13, and / or deletion of chromosome position 13q14.1, and / or trisomy of chromosome 12, and / or deletion of the long arm of chromosome 12, and / or deletion of the long arm of chromosome 11, and / or deletion of 11q, and / or deletion of the long arm of chromosome 6, and / or deletion of 6q, and / or deletion of the short arm of chromosome 17, and / or deletion of 17p, and / or t(11:14) translocation, and Examples include translocations of / or (q13:q32), and / or rearrangement of the antigen gene receptor, and / or rearrangement of BCL2, and / or rearrangement of BCL6, and / or translocation of t(14:18), and / or translocation of t(11:14), and / or translocation of (q13:q32), and / or translocation of (3:v), and / or translocation of (8:14), and / or translocation of (8:v), and / or translocation of t(11:14) and (q13:q32).

[0205] It is known that cancer patients exhibit certain physical symptoms, which are often a result of the burden cancer places on the body. These symptoms often recur in the same cancer and can therefore be characteristic of the diagnosis, and / or prognosis, and / or progression of the disease. Those skilled in the medical field will understand which physical symptoms are associated with which cancers, and how the evaluation of these bodily systems may correlate with the diagnosis, and / or prognosis, and / or progression of the disease. Examples of “physical symptoms” include hepatomegaly and / or splenomegaly.

[0206] In some embodiments, the cancer is one that is resistant to treatment with therapeutic anti-cancer antibodies. Such resistant cancers may be recurrent and / or refractory cancers.

[0207] Recurrent cancer is cancer that has been previously treated, and as a result of that treatment, the subject has recovered completely or partially (i.e., the subject is said to be in remission), but has returned or worsened after treatment was discontinued. In other words, recurrent cancer is cancer that has become resistant to treatment after a period in which it was effective and the subject had recovered completely or partially.

[0208] Refractory cancer is cancer that is being treated but is not responding to treatment and / or has progressed during treatment. In other words, refractory cancer is cancer that is resistant to treatment. It will be understood that cancer can be refractory due to its inherent resistance. “Inherent resistance” means that the cancer, and / or the subject, and / or target cells are resistant to a particular treatment from the time it is first administered, or even before it is administered.

[0209] Recurrent and / or refractory cancers will be readily diagnosed by those skilled in the medical field.

[0210] In embodiments of the present invention, an antibody molecule that specifically binds to FcγRIIb is formulated and / or adapted for delivery via a route selected from the group including intravenous, intramuscular, and subcutaneous. In some embodiments, an antibody molecule that specifically binds to FcγRIIb is formulated and / or adapted for intravenous (i.e., iv or iv) delivery. In other embodiments, an antibody molecule that specifically binds to FcγRIIb is formulated and / or adapted for subcutaneous (i.e., sc or sc) delivery.

[0211] In embodiments of the present invention, an antibody molecule that specifically binds to FcγRIIb is delivered to a target via a route selected from the group including intravenous, intramuscular, and subcutaneous. Preferably, the antibody molecule that specifically binds to FcγRIIb is delivered intravenously.

[0212] Therefore, in a preferred embodiment, first and / or second and / or further doses of the antibody molecule that specifically binds to FcyRllb are formulated for intravenous delivery to a subject and / or delivered by intravenous delivery to a subject.

[0213] Methods and formulations for intravenous administration of antibody molecules are well known in the art. In the present invention, any type of intravenous administration, such as injection or infusion, can be used.

[0214] In embodiments of the present invention, the corticosteroid is formulated and / or adapted for delivery by a route selected from the group including intravenous and oral.

[0215] In embodiments of the present invention, corticosteroids are delivered to a subject by a route selected from the group including intravenous and oral.

[0216] Therefore, in a preferred embodiment, further doses of the first and / or second and / or corticosteroid are formulated for intravenous or oral delivery to the subject and / or delivered by intravenous or oral delivery to the subject.

[0217] Methods and formulations for intravenous or oral administration of corticosteroids are well known in the art.

[0218] Antibody molecules that specifically bind to FcγRIIb and / or corticosteroids as defined herein can be combined with excipients and / or pharmaceutically acceptable carriers and / or pharmaceutically acceptable diluents and / or adjuvants.

[0219] For example, antibodies that specifically bind to FcγRIIb and / or corticosteroids can be formulated as aqueous and / or non-aqueous sterile suspensions which may contain antioxidants, and / or buffers, and / or bacteriostatic agents, and / or solutes that make the formulation isotonic with the blood of the intended recipient, and / or suspending agents and / or thickeners. Such formulations may be supplied in unit or multi-dose containers (e.g., sealed ampoules and vials) and may be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier (e.g., water) immediately before use.

[0220] Immediate injection solutions and suspensions may be prepared from sterile powders, and / or granules, and / or tablets of types known in the art.

[0221] Antibodies that specifically bind to FcγRIIb and / or corticosteroids can be formulated with pharmaceutically acceptable acid-addition salts or base-addition salts. Acids used to prepare pharmaceutically acceptable acid-addition salts are, in particular, those that form salts containing pharmaceutically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidic phosphate, acetate, lactate, citrate, acidic citrate, tartrate, bisulfate, succinate, maleate, fumarate, gluconate, sugarate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3 naphthoate)] salt. Alternatively, pharmaceutically acceptable base-addition salts may be used to obtain pharmaceutically acceptable salt forms. Chemical bases that can be used as reagents for preparing pharmaceutically acceptable base salts are those that form non-toxic base salts. Such non-toxic base salts include, but are not limited to, those derived from such pharmaceutically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts (e.g., N-methylglucamine-(meglumine) and lower alkanolammonium), and base salts of other pharmaceutically acceptable organic amines.

[0222] Antibody molecules that specifically bind to FcγRIIb and / or corticosteroids may be lyophilized for storage and reconstituted on a suitable carrier before use. Any suitable lyophilization method (e.g., spray drying, cake drying) and / or reconstitution technique may be used. Those skilled in the art will understand that lyophilization and reconstitution may lead to varying degrees of loss of antibody activity (for example, in conventional immunoglobulins, IgM antibodies tend to lose more activity than IgG antibodies), and that it may be necessary to compensate by upregulating the level of use. In one embodiment, a lyophilized (freeze-dried) antibody molecule, upon rehydration, loses about 20% or less, or about 25% or less, or about 30% or less, or about 35% or less, or about 40% or less, or about 45% or less, or about 50% or less of its activity (before lyophilization).

[0223] As discussed above and demonstrated in the attached examples, the systems, combinations, methods, or uses of the present invention improve the tolerance of antibody molecules that specifically bind to FcyRllb in a subject. In other words, the systems, combinations, methods, or uses of the present invention reduce or prevent adverse effects associated with the administration of antibody molecules (particularly those associated with intravenous administration of antibody molecules).

[0224] In preferred embodiments of the systems, combinations, methods, or uses of the present invention, injection-related reactions associated with the administration of antibody molecules that specifically bind to FcyRllb are reduced or eliminated. Such injection-related reactions are described herein, and the systems, combinations, methods, or uses of the present invention are intended to reduce or eliminate one or more of these injection-related reactions.

[0225] In preferred embodiments, changes in the subject's body temperature, and / or platelet count, and / or blood levels of liver enzymes (e.g., ALAT or ASAT), and / or blood levels of cytokines (e.g., IL-6) are reduced. Preferably, the IRR is reduced to an acceptable level (i.e., less than grade 3) as defined herein by the Common Terminology Criteria for Adverse Events (CTCAE), at least 24 hours after administration of a second dose of the antibody molecule that specifically binds to FcyRllb. Most preferably, the IRR is completely prevented by the subject's normalized body temperature, and / or platelet count, and / or blood levels of liver enzymes (e.g., ALAT or ASAT), and / or blood levels of cytokines (e.g., IL-6).

[0226] As defined above, some of these parameters have normal levels as follows: ●Body temperature: 36.1℃~37.9℃ ●Platelet count: 145 x 10 per liter 9 ~400×10 9 , ● ALAT blood levels: 0-1.09 μkT / L, 16-63 U / L ● ASAT blood levels: 0-0.759 μkT / L, 15-37 U / L ● Blood IL-6 levels: 0.16~27.2 pg / ml, median 0.47 pg / ml.

[0227] "Acceptable level" includes reducing the clinical grading of the IRR to at least Grade 2 (using the CTCAE scale as defined in the art and herein). In some preferred embodiments, the grading of the IRR is reduced to Grade 1. As discussed herein, those skilled in the art will recognize the method of grading the IRR according to the CTCAE scale.

[0228] A fifth aspect of the present invention provides a kit, (i) an antibody molecule that specifically binds to FcyRllb, preferably an antibody molecule as defined herein, (ii) corticosteroids, preferably corticosteroids as defined herein, (iii) optionally including instructions for use, An antibody molecule is provided in at least a first dose and a second dose, wherein the first dose of the antibody molecule is lower than the maximum therapeutically effective dose of the antibody molecule, and optionally, the first dose is as defined herein, and optionally, the second dose is as defined herein. The doses of the antibody molecule and embodiments thereof of the present invention are as defined herein.

[0229] Preferably, the kit of the present invention is for improving the tolerance of antibody molecules in a subject, as described herein.

[0230] Preferably, in the kit of the present invention, the corticosteroid is provided in a dose as defined herein.

[0231] In a preferred embodiment, the kit of the present invention further comprises one or more therapeutic antibodies as defined herein. For example, the therapeutic antibody is one or more selected from the group including rituximab, pembrolizumab, nivolumab, semiprimab, camrelizumab, dostallimab, obinutuzumab, ofatumumab, and their biosimilars or equivalents.

[0232] If one or more therapeutic antibodies are present in the kit, it will be understood that the kit of the present invention is intended for use in the treatment of cancer in a subject, as described herein.

[0233] Further aspects of the present invention In a sixth aspect, a method (or model) for predicting whether a therapeutic antibody molecule that specifically binds to a human target is associated with tolerance issues related to intravenous administration to humans is disclosed herein, and the steps are as follows: (i) In the case of cross-reactivity with a mouse target or surrogate antibody, a step of administering a therapeutic antibody molecule intravenously or intraperitoneally to a mouse, and observing the mouse during the period immediately following the administration of the therapeutic antibody or surrogate antibody, wherein the presentation of isolated macroscopic symptoms and decreased activity during the period following the recovery of the mouse's condition to a normal state indicates that intravenous administration of the therapeutic antibody molecule to humans is likely to be associated with tolerability issues; The process also includes the step of predicting whether prophylactic or therapeutic measures, changes in the route of administration, and / or modifications of the therapeutic antibody molecule can prevent or mitigate tolerance issues associated with the intravenous administration of a therapeutic antibody molecule that specifically binds to a human target to humans, In addition to (i) above, the following steps: (ii) A step of administering a prophylactic or therapeutic agent to a mouse, and concurrently administering a therapeutic antibody or surrogate antibody intravenously or intraperitoneally to the mouse, and observing the mouse during the period immediately following the administration of the therapeutic antibody or surrogate antibody, wherein the presentation of macroscopic symptoms is reduced compared to the macroscopic symptoms presented by the mouse in (i), or the absence of macroscopic symptoms during that period indicates that the administration of the therapeutic antibody molecule to humans in combination with pretreatment with the prophylactic or therapeutic agent can prevent or mitigate tolerance issues, or otherwise be associated with intravenous administration of the therapeutic antibody molecule to humans; (iii) a step of administering a therapeutic antibody or surrogate antibody to a mouse by a route of administration other than intravenous or intraperitoneal administration, and observing the mouse during the period immediately following the administration of the therapeutic antibody or surrogate antibody, wherein the presentation of macroscopic symptoms is reduced compared to the macroscopic symptoms presented by the mouse in (i), or the absence of macroscopic symptoms during that period indicates that other routes of administration can be used for the administration of the therapeutic antibody molecule to humans in order to prevent or mitigate tolerability issues that may be associated with the intravenous administration of the therapeutic antibody molecule to humans, and / or (iv) The step of administering a modified form of therapeutic antibody or surrogate antibody to a mouse by an administration route other than intravenous or intraperitoneal administration intravenously or intraperitoneally, and observing the mouse during the period immediately following the administration of the therapeutic antibody or surrogate antibody, the observation that the presentation of macroscopic symptoms is reduced compared to the macroscopic symptoms presented by the mouse in (i), or that there is no presentation of macroscopic symptoms during that period, indicates that the administration of a modified form of therapeutic antibody molecule to humans can prevent or mitigate tolerability issues that may be associated with intravenous administration of therapeutic antibody molecules to humans.

[0234] In a seventh aspect, corticosteroids for use in a drug regimen to prevent or mitigate tolerability issues associated with the intravenous administration of therapeutic antibody molecules to a subject are also disclosed herein. Therapeutic antibody molecules are expected to be associated with tolerability issues related to intravenous administration to humans using the above method, and / or administration of therapeutic antibody molecules to humans in combination with corticosteroid pretreatment is expected to prevent or mitigate tolerability issues, and otherwise be associated with intravenous administration of therapeutic antibody molecules to humans using the above method. The medication regimen includes administration of corticosteroids to the subject in at least two doses prior to intravenous administration of the therapeutic antibody molecule, with one dose of corticosteroid administered 10 to 48 hours before the initiation of administration of the therapeutic antibody molecule ("first dose") and another dose of corticosteroid administered 5 minutes to 5 hours before the initiation of administration of the therapeutic antibody molecule ("second dose").

[0235] A variation of this embodiment relates to a corticosteroid for use in a drug regimen to prevent or mitigate tolerability issues associated with the intravenous administration of therapeutic antibody molecules to a subject, The therapeutic antibody molecule is the anti-FcγRIIB antibody. The medication regimen includes administration of corticosteroids to the subject in at least two doses prior to intravenous administration of the therapeutic antibody molecule, with one dose of corticosteroid administered 10 to 48 hours before the initiation of administration of the therapeutic antibody molecule ("first dose") and another dose of corticosteroid administered 5 minutes to 5 hours before the initiation of administration of the therapeutic antibody molecule ("second dose").

[0236] In the eighth aspect, a therapeutic antibody molecule for use in the treatment of cancer is also disclosed herein, which is expected to be associated with tolerability issues related to intravenous administration to humans using the above method, and / or a subcutaneous administration route of the therapeutic antibody molecule to humans is expected to prevent or mitigate tolerability issues and otherwise be associated with intravenous administration of the therapeutic antibody molecule to humans using the above method, wherein the antibody is formulated for subcutaneous administration.

[0237] In a ninth aspect, a modified form of a therapeutic antibody molecule for use in the treatment of cancer is also disclosed herein, which is expected to be associated with tolerability issues associated with intravenous administration to humans using the above method, and / or administration of the modified form of the therapeutic antibody molecule to humans is expected to prevent or mitigate tolerability issues, and otherwise would be associated with intravenous administration of the therapeutic antibody molecule to humans using the above method, wherein the therapeutic antibody molecule is an Fc receptor-binding antibody, and the modified form is an antibody having the same Fv variable sequence but having reduced, impaired, or inactivated FcγR binding compared to the therapeutic antibody molecule.

[0238] In a tenth aspect, a method for preventing or mitigating tolerance issues associated with the intravenous administration of a therapeutic antibody molecule to a subject, including a corticosteroid dosing regimen, wherein the therapeutic antibody molecule is predicted to be associated with tolerance issues associated with intravenous administration to a human, using the prediction method described above, and / or administration of the therapeutic antibody molecule to a human in combination with corticosteroid pretreatment will prevent or mitigate tolerance issues, and otherwise will be associated with intravenous administration of the therapeutic antibody molecule to a human, using the prediction method described above, wherein the dosing regimen includes administration of a corticosteroid to the subject in at least two doses prior to the intravenous administration of the therapeutic antibody molecule, one dose of the corticosteroid administered 10 to 48 hours before the start of administration of the therapeutic antibody molecule ("first dose"), and one dose of the corticosteroid administered 5 minutes to 5 hours before the start of administration of the therapeutic antibody molecule ("second dose").

[0239] In an eleventh aspect, a method for treating cancer is also disclosed, in which, using the above-described prediction method, a subcutaneous administration of a therapeutically active amount of a therapeutic antibody molecule and / or a subcutaneous administration route of the therapeutic antibody molecule to humans is predicted to prevent or mitigate tolerance issues associated with intravenous administration to humans, and otherwise, using the above-described prediction method, is predicted to be associated with intravenous administration of the therapeutic antibody molecule to humans.

[0240] In a twelfth aspect, a method for treating cancer is also disclosed, comprising administering a therapeutically effective dose of a modified form of a therapeutic antibody, wherein the therapeutic antibody molecule is predicted, using the above-described prediction method, to be associated with tolerability issues related to intravenous administration to humans, and / or, using the above-described method, administration of the modified form of the therapeutic antibody molecule to humans is predicted to prevent or mitigate tolerability issues and otherwise be associated with intravenous administration of the therapeutic antibody molecule to humans, wherein the therapeutic antibody molecule is an Fc receptor-binding antibody, and the modified form is an antibody having the same Fv variable sequence, but with impaired or inactivated FcγR binding compared to the therapeutic antibody molecule.

[0241] Further Description of Aspects of the Invention In short, these further aspects of the present invention describe models for predicting whether therapeutic antibodies constituting human targets are associated with tolerability issues related to intravenous administration, and / or whether pretreatment, modification of the route of administration, or modification of the antibody can prevent tolerability issues associated with intravenous administration of therapeutic antibodies to humans. The model includes intravenous or intraperitoneal administration of the antibody to mice and observation of the mice immediately after administration for any transient presentation of isolated macroscopic symptoms and reduced activity. The model may also include administration of pretreatment in combination with antibody administration, administration of therapeutic antibodies via routes of administration other than intravenous or intraperitoneal administration, or administration of modified forms of the antibody to mice, and observation of the mice immediately after such administration for any transient presentation of isolated macroscopic symptoms and reduced activity, and comparison with transient presentation of isolated macroscopic symptoms and reduced activity after intravenous or intraperitoneal administration of an unmodified antibody without pretreatment. Analysis of related microscopic symptoms, biochemical parameters, or cellular parameter changes can help gather information about the nature of the IRR, as described below, and may lead to testing candidate prophylactic premedication or IRR-reducing interventions in the model.

[0242] In a further aspect of the present invention, the predictive method described herein makes it possible to predict whether a therapeutic antibody molecule against a given target will be associated with, or is likely to be associated with, tolerance issues related to its intravenous administration to a human subject. Additionally or alternatively, it becomes possible to predict whether prophylactic or therapeutic measures, changes in the route of administration, and / or modifications of the therapeutic antibody molecule can be used to prevent or mitigate tolerance issues associated with the intravenous administration of a therapeutic antibody molecule that specifically binds to a human target to a human subject.

[0243] In these further embodiments of the present invention, the therapeutic antibody molecule specifically binds to a human target. Specific binding of the antibody to a target means that it specifically binds to or interacts with a given target molecule or antigen, which means that the antibody preferentially and selectively binds to its target rather than to non-target molecules.

[0244] The targets to which therapeutic antibody molecules bind can be receptors or antigens found on any human cell. Examples of such cells include leukocytes, myeloid cells, and B cells.

[0245] In some embodiments, the target is FcγRII(CD32).

[0246] In some embodiments, the target is FcγRIIB(CD32b).

[0247] In some embodiments, the target is FcγRIIA(CD32a).

[0248] In some embodiments, the target is CD40.

[0249] In these further embodiments of the present invention, the therapeutic antibody molecule may be any therapeutic antibody molecule approved by regulatory authorities for use in humans, or a therapeutic antibody molecule in clinical development, or any antibody that binds to a human target antigen intended or hypothesized for use in the therapy of a human disease. As used herein, the term therapeutic antibody molecule also includes antibodies in preclinical development that are being considered for therapeutic use or are assumed to be developed for that purpose. Thus, a therapeutic antibody molecule is an antibody that has a therapeutic effect on humans. In the prediction method described herein, a therapeutic antibody molecule (in the case of cross-reactivity) or a surrogate antibody against a similar mouse target may be administered to a mouse. The mice used are immunocompetent laboratory mice. Inbred or uninbred mice with different genetic backgrounds may be used. Furthermore, transgenic mice for human targets of the therapeutic antibody molecule may be used.

[0250] In many cases, such therapeutic antibody molecules are monoclonal antibodies. Often, they are human antibodies or humanized antibodies.

[0251] In these further embodiments of the present invention, the therapeutic antibody molecule may be any type of antibody, such as immunoglobulin G (IgG), immunoglobulin A (IgA), or immunoglobulin M (IgM). In some embodiments, it is IgG. It may also be any subclass, such as IgG1, IgG2, IgG3, or IgG4. It may be an antibody molecule engineered for enhanced, reduced, or mitigated FcγR-dependent engagement and function. Furthermore, the therapeutic antibody molecule may be monospecific, bispecific, or triplicate to the same or different targets and may contain or be fused to an antibody Fc domain. Furthermore, the therapeutic antibody molecule may be monospecific, bispecific, or triplicate to the same or different targets and may not contain an antibody Fc domain. Furthermore, therapeutic antibody molecules may be functional fragments of antibodies such as Fv, which consists of the variable domain of the antibody; Fab, also represented as F(ab), which is a monovalent antigen-binding fragment that does not contain the Fc portion; or F(ab')2, which is a bivalent antigen-binding fragment containing two antigen-binding Fab portions linked together by a disulfide bond; or F(ab') (i.e., a monovalent variant of F(ab')2). Such fragments may also be single-chain variable fragments (scFv).

[0252] In some embodiments, the therapeutic antibody molecule is an antibody used in or intended for cancer therapy. Monoclonal antibodies have been developed for several cancers, and it is likely that more cancers will follow. Some examples include brain cancer, breast cancer, chronic lymphocytic leukemia, colorectal cancer, head and neck cancer, Hodgkin lymphoma, lung cancer, melanoma, non-Hodgkin lymphoma, prostate cancer, and gastric cancer. Some antibodies have been approved for use in different indications. For example, rituximab, an anti-CD20 antibody, has been approved for use in both cancer (NHL and CLL) and autoimmune diseases (rheumatoid arthritis). However, the methods described herein are not limited to antibodies used in cancer therapy or autoimmune / inflammatory disease therapy.

[0253] As described above, in some embodiments, the target is FcγRIIB. In some preferred embodiments, the therapeutic antibody molecule has the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2.

[0254] In these further aspects of the present invention, the intravenous (iv) administration method used to administer a therapeutic antibody molecule to a human may be any type of intravenous administration, such as injection or infusion.

[0255] In these further embodiments of the present invention, the prediction methods described herein utilize mice as a model to predict what will happen in humans. If the therapeutic antibody molecule being tested is cross-reactive with a known mouse homolog of the human target, the therapeutic antibody molecule can be used in the prediction method. If the therapeutic antibody molecule being tested is not cross-reactive with a known mouse homolog of the human target, a surrogate antibody must be used. A surrogate antibody is an antibody specific to the mouse homolog of the human target to which the therapeutic antibody molecule binds. For example, in this context, the mouse homolog of the human target FcγRIIB is mouse FcγRII, the mouse homolog of the human target FcγRIIA is mouse FcγRIII, and the mouse homolog of the human target CD40 is mouse CD40. The surrogate antibody may be a mouse antibody or an antibody derived from another species (e.g., rat, rabbit, monkey, or chicken). Sometimes, it may be preferable to use a surrogate antibody even if the therapeutic antibody molecule being tested is cross-reactive with a known mouse homolog of the human target. This may be because the binding and interaction of the surrogate antibody with mouse target antigens and mouse immunoproteins (e.g., FcγR) that modulate antibody activity better reflects the interaction of the human candidate antibody with human targets and human immunoproteins (e.g., FcγR) that modulate antibody activity, compared to the therapeutic antibody molecule itself. Preferably, and where available, both the cross-reactive therapeutic antibody molecule and the mouse surrogate antibody can be used in parallel with testing for tolerability issues, as described herein.

[0256] In these further embodiments of the present invention, the therapeutic antibody molecule may be an antibody that binds to or does not bind to the Fc receptor. Then, modified forms, i.e., antibody variants with low Fc-FcgR engagement by isotype switching or Fc engineering, can be used. When the surrogate antibody is used to predict or model the tolerance issues of the therapeutic antibody molecule to the same or homologous target, the Fc of the surrogate antibody must be selected to match the Fc of the therapeutic antibody molecule with respect to FcγR binding and functional binding / non-binding (or engagement / non-engagement). For example, it is well known that both human IgG1, IgG3, and IgG4 productively bind to and engage with human FcγR despite having different absolute and relative affinities. Similarly, in mice, mIgG2a binds strongly and broadly to different mouse FcγRs, while mIgG1 binds only to mouse FcγRII and FcγRIII. Furthermore, it is well known that deglycosylation of antibodies, specifically at position 297 (one of the following mutations: N297A, N297Q, or N297G), impairs and / or reduces, or severely reduces, the binding of both human and mouse IgG to FcγR. In this context, Fc binding means that the Fc portion of the therapeutic antibody molecule binds to FcγR, which leads to the involvement of Fc:FcγR-dependent activity or function. Moreover, impaired or inactivated FcγR binding means that the modified form does not bind to FcγR at all, or does not bind to FcγR as strongly as the unmodified therapeutic antibody.

[0257] In these further embodiments of the present invention, the therapeutic antibody molecule or surrogate antibody is administered to mice intravenously or intraperitoneally. In some cases, the dose of the therapeutic antibody molecule or surrogate antibody administered to the mice is a dose that results in high receptor saturation. In some cases, the dose of the therapeutic antibody molecule or surrogate antibody administered to the mice is a dose that results in at least 90% receptor saturation. In some cases, the dose of the therapeutic antibody molecule or surrogate antibody administered to the mice is a dose that results in 100% or near 100% receptor saturation.

[0258] When an antibody is administered to a mouse, the animal will exhibit visual and physical responses, particularly behavioral changes or macroscopic symptoms. If the therapeutic antibody molecule is one that would be associated with tolerance issues related to intravenous administration to humans, the mouse will begin to show isolated macroscopic symptoms and decreased activity very soon after administration of the therapeutic or surrogate antibody (i.e., within minutes, e.g., 5-10 minutes). In some cases, the mouse will also show signs of balance disturbance, piloerection, and / or kyphosis, followed by unnatural posture. These three additional macroscopic symptoms are observed within the same timeframe as isolation and decreased activity, i.e., within minutes (e.g., 5-10 minutes) after administration of the therapeutic or surrogate antibody. The presentation of one, two, or three of these additional macroscopic symptoms is a stronger predictive marker and suggests that a therapeutic antibody molecule that specifically binds to a human target is more likely to be associated with tolerance issues related to intravenous administration to humans compared to the case where the mouse would only show signs of isolation and decreased activity.

[0259] These signs are easily observable and represent a significant change in mouse behavior before administration of a therapeutic or surrogate antibody. Therefore, anyone with experience working with laboratory mice will immediately notice these changes in a mouse's behavior. The symptoms are clearly apparent, and the mouse is obviously unwell. After an approximately one-hour period (e.g., 45 minutes to 1.5 hours) following the injection of the antibody (therapeutic or surrogate antibody), the mouse no longer exhibits macroscopic symptoms. Instead, the antibody's behavior returns to normal, i.e., to its behavior before administration of the antibody (therapeutic or surrogate antibody).

[0260] In addition to the macroscopic symptoms described above, mice may exhibit other symptoms. One such symptom is a decrease in blood pressure. Another such symptom is a decrease in platelet count. Yet another such symptom is an increase in the levels of two liver enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Unlike macroscopic symptoms, these cannot be determined simply by observing the mouse. Instead, they can be determined by blood analysis. To confirm these "non-macroscopic" symptoms, blood is collected from the mouse approximately 5 minutes after injection of an antibody (therapeutic antibody or surrogate antibody). The blood is then analyzed for platelet count and / or AST and / or ALT levels. A decrease in blood pressure can be determined in this way. If blood pressure is decreased, it is impossible to collect blood from the mouse during the period when macroscopic symptoms are present. To determine whether platelet count is decreased and / or AST and / or ALT levels are elevated, blood samples taken from mice before administration of the therapeutic antibody molecule or surrogate antibody can be compared to samples taken from control mice. The decrease in blood pressure recovers within the same timeframe as the macroscopic symptoms. Platelet count, AST levels, and ALT levels take a little longer to recover, normalizing within 6-10 hours (e.g., within 8 hours).

[0261] In these further embodiments of the present invention, the prediction methods described herein can be used to predict whether a therapeutic antibody molecule that specifically binds to a human target is associated with tolerance issues related to intravenous administration to humans.

[0262] Furthermore, in these further embodiments of the present invention, the predictive methods described herein can be used to test strategies for overcoming such tolerance problems. More precisely, a particular strategy can be used to predict whether it can prevent or mitigate tolerance problems associated with the intravenous administration of therapeutic antibody molecules that specifically bind to human targets to humans. This is useful, for example, for therapeutic antibody molecules that are being clinically developed or are already in clinical use where tolerance problems have been observed.

[0263] Furthermore, the prediction methods described herein can be used in these further embodiments of the invention to predict whether a therapeutic antibody molecule that specifically binds to a human target is associated with tolerance issues related to intravenous administration to humans, and to predict whether a particular strategy can prevent or mitigate these tolerance issues. This can be important, for example, when developing drugs, as it enables both the identification of potential problems and the means of finding solutions to those problems.

[0264] If the predictive method described herein, in relation to these further problems of the present invention, is used solely to predict whether a therapeutic antibody molecule that specifically binds to a human target is associated with tolerance issues related to intravenous administration to humans, the method is carried out as described above, along with the administration of the therapeutic antibody or surrogate antibody, followed by observation of mice. Typically, a test group of several mice (e.g., 5-10 mice) rather than just one mouse would be used, and the experiment would be repeated to confirm that any observed changes are representative, reproducible, and statistically significant.

[0265] In these further embodiments of the present invention, if the predictive method described herein is used solely to predict whether a particular strategy can prevent or mitigate tolerability issues associated with the intravenous administration of a therapeutic antibody molecule that specifically binds to a human target to humans, or in addition to that, the method is performed on control mice, or preferably a group of control mice (e.g., 5 to 10 mice). In addition, a second group of mice, or preferably a second group of mice (e.g., 5 to 10 mice), is treated according to the particular strategy to be tested. The results of the second group of mice are compared with the results of the control mice or group of control mice.

[0266] Examples of strategies to overcome tolerability issues arising in connection with the intravenous administration of therapeutic antibody molecules to humans include different prophylactic measures, different therapeutic measures, changes in the route of administration, and / or modifications of the therapeutic antibody molecule. By testing such strategies described herein, data can be obtained that can be used to predict whether the particular strategy can prevent or mitigate tolerability issues that may arise in connection with the intravenous administration of a particular therapeutic antibody molecule to humans. Thus, reliable data can be obtained without testing the effects of different strategies on humans who will first experience tolerability issues.

[0267] If the strategy to overcome tolerance issues is a prophylactic measure, the prophylactic agent is administered to a second mouse or second mouse group prior to the intravenous or intraperitoneal administration of the therapeutic antibody or surrogate antibody to the mouse or mouse group. Thus, this strategy is a pretreatment with a prophylactic agent. The second mouse or second mouse group is observed during the period immediately following the administration of the therapeutic antibody or surrogate antibody. The results of the second mouse or second mouse group are compared to the results of control mice or control mice that were not administered the prophylactic agent. A reduction in the presentation of macroscopic symptoms in the second mouse or second mouse group, or the absence of macroscopic symptoms in the second mouse or second mouse group, compared to the control mice or control mouse group during that period, indicates that the administration of a prophylactic agent can prevent or mitigate tolerance issues that may be associated with the intravenous administration of therapeutic antibody molecules to humans.

[0268] The preventive agents tested in this manner may be any agent known to prevent or mitigate tolerance issues, or any agent that has been assumed or screened for its ability to help mitigate tolerance issues.

[0269] In some embodiments of these further aspects of the present invention, the prophylactic treatment is a corticosteroid pretreatment. In some such embodiments, the pretreatment comprises two doses of a corticosteroid. The corticosteroid is preferably a potent corticosteroid, and more preferably a corticosteroid with the highest possible or available efficacy. Examples of such corticosteroids are dexamethasone and betamethasone.

[0270] When pretreatment with a corticosteroid such as dexamethasone or betamethasone is used, it may include two doses of the corticosteroid before administration of the therapeutic antibody or surrogate antibody. In some such embodiments, one dose of the corticosteroid is administered 10 to 48 hours before administration of the therapeutic antibody or surrogate antibody, and the other is administered 5 minutes to 5 hours before administration of the therapeutic antibody or surrogate antibody. In some such embodiments, one dose of the corticosteroid is administered 6 to 36 hours before administration of the therapeutic antibody or surrogate antibody, and the other is administered 15 to 120 minutes before administration of the therapeutic antibody or surrogate antibody. In some such embodiments, the first dose of the corticosteroid is administered 16 to 24 hours before administration of the therapeutic antibody or surrogate antibody. In some such embodiments, the second dose of the corticosteroid is administered 30 to 60 minutes before administration of the therapeutic antibody or surrogate antibody.

[0271] If the strategy to overcome tolerance issues is a therapeutic measure, this may be done by administering a therapeutic agent to a second mouse or second group of mice, and concurrently administering a therapeutic antibody or surrogate antibody intravenously or intraperitoneally to the mouse or group of mice. In this context, concurrently means essentially simultaneously or immediately afterward. The second mouse or second group of mice is observed during the period immediately following the administration of the therapeutic antibody or surrogate antibody. The results of the second mouse or second group of mice are compared to the results of control mice or control mouse groups that were not administered the therapeutic agent. A reduction in the presentation of macroscopic symptoms in the second mouse or second group of mice, or the absence of the presentation of macroscopic symptoms in the second mouse or second group of mice, compared to control mice or control mouse groups during that period, indicates that the administration of a therapeutic agent can prevent or mitigate tolerance issues that may be associated with the intravenous administration of therapeutic antibody molecules to humans.

[0272] The therapeutic agents tested in this manner may be any agents or drugs known to reverse or control adverse events. These include immunomodulatory agents such as antibodies, for example, anti-IL-6 antibodies known for their use in cytokine release syndrome (Frey NV, Porter DL. Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2016;2016:567-572), or immunosuppressants and / or anti-inflammatory agents such as corticosteroids and antihistamines.

[0273] If the strategy for overcoming tolerance issues involves a different route of administration, the therapeutic antibody or surrogate antibody is administered to a second mouse or second mouse group via a route other than intravenous or intraperitoneal administration. The second mouse or second mouse group is observed for the period immediately following the administration of the therapeutic antibody or surrogate antibody. The results of the second mouse or second mouse group are compared to the results of control mice or control mouse groups administered the therapeutic antibody or surrogate antibody via intravenous or intraperitoneal administration. A reduction in the presentation of macroscopic symptoms in the second mouse or second mouse group, or the absence of macroscopic symptoms in the second mouse or second mouse group, compared to the control mice or control mouse group during that period, indicates that the administration of therapeutic antibody molecules to humans via routes other than intravenous or intraperitoneal administration can prevent or mitigate tolerance issues that may be associated with intravenous administration of therapeutic antibody molecules to humans.

[0274] The administration route tested in this manner may be any route known to those skilled in the art, which is suitable for administering therapeutic antibody molecules to humans and is also feasible for administering therapeutic antibodies or surrogate antibodies to mice.

[0275] In some embodiments of these further aspects of the present invention, a different route of administration (i.e., a route of administration other than intravenous or intraperitoneal administration) is subcutaneous administration. The therapeutic antibody or surrogate antibody then needs to be prepared or formulated for subcutaneous administration to a second mouse or a second group of mice.

[0276] If a strategy to overcome tolerance issues involves using a modified form of the therapeutic antibody or surrogate antibody, this modified form is administered intravenously or intraperitoneally to a second group of mice. The second group of mice is observed during the period immediately following administration of the modified therapeutic antibody or surrogate antibody. The results of the second group of mice are compared to those of control mice or control mice administered with the unmodified therapeutic antibody or surrogate antibody via intravenous or intraperitoneal administration. A reduction in the presentation of macroscopic symptoms in the second group of mice, or the absence of macroscopic symptoms in the second group of mice, compared to the control mice or control mice, during that period, indicates that the administration of a modified therapeutic antibody molecule to humans can prevent or mitigate tolerance issues that may be associated with intravenous administration of therapeutic antibody molecules to humans.

[0277] Modifications to therapeutic antibody molecules tested in this manner may be any known or unknown modifications that cause fewer or milder toxic events in humans. For example, if a therapeutic antibody molecule that has been found to be associated with tolerance issues related to intravenous administration to humans is an antibody that engages the Fc receptor, such modifications may be made to modify the antibody so that it does not engage the Fc receptor, or so that FcγR binding is impaired or inactivated compared to the unmodified therapeutic antibody, while the Fv variable sequence of the modified antibody remains the same as that of the therapeutic antibody molecule. As described above, the Fc of the surrogate antibody must be selected to match that of the therapeutic antibody molecule in terms of FcγR binding and binding / unbinding (or involvement / non-involvement) of function.

[0278] In some embodiments of these further aspects of the present invention, the modification is one that results in increased involvement of the Fc receptor.

[0279] It is possible to simultaneously test two or more of the above strategies, or one or more variants of the above strategies, by further including mice or groups of mice (one mouse or group of mice for each strategy, or each variant of a strategy).

[0280] Further aspects of the present invention also describe corticosteroids for use in drug regimens for preventing or mitigating tolerance issues associated with intravenous administration of therapeutic antibody molecules to a subject, and methods for preventing or mitigating tolerance issues associated with intravenous administration of therapeutic antibody molecules to a subject, including drug regimens for administering corticosteroids to a subject.

[0281] In these further embodiments of the present invention, the therapeutic antibody molecule may be one that is predicted to be associated with tolerability issues related to intravenous administration to humans, using the prediction method described above. Additionally or alternatively, corticosteroid pretreatment in combination with administration of the therapeutic antibody molecule to humans using the prediction method described above may have been used to predict that the tolerability issues would be prevented or mitigated and otherwise likely to be associated with intravenous administration of the therapeutic antibody molecule to humans.

[0282] The drug regimen includes administering corticosteroids to the subject in at least two doses prior to the intravenous administration of the therapeutic antibody molecule. One dose of corticosteroid ("first dose") is administered 10 to 48 hours before the initiation of administration of the therapeutic antibody molecule, and another dose of corticosteroid ("second dose") is administered 5 minutes to 5 hours before the initiation of administration of the therapeutic antibody molecule. In addition to these two doses, further doses may be used, such as one dose prior to the "first dose" and / or one dose between the "first dose" and the "second dose". In many cases, the patient receives several doses of the therapeutic antibody molecule during the entire therapy. The two doses of corticosteroids may then be administered to the patient in connection with one or more doses of the therapeutic antibody molecule. Preferably, the two doses are administered to the patient in connection with each dose of the therapeutic antibody molecule.

[0283] In some cases, the first dose of corticosteroids is administered 6 to 36 hours before the start of administration of the therapeutic antibody molecule, and the second dose of corticosteroids is administered immediately before the start of administration of the therapeutic antibody molecule. In this context, "immediately before" means approximately 15 to 120 minutes before the start of administration of the therapeutic antibody molecule.

[0284] In some cases, the first dose of corticosteroids is administered 8 to 30 hours before the start of administration of the therapeutic antibody molecule.

[0285] In some cases, the first dose of corticosteroids is administered 16 to 24 hours before the start of administration of the therapeutic antibody molecule.

[0286] In some cases, a second dose of corticosteroids is administered 30 to 60 minutes before the start of administration of the therapeutic antibody molecule.

[0287] In some cases, the first dose of corticosteroids is administered 16 to 24 hours before the start of administration of the therapeutic antibody molecule, and the second dose of corticosteroids is administered 30 to 60 minutes before the start of administration of the therapeutic antibody molecule.

[0288] In some cases, the medication regimen includes the administration of at least two doses of corticosteroids before each antibody infusion during the course of antibody therapy.

[0289] The corticosteroid used is preferably a potent corticosteroid, and more preferably a corticosteroid with the highest possible or available efficacy. Examples of such corticosteroids are dexamethasone and betamethasone. Either dexamethasone or betamethasone, or a combination of dexamethasone and betamethasone, may be used.

[0290] In some cases, when dexamethasone is used, the first dose is 4-20 mg. In some cases, when dexamethasone is used, the second dose is 4-25 mg. In some cases, when dexamethasone is used, the first dose is 4-20 mg and the second dose is 4-25 mg. In some cases, when dexamethasone is used, the first dose is 10-12 mg.

[0291] In some cases, when dexamethasone is used, the second dose is 20 mg. In some cases, when dexamethasone is used, the first dose is 10-12 mg and the second dose is 20 mg. In some cases, when betamethasone is used, the first dose is 3.2-16 mg. In some cases, when betamethasone is used, the second dose is 3.2-20 mg.

[0292] In some cases, when betamethasone is used, the first dose is 3.2-16 mg and the second dose is 3.2-20 mg. In some cases, when betamethasone is used, the first dose is 8-9.6 mg. In some cases, when betamethasone is used, the second dose is 16 mg. In some cases, when betamethasone is used, the first dose is 8-9.6 mg and the second dose is 16 mg.

[0293] In some cases, the medication regimen includes the administration of antihistamines in addition to at least two doses of corticosteroids. In some cases, antihistamines are administered 10 minutes to 24 hours before the start of administration of the therapeutic antibody molecule. In some cases, antihistamines are administered 30 to 60 minutes before the start of administration of the therapeutic antibody molecule.

[0294] Therapeutic antibody molecules are used, for example, with corticosteroids to prevent or mitigate tolerability issues associated with intravenous administration, and are sometimes Fc receptor-binding antibodies. In some cases, it is an anti-FcγRIIB antibody. In some cases, it is an anti-FcγRIIB antibody in which the antibody has a light chain of SEQ ID NO: 1 and a heavy chain of SEQ ID NO: 2.

[0295] A thirteenth aspect of the present invention also describes a therapeutic antibody molecule for use in the treatment of cancer, wherein the therapeutic antibody molecule is formulated for subcutaneous administration in order to prevent or mitigate tolerance issues that may arise in connection with the intravenous administration of the therapeutic antibody molecule to a subject, and a method for treating cancer comprising subcutaneous administration of the therapeutic antibody instead of intravenous administration in order to prevent or mitigate tolerance issues.

[0296] In some cases, the therapeutic antibody molecule formulated for subcutaneous administration is an anti-FcγRIIB antibody. In some such cases, the therapeutic antibody molecule is an antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2.

[0297] A fourteenth aspect of the present invention also describes a modified therapeutic antibody molecule for use in the treatment of cancer, wherein the modification of the therapeutic antibody molecule is made to prevent or mitigate tolerance issues that may arise in connection with the intravenous administration of the therapeutic antibody molecule to a subject, and a method for treating cancer comprising the administration of such modified therapeutic antibody.

[0298] Modifications to the therapeutic antibody molecules used may be any modifications known to cause fewer or milder toxic events in humans.

[0299] As described above, modifications of therapeutic antibodies may be previously unknown modifications that cause fewer or milder toxic events in humans, and have been tested using the predictive models described herein and found to be useful in preventing or mitigating tolerability issues that may arise in connection with the intravenous administration of therapeutic antibody molecules to subjects.

[0300] As mentioned above, in the case of a therapeutic antibody molecule that is involved with the Fc receptor and has been found to be associated with tolerability issues related to intravenous administration to humans, the modification used in this context may be to modify the antibody so that it is not involved with the Fc receptor, or so that the FcγR binding is impaired or inactivated compared to the unmodified therapeutic antibody, but the Fv variable sequence of the modified antibody remains the same as that of the therapeutic antibody molecule.

[0301] Therefore, in some such cases, the therapeutic antibody molecule is an Fc receptor-binding antibody, and the modified form is an antibody that has the same Fv variable sequence but in which the FcγR binding is impaired or inactivated compared to the therapeutic antibody molecule. In some cases, the therapeutic antibody is an FcγRIIB antibody, which is an Fc receptor-binding antibody, and in some such cases, the modified form is an anti-FcγRIIB antibody, which has the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 195.

[0302] In some cases, anti-FcgRIIB antibodies are used as monotherapy. In other cases, they are used to enhance the activity of other therapeutic antibodies whose activity is regulated by FcgRs (e.g., anti-CD20 or anti-PD-1) or to overcome resistance.

[0303] Regarding combination therapy with anti-CD20 antibodies, anti-FcgRIIB may be used in the treatment of both cancer and inflammatory / autoimmune diseases for which anti-CD20 antibodies are approved for therapy. As used herein, the term "subject" refers to a person diagnosed with a particular disease. Herein, the terms "subject" and "patient" are used interchangeably.

[0304] In some cases, the subject has been diagnosed with cancer. In some cases, the cancer is a B-cell malignancy. In some cases, the cancer is selected from a group consisting of follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, or non-Hodgkin lymphomas such as chronic lymphocytic leukemia.

[0305] In some cases, the tolerability issue that can be prevented or mitigated is thrombocytopenia (a decrease in platelets). In some such cases, it is transient thrombocytopenia.

[0306] In some cases, the tolerability issue that can be prevented or mitigated is cytokine release syndrome. In some such cases, it is transient cytokine release.

[0307] In some cases, the tolerability issue that can be prevented or mitigated is elevated liver enzymes. In some such cases, this is elevated levels of aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT).

[0308] In a fifteenth aspect of the present invention, a therapeutic antibody molecule is provided for use in the treatment of cancer, autoimmune diseases, inflammatory diseases, immune diseases, and / or infectious diseases, wherein the therapeutic antibody molecule is an anti-FcγRIIB antibody, and the therapeutic antibody molecule is formulated for subcutaneous administration.

[0309] In a sixteenth aspect of the present invention, a therapeutic antibody molecule is provided for the manufacture of a pharmaceutical product for use in the treatment of cancer, autoimmune diseases, inflammatory diseases, immune diseases, and / or infectious diseases, wherein the therapeutic antibody molecule is an anti-FcγRIIB antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2, and the pharmaceutical product is formulated for subcutaneous administration.

[0310] In a 17th aspect of the present invention, a pharmaceutical formulation is provided comprising a therapeutic antibody molecule, wherein the therapeutic antibody molecule is an anti-FcγRIIB antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2, and comprises a pharmaceutically acceptable diluent or excipient, and is formulated for subcutaneous administration.

[0311] Preferably, the therapeutic antibody in these embodiments of the present invention is an Fc receptor-binding antibody. More preferably, the therapeutic antibody is an anti-FcγRIIB antibody.

[0312] In alternative embodiments of these aspects of the present invention, the therapeutic antibody molecule is one described herein in any of the prior embodiments of the present invention.

[0313] However, in a preferred embodiment, the pharmaceutical composition comprises a therapeutic antibody molecule having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2 (this antibody is represented as BI-1206 as described herein). Preferably, the therapeutic antibody molecule comprises the light chain of SEQ ID NO: 1, the heavy chain of SEQ ID NO: 2, and the constant regions of SEQ ID NOs: 202 and 203.

[0314] Therefore, the present invention also provides: -A therapeutic antibody molecule for use in the treatment of cancer, wherein the therapeutic antibody molecule is an anti-FcγRIIB antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2, and the therapeutic antibody molecule is formulated for subcutaneous administration. - Use of a therapeutic antibody molecule in the manufacture of a pharmaceutical product for use in the treatment of cancer, wherein the therapeutic antibody molecule is an anti-FcγRIIB antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2, and the therapeutic antibody molecule and / or pharmaceutical product are formulated for subcutaneous administration, - A pharmaceutical formulation comprising a therapeutic antibody molecule, wherein the therapeutic antibody molecule is an anti-FcγRIIB antibody as defined herein (preferably an anti-FcγRIIB antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2), and the pharmaceutical formulation comprises a pharmaceutically acceptable diluent or excipient and is formulated for subcutaneous administration.

[0315] Preferably, the therapeutic antibody molecule for use, the use of the therapeutic antibody molecule, or the pharmaceutical preparation according to the above aspects of the present invention (including aspects 15, 16, and 17 of the present invention) is for the treatment of cancer.

[0316] It will be understood that the pharmaceutical formulations of these embodiments of the present invention contain a therapeutically effective dose of a therapeutic antibody. Preferably, the therapeutic antibody is present at a concentration of about 90 mg / mL to about 220 mg / mL. For example, the therapeutic antibody may be present at a concentration of about 90 mg / mL, or about 100 mg / mL, or about 110 mg / mL, or about 120 mg / mL, or about 130 mg / mL, or about 140 mg / mL, about 150 mg / mL, or about 160 mg / mL, or about 170 mg / mL, about 180 mg / mL, or about 190 mg / mL, or about 200 mg / mL, about 210 mg / mL, or about 220 mg / mL. A concentration of about 150 mg / mL is particularly preferred.

[0317] The pharmaceutical formulations of these embodiments of the present invention are preferably sterile.

[0318] In preferred embodiments, the pharmaceutical formulations of these aspects of the present invention further comprise about 5 mM to about 20 mM of acetate (for example, about 10 mM of acetate or about 15 mM of acetate). Particularly preferred is about 5 mM of acetate.

[0319] In preferred embodiments, the pharmaceutical formulations of these embodiments of the present invention further comprise about 50 mM to about 250 mM NaCl, for example, about 60 mM NaCl, or about 70 mM NaCl, or about 80 mM NaCl, or about 90 mM NaCl, or about 100 mM NaCl, or about 110 mM NaCl, or about 120 mM NaCl, or about 130 mM NaCl, or about 140 mM NaCl, or about 150 mM NaCl, or about 160 mM NaCl, or about 170 mM NaCl, or about 180 mM NaCl, or about 190 mM NaCl, or about 200 mM NaCl, or about 210 mM NaCl, or about 220 mM NaCl. Particularly preferred is about 110 mM NaCl.

[0320] In preferred embodiments, the pharmaceutical formulations of these aspects of the present invention further comprise about 0.05% (w / v) polysorbate 20, for example, Tween 20 (polysorbate) EMPROVE® ESSENTIAL Ph Eur, JPE, NF from Merck / Sigma-Aldrich (catalog no. 8.17072.1000).

[0321] In preferred embodiments, the pharmaceutical formulations of these embodiments of the present invention have a pH of approximately 5.0 to approximately 5.8, for example, approximately 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, or 5.7. Particularly preferred is a pH of approximately 5.8.

[0322] In particularly preferred embodiments, the pharmaceutical formulations of these aspects of the present invention include or consist of: - Therapeutic antibody at a concentration of -150 mg / mL, -5 mM acetate, -110 mM NaCl, -0.05% (w / v) polysorbate 20, and pH 5.8.

[0323] In an eighteenth aspect of the present invention, a method is provided for the treatment of cancer, autoimmune diseases, inflammatory diseases, immune diseases, and / or infectious diseases in a subject, the method comprising the step of administering a therapeutic antibody molecule to the subject, wherein the therapeutic antibody molecule is an Fc receptor-binding antibody, and the therapeutic antibody molecule is formulated for subcutaneous administration.

[0324] Preferably, in the 18th aspect of the present invention, the Fc receptor-binding antibody is an anti-FcγRIIB antibody. More preferably, the Fc receptor-binding antibody is an anti-FcγRIIB antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2.

[0325] Therefore, in a preferred embodiment, the present invention provides the following: - A method for treating cancer, autoimmune disease, inflammatory disease, immune disease, and / or infectious disease in a subject, comprising the step of administering a therapeutic antibody molecule to the subject, wherein the therapeutic antibody molecule is an anti-FcγRIIB antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2, and the therapeutic antibody molecule is formulated for subcutaneous administration. In the 18th aspect of the present invention, it should be understood that the therapeutic antibody is preferably administered to the subject via a subcutaneous route.

[0326] A 19th aspect of the present invention provides a method for treating cancer, autoimmune diseases, inflammatory diseases, immune diseases, and / or infectious diseases in a subject, the method comprising the step of administering a pharmaceutical formulation of the 17th aspect of the present invention to the subject. In the 19th aspect of the present invention, it should be understood that the pharmaceutical formulation is preferably administered to the subject by a subcutaneous route. The method is preferably for the treatment of cancer.

[0327] Herein, preferred non-limiting embodiments that embody a particular aspect of the present invention will be described with reference to the following drawings and examples. [Brief explanation of the drawing]

[0328] [Figure 1]A mouse model that replicates the BI-1206 tolerance profile. When a mouse surrogate anti-CD32b antibody (AT-130-2 IgG2a) is injected intravenously (iv) or intraperitoneally (ip) into wild-type C57 / BL6 mice, the mice exhibit a response that replicates the clinical tolerance profile of BI-1206. A. The percentage of mice that exhibit macroscopic IRR (Internal Reaction Responsibility) after injection, such as isolation, decreased activity, balance disorders, piloerection, kyphosis, and subsequent unnatural posture, is shown. When intravenous doses were titrated, the same timing and severity of macroscopic symptoms were observed up to 10 mg (0.5 mg / kg). However, no IRR was observed at 4 mg (0.2 mg / kg). When 200 mg (10 mg / kg) was administered intraperitoneally, IRR appeared 20-30 minutes after injection, showing a delay in the onset of IRR compared to intravenous injection. However, when the intraperitoneal dose was increased to 400 mg (20 mg / kg), the onset of IRR was still delayed compared to the intravenous injection route, but all mice showed IRR of the same degree and grade as the 200 mg intravenous dose. All mice had fully recovered 1 hour after injection. B. Analysis of fresh blood PLT (platelet count) using Vetscan revealed that mice showing IRR (gray bars) also showed a decrease in platelet count. C. Analysis of blood samples for AST showed an increase in the group administered 200 ug of anti-CD32b antibody intravenously. D. Time course of IL-6 levels in the blood of mice injected intraperitoneally with 200 ug of anti-CD32b antibody after injection. A peak was seen 1 hour after injection, and the level returned to normal 8 hours after injection (gray area). Similar patterns were observed for IL-5, IL-10, KC / GRO, and TNF-α. [Figure 2]Premedication with two doses of corticosteroids dose-dependently blocks or reduces the IRR in vivo. Mice were pre-treated with either A: 40 mg / kg or B: 10 mg / kg betamethasone 24 hours and 1 hour prior to intravenous injection of AT-130-2 IgG2a (premedication). Blood was collected from the mice 20 minutes after injection. Blood was analyzed for platelet count. Premedication with 10 mg / kg betamethasone did not completely inhibit the IRR or showed a decrease in platelet count B (striped bars), suggesting that reducing the premedication dose may inhibit the IRR and decrease the platelet count. [Figure 3] Divided dose-based premedication of a small amount of Ab reduces the severity of IRR and decreases platelet count. A. Intravenous divided doses of 8 μg / mouse anti-CD32B AT-130-2 IgG2a were initiated, followed 1 hour later by a bulk dose of 200 μg / mouse. In parallel, mice were injected with the bulk dose only. IRR was tested (visualized in the figure according to the grading system in B), platelet count and body temperature were measured and compared. Small premedication of AT-130 (8 ug) reduces the severity / protection against IRR, thrombocytopenia, and hypothermia when administered with a large / main dose (200 ug). The gray area indicates the normal range for PLT (platelet count in the blood) and body temperature. The premedication should be 8 ug (the dose at which IRR is observed in 50% of mice C), and lower doses are not protective. [Figure 4]Complete (antibody) tolerance and protection against IRR require a combination of steroid premedication and divided antibody dosing. Divided dosing was initiated in one of the following ways: 24 hours after suboptimal corticosteroid treatment (10 mg / kg), or without corticosteroid premedication, intravenous administration of 8 μg / mouse anti-CD32B AT-130-2 IgG2a, followed 1 hour later by a bulk dose of 200 μg / mouse. In parallel, mice were injected with the bulk dose only. IRR was tested, and platelet count and body temperature were measured and compared. If a “low dose” of corticosteroid (10 mg / kg) was administered 24 hours prior, a small predose of AT-130 (8 ug) is well tolerated. Suboptimal premedication with a small predose of AT-130 (8 ug) provides complete protection from the IRR and thrombocytopenia associated with a large Ab dose (200 ug). The suboptimal dose of corticosteroids (10 mg / kg) itself is not protective. The gray area indicates the normal range for PLT and body temperature. [Figure 5] Premedication with several different clinically relevant substances did not inhibit IRR associated with AT-130-2 IgG2a administration. In this model, mice were premedicated with anti-PAF, anti-IL6, antihistamine, or leukotriene antagonists to evaluate whether premedication with substances commonly used clinically to treat IRR could inhibit it. These premedications were administered intraperitoneally one hour before intravenous injection of mouse anti-CD32B AT-130-2 IgG2a as a bulk dose of 200 ug / mouse. Mice were observed for macroscopic IRR (e.g., isolation, motility, and fur condition). None of these premedications inhibited IRR. [Figure 6]Tolerability profile observed in human subjects with non-Hodgkin B-cell lymphoma after administration of BI-1206 at doses of 70-100 mg. (A) Thrombocytopenia after treatment with BI-1206. The decrease was transient, with most episodes resolving within one week, and none involving serious bleeding or bleeding-related events. Each point represents the measured value and median line. The vertical stripe indicates administration of BI-1206. (B) Thrombocytopenia is associated with elevated ALT. Elevated ALT / AST was significant in only 3 out of 14 patients. (C) Frequency of detected cytokine elevation after treatment with BI-1206. Transient cytokine release was detected in 7 out of 8 subjects for which serum / plasma was available for analysis. The peak of cytokine release was observed immediately after infusion and always disappeared within 24 hours. (D) Dynamics of thrombocytopenia, ALT, and cytokine elevation are illustrated by individual 504-001. Cytokines are illustrated here by IL-6. [Figure 7]FcgRIIb receptor occupancy translates to B cell depletion. Clinical data are consistent with preclinical data from an in vivo model using hFcgRIIB transgenic mice, where sustained receptor saturation is required to achieve sustained B lymphocyte depletion. Two doses of corticosteroids prior to administration of anti-FcgRIIb mAb, and a small pre-dose of mAb (divided dose), improve tolerability (IRR). FcgRIIb receptor occupancy at the peripheral B cell level (A) and peripheral B cell level (B) in human subjects with non-Hodgkin B-cell lymphoma treated with 100 mg BI-1206 monotherapy. FcgRIIb receptor occupancy (E) and peripheral B cell depletion (F) in hFcgRIIB transgenic mice after intravenous administration of escalating doses of BI-1206. (C) Grade of infusion-related response (IRR) in human subjects with non-Hodgkin B-cell lymphoma treated with 70-100 mg of BI-1206. Dark gray bars with black symbols indicate administration without premedication with two doses of corticosteroids, while light gray bars and hollow white symbols indicate administration with premedication with two doses of corticosteroids. The X-axis shows the subject's ID and the antibody dose. (D) Significantly lower frequency and severity of IRR are observed after premedication with two doses of corticosteroids in the clinical protocol. Black symbols indicate administration without two doses of corticosteroids, gray symbols indicate administration with two doses of corticosteroids. P<0.0001 using the Mann-Whitney U test. (G) Infusion-related response after intravenous administration of anti-FcgRIIb mAb (AT-130-2 mIgG2a) in wild-type mice. Dose titrations show that an Ab IRR of 0.4 mg / kg occurs in approximately 50% of animals, and intravenous doses exceeding the IRR are observed in 100% of animals. Premedication with two 40 mg / kg doses of betapred completely blocks the IRR, but two 40 mg / kg doses of betapred partially block the IRR. Suboptimal premedication with 10 mg / kg of betapred in divided doses blocks the IRR. The divided dose is a small predication dose of 0.4 mg / kg of Ab followed by a larger dose of 10 mg / kg of Ab.(H) Improved tolerability and sustained efficacy are observed after the administration of two doses of corticosteroid premedication in the clinical protocol. CR: complete response, PR: partial response, SD: stable disease, DLT: dose-limiting toxicity. [Figure 8] Transient FcγRIIB receptor occupancy and peripheral lymphocyte depletion after BI-1206 infusion. Figure 8A) In subjects (n=8) administered 100 mg of BI-1206, FcγRIIB receptor occupancy on peripheral B cells was tracked over time after BI-1206 infusion. Vertical dashed lines represent BI-1206 infusions. Receptor occupancy data for the second and third BI-1206 infusions are only available before infusion. Lines represent the median. Based on preliminary data. Figure 8B) In subjects (n=9) administered 100 mg of BI-1206, peripheral lymphocytes were tracked over time after BI-1206 infusion. Vertical dashed lines represent BI-1206 infusions. Lines represent the median. Based on preliminary data. [Figure 9] Transient platelet counts are associated with an increase in ALT after BI-1206 infusion. Figure 9A) Platelet counts were tracked over time after BI-1206 infusion in subjects administered 70-100 mg of BI-1206 (n=16). Vertical dashed lines represent BI-1206 infusions. Lines represent the median. Based on preliminary data. Figure 9B) ALT multiplier increase compared to thrombocytopenia percentage (n=16). Changes are calculated in relation to day 1 before BI-1206 infusion. Based on preliminary data. [Figure 10] Cytokine release after BI-1206 infusion. Number of patients with increased plasma / serum levels of different cytokines detected at the end of BI-1206 infusion. To be considered positive, an increase of more than 10 times compared to pre-infusion levels and more than 10 times above the upper limit of normal (ULN) range were required. Samples for analysis were available from 5 subjects who received 70 mg or more of BI-1206. Based on preliminary data. [Figure 11]In two subjects treated with BI-1206, two doses of dexamethasone mitigated IRR, thrombocytopenia, and transaminases. Platelet count and ALT in subjects 501-001 (Figure 11A) and 503-002 (Figure 11B). Vertical dashed lines represent antibody infusions. The initial infusion in each subject was rituximab alone, followed by BI-1206 and rituximab. The IRR grade at each antibody infusion is shown. During induction therapy, subjects 501-001 and 503-002 received 12 mg and 4 mg of dexamethasone, respectively, in the evening prior to the third dose of BI-1206 (70 mg), and another 20 mg of dexamethasone 30 minutes prior. Neither subject experienced an IRR after this two-dose dexamethasone premedication regimen. In subjects 501-001 and 503-002, premedication with two doses of dexamethasone (20 mg) administered just 30 minutes prior to the infusion resulted in an IRR (grade 2-3) during the two preceding infusions with BI-1206. In addition, subjects 501-001 and 503-002 showed no or minimal thrombocytopenia when premedicated with two doses of dexamethasone, and no increase in ALT / AST was observed after BI-1206 administration. [Figure 12]Macroscopic symptoms after injection of mouse surrogate anti-CD32b (AT-130-2 IgG2a). Wild-type C57 / BL6 mice were injected with mouse surrogate anti-CD32b (AT-130-2 IgG2a) via three different injection routes: intravenous (iv), intraperitoneal (ip), or subcutaneous (sc). Macroscopic symptoms were observed after intravenous and intraperitoneal injections. These symptoms included isolation, decreased activity, balance disorders, piloerection, kyphosis, and subsequent unnatural postures. Macroscopic symptoms were scored from 0 to 2 based on observation. Titration of intravenous doses revealed a rapid onset of IRR 5–7 minutes after injection. Macroscopic symptoms of the same timing and severity were observed up to 10 μg (0.5 mg / kg). However, no macroscopic symptoms were observed at 1 μg (0.05 mg / kg). Intraperitoneal administration of 200 μg (10 mg / kg) resulted in a delayed onset of macroscopic symptoms compared to intravenous injection, with symptoms appearing 20-30 minutes after injection. In contrast to the intravenous injection route, all mice in this group showed no macroscopic symptoms, and some mice showed milder symptoms. Increasing the intraperitoneal dose to 400 μg (20 mg / kg) still delayed the onset of macroscopic symptoms compared to the intravenous injection route, but all mice showed macroscopic symptoms to the same degree and grade as with 200 μg intravenous administration. All mice had fully recovered 1 hour after injection. Finally, subcutaneous administration of 200 μg to mice did not result in macroscopic symptoms (up to 24 hours after injection). Increasing the subcutaneous dose to 400 μg did not affect the mice. [Figure 13]Pharmacokinetic profiles of AT-130-2 IgG2a in C57BL / 6 mice. Serum concentrations of AT-130-2 observed in mice treated with AT-130 via three different administration routes (200 μg AT-130-2 by intravenous injection, 200 μg AT-130-2 by intraperitoneal injection, and 400 μg AT-130-2 by subcutaneous injection). Presented data are mean values ​​for 1-4 mice / dose group. Abbreviations: h = time, ip = intraperitoneal, iv = intravenous, sc = subcutaneous. It should be noted that complete and sustained FcgRIIB receptor saturation is achieved subcutaneously, but is achieved with subcutaneous administration of AT130 as described below. CMax is low, and kinetics to achieve complete saturation are slower compared to intravenous or intraperitoneal administration. [Figure 14] Correlation between macroscopic symptoms (represented as IRR in this figure) and rapid exposure to AT-130-2, rather than FcγRIIB saturation time. Serum concentrations of AT-130-2 IgG2a (dotted lines) were plotted against the grade of macroscopic symptoms (squared lines) for different administration routes (A: intravenous, B: intraperitoneal, and C: subcutaneous). Comparing serum concentrations of AT-130-2 and estimated receptor occupancy (RO) (dotted lines, 100% receptor saturation at 10 mg / ml) with the onset, severity, and duration of IRR, a correlation is clearly observed between high and rapid exposure to AT-130-2, rather than FcγRIIB saturation time. Tolerability showed a clear pattern of subcutaneous > intraperitoneal > intravenous, with RO being maintained for a long period after recovery of macroscopic symptoms. [Figure 15A]The timing of the lowest platelet (PLT) count correlates with the administration route and the time to FcγRIIB saturation. Blood samples were collected from mice at different time points after AT-130-2 IgG2a injection, and the blood was analyzed for platelet count (PLT) using automated Vetcount. The lowest platelet count was observed simultaneously with the onset of macroscopic symptoms after AT-130-2 injection via both intravenous and intraperitoneal routes. For the subcutaneous administration route, where no macroscopic symptoms were observed, a moderate decrease was seen 10 hours after injection, correlating with the time to FcγRIIB saturation by PK. In all cases, the decrease in PLT was transient and recovered to normal levels within 8 hours after injection. Mice exhibiting macroscopic symptoms are indicated by filled-in bars. [Figure 15B] This study demonstrates that using the subcutaneous administration route avoids the increase in transaminases after injection of AT-130-2 IgG2a. Blood samples were collected from mice after injection of AT-130-2 IgG2a, and the blood was analyzed for transaminases. For the intravenous administration route, an increase in transaminases (AST) was observed 1 hour after the onset of macroscopic symptoms (previously established as the time of peak transaminases). For the subcutaneous administration route, where no macroscopic symptoms were observed, no increase in transaminases was observed 11 hours after injection (1 hour after the saturation time of FcγRIIB by PK (10 hours)). [Figure 16]Transient thrombocytopenia, transaminases, and cytokine release following administration of AT-130-2 IgG2a. Blood samples were collected from mice at different time points after intraperitoneal injection of 200 μg of AT-130-2, and the blood was analyzed for platelet count (Figure 16A), transaminases (Figure 16B), and cytokines (Figure 16C). A transient decrease in PLT count was observed, which fully recovered 8 hours after injection (Figure 16A). Increases in transaminases (AST and ALT), peaking 1 hour after injection, were the only clinical chemistry parameters affected by AT-130-2 injection (Figure 16B). These increases, like the decrease in PLT, were transient. The same transient increases were observed with intravenous injection of AT-130-2. No increase in transaminases was detected with subcutaneous injection of AT-130-2 (data not shown). A panel of cytokines, including the analytes IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, KC / GRO, and TNF-α, was analyzed at different time points after a 200 mg intraperitoneal injection. Of the analyzed cytokines, IL-5, IL-6, IL-10, KC / GRO, and TNF-α all showed transient increases, except for IL-5, which peaked 1–3 hours after injection (Figure 16C). IL-5 showed a delayed peak 3–8 hours after injection (Figure 16C). These are the same cytokines that have been shown to increase in some patients in clinical trials using BI-1206. [Figure 17]Premedication with two doses of corticosteroids inhibits macroscopic symptoms associated with AT-130-2 IgG2a administration. Mice were either pre-treated with 40 mg / kg betamethasone 24 hours and 1 hour prior to administration, or left untreated before intravenous injection of 10 mg / kg AT-130-2 IgG2a. Mice were observed for macroscopic symptoms (Figure 17A), and blood was collected 20 minutes after injection. Blood was analyzed for platelet count (Figure 17B), transaminases (Figure 17C), and cytokines. Premedication with betamethasone completely inhibited macroscopic symptoms (Figure 17A), reduced platelet count (Figure 17B), and decreased transaminases (Figure 17C). Transient cytokine release observed after intravenous injection of AT-130-2 was also inhibited by premedication (data not shown). The same results were observed when dexamethasone was used (data not shown). [Figure 18] The dosage of premedication is important. Mice were pre-treated with either 40 mg / kg or 10 mg / kg betamethasone 24 hours and 1 hour (premedication) before intravenous injection of 10 mg / kg AT-130-2 IgG2a. Mice were observed for macroscopic symptoms (Figure 18A), and blood was collected 20 minutes after injection. Blood was analyzed for platelet count (Figure 18B). Premedication with 10 mg / kg betamethasone did not completely inhibit macroscopic symptoms (Figure 18A) or platelet count reduction (Figure 18B). This suggests that reducing the premedication dose may reduce the likelihood of inhibiting macroscopic symptoms and platelet count reduction. [Figure 19]Steroid premedication one hour prior to infusion is insufficient to inhibit the IRR. Mice were pre-treated with 40 mg / kg betamethasone 24 hours, 1 hour, or 24 hours + 1 hour prior to intravenous injection of 10 mg / kg AT-130-2 IgG2a. Mice were observed for macroscopic symptoms (Figure 19A), and blood was collected 10–20 minutes after injection. Blood was analyzed for platelet count (Figure 19B). A single premedication with betamethasone one hour after AT-130-2 injection did not inhibit macroscopic symptoms (Figure 19A) or thrombocytopenia (Figure 19B). A single premedication with betamethasone 24 hours after AT-130-2 injection only reduced macroscopic symptoms to grade 1. This indicates that two steroid treatments are necessary to completely inhibit tolerability issues. [Figure 20] Premedication with antihistamines is insufficient to inhibit the tolerability issues associated with AT-130-2 IgG2a administration. Mice were premedicated with either antihistamines alone or 40 mg / kg betamethasone (24 hours and 1 hour) before intravenous injection of 10 mg / kg of AT-130-2 IgG2a, with or without antihistamines. Mice were observed for macroscopic symptoms (Figure 20A), and blood was collected approximately 20 minutes after injection. Blood was analyzed for platelet count (Figure 20B). Premedication with antihistamines alone did not inhibit macroscopic symptoms (Figure 20A), but did not appear to improve the decrease in platelet count (Figure 20B). Adding an antihistamine to 40 mg / kg betamethasone (24-hour and 1-hour) prior to intravenous injection of 10 mg / kg AT-130-2 IgG2a did not affect macroscopic symptoms or platelet count. The same results were observed with the use of three different types of antihistamines (Zyrlex, Zantac, or Au; data not shown). [Figure 21]This study demonstrates that some, though not all, surrogate antibodies induce IRR. Mouse surrogate anti-CD32b antibody (AT-130-2 mIgG2a), anti-CSFR1 (AFS98 rIgG2a), anti-EGFR (7A7 mIgG2a), anti-CD40 (FGK4.5 rIgG2a), and anti-FcγRIII (AT154-2 mIgG2a) were intravenously injected into wild-type C57 / BL6 mice. IRR was observed after injection of anti-CD32b, anti-CD40, and anti-FcγRIII. IRR included isolation, decreased activity, balance disorders, piloerection, kyphosis, followed by unnatural posture. IRR was scored from 0 to 2 based on observation. No IRR was observed for anti-EGFR or anti-CSFR1. When mice were pre-treated with 40 mg / kg betamethasone 24 hours and 1 hour prior to injection of anti-CD32b or anti-CD40, no IRRs were observed (anti-FcγRIII was not evaluated with pre-medication). This suggests that pre-medication can inhibit IRRs associated with different antibodies and targets. [Figure 22] Antibodies that induce IRR also induce thrombocytopenia. Mouse surrogate anti-CD32b antibody (AT-130-2 mIgG2a), anti-CD40 (FGK4.5 rIgG2a), and anti-FcγRIII (AT154-2 mIgG2a) were intravenously injected into wild-type C57 / BL6 mice. Fresh blood platelet counts were analyzed 20 minutes after injection using Vetscan (Vetscan HM5 Abaxis, Triolab). A decrease in platelet count was observed after injection of anti-CD32b, anti-CD40, and anti-FcγRIII. When mice were pre-treated with 40 mg / kg betamethasone 24 hours and 1 hour prior to anti-CD32b or anti-CD40 injection, no platelet decrease was observed (anti-FcγRIII was not evaluated with premedication). This suggests that premedication can inhibit platelet decrease associated with different antibodies and targets.

[0329] Herein, we will describe certain non-limiting embodiments that embody specific aspects of the present invention. These embodiments should be read in conjunction with the brief description of the drawings provided above. [Examples]

[0330] Example 1 overview Divided-dose regimens combined with corticosteroid pretreatment were evaluated in an in vivo model, and the tolerability profile observed in BI-1206 mice was replicated using BI-1206 mouse surrogate AT-130-2 IgG2a. Divided-dose regimens combined with corticosteroid pretreatment improve the tolerability profile of anti-FCγRIIb treatment. Macroscopic IRR and platelet counts improve with divided dosing. The time span between the first and second doses does not appear to be critical, but the correct timing of corticosteroid pretreatment seems important for complete tolerability of the first dose.

[0331] Materials and methods Test substance The anti-mouse CD32B IgG2a clone AT130-2 was transiently expressed in HEK293 cells. Specificity of the purified study batch was demonstrated by luminescence-based ELISA or FACS analysis. The antibody endotoxin level was found to be <0.1 IU / mL, as determined by the LAL-amebocytosis assay. [Table 2]

[0332] mouse Female C57 / BL6 and BalbC mice aged 6-8 weeks (17-20g) were obtained from Taconic or Janvier. The mice were intravenously administered mouse anti-CD32B AT-130-2 IgG2a at a bulk dose of 200 ug / mouse, or as a divided dose of 8 ug / mouse followed by 200 ug / mouse.

[0333] Premedication For corticosteroid treatment, Betapred (betamethasone, VNR:008938, Alfasigma SPA) was used at 10 mg / kg (this is a suboptimal dose for these mouse models).

[0334] Divided medication Divided dosing was initiated 24 hours after corticosteroid treatment (8 μg / mouse, followed 20-40 minutes later by a bulk dose of 200 μg / mouse of mouse anti-CD32B AT-130-2 IgG2a). In parallel, mice were injected with only the bulk dose.

[0335] Animal monitoring Mice were monitored after injection for behavioral changes such as isolation, motility, and fur condition, as well as macroscopic symptoms. Based on the observations, a macroscopic IRR scoring system of 0-2 was established. [Table 3]

[0336] Body temperature Body temperature was measured using a mouse thermometer 20 minutes after the bulk dose injection.

[0337] Blood sample Blood samples were collected from the saphenous vein 20 minutes after injection of the bulk dose of anti-CD32B for immediate blood cell count analysis. For liver enzyme and cytokine analysis, blood was collected from the aorta of mice under isoflurane anesthesia immediately before euthanasia. Liver enzyme and cytokine samples were collected 1 and 3 hours after the bulk dose, respectively.

[0338] Platelet count Platelet counts in fresh blood were analyzed using Vetscan (Vetscan HM5 Abaxis, Triolab).

[0339] Transaminase Transaminases were analyzed by shipping frozen serum samples to IDEXX BioResearch Vet Med Labor GmbH.

[0340] Results and Discussion Divided-dose regimens combined with corticosteroid pretreatment improve the tolerability profile of anti-CD32b treatment. The tolerability profile of anti-CD32b treatment alone can be seen in Figure 1. Macroscopic IRR and platelet count are improved with divided dosing combined with the initial dose of corticosteroid (Figures 2, 3, and 4). This was evaluated in an in vivo model, and the tolerability profile observed in BI-1206 was reproduced using BI-1206 mouse surrogate AT-130-2 IgG2a. The time span between the first and second doses does not appear to be critical, but the correct timing of corticosteroid pretreatment appears to be important for complete tolerability of the first dose.

[0341] Example 2 overview To evaluate whether pretreatment with other substances commonly used clinically to treat IRR (excluding corticosteroids) could inhibit IRR in this model, the inventors pretreated mice with several other clinically relevant substances. In this model, none of the premedications tested inhibited IRR, suggesting they were not useful in preventing adverse effects associated with BI-1206 administration.

[0342] Materials and methods Test substance The anti-mouse CD32B IgG2a clone AT130-2 was transiently expressed in HEK293 cells. Specificity of the purified study batch was demonstrated by luminescence-based ELISA or FACS analysis. The antibody endotoxin level was found to be <0.1 IU / mL, as determined by the LAL-amebocytosis assay. [Table 4]

[0343] mouse Female C57 / BL6 and BalbC mice aged 6-8 weeks (17-20g) were obtained from Taconic or Janvier. The mice were intravenously administered mouse anti-CD32B AT-130-2 IgG2a at a bulk dose of 200 ug / mouse, or as a divided dose of 8 ug / mouse followed by 200 ug / mouse.

[0344] Premedication For corticosteroid treatment, Betapred (betamethasone, VNR:008938, Alfasigma SPA) was used at 10 mg / kg (this is a suboptimal dose for these mouse models).

[0345] Other premedications evaluated included anti-PAF (CV3988, sc-2015, Santa Cruz 20 mg / kg), anti-IL6 (clone 15A7, BE0047, Bioxcell, 10 mg / kg), antihistamine (Zantac, VNR:077875, GlaxoSmithKline AB, 5 mg / kg), or leukotriene antagonist (131064, Apoex, 4 mg / kg). These premedications were administered intraperitoneally at a bulk dose of 200 ug / mouse one hour before injection of mouse anti-CD32B AT-130-2 IgG2a.

[0346] Divided medication Twenty-four hours after corticosteroid treatment, intravenous fractional administration of 8 μg / mouse anti-CD32B AT-130-2 IgG2a mouse anti-CD32B AT-130-2 IgG2a was initiated, followed 20-40 minutes later by a bulk dose of 200 μg / mouse. In parallel, mice were injected with only the bulk dose.

[0347] Animal monitoring Mice were monitored after injection for behavioral changes such as isolation, motility, and fur condition, as well as macroscopic symptoms. Based on the observations, a macroscopic IRR scoring system of 0-2 was established. [Table 5]

[0348] Body temperature Body temperature was measured using a mouse thermometer 20 minutes after the bulk dose injection.

[0349] Blood sample Blood samples were collected from the saphenous vein 20 minutes after injection of the bulk dose of anti-CD32B for immediate blood cell count analysis. For liver enzyme and cytokine analysis, blood was collected from the aorta of mice under isoflurane anesthesia immediately before euthanasia. Liver enzyme and cytokine samples were collected 1 and 3 hours after the bulk dose, respectively.

[0350] Platelet count Platelet counts in fresh blood were analyzed using Vetscan (Vetscan HM5 Abaxis, Triolab).

[0351] Transaminase Transaminases were analyzed by shipping frozen serum samples to IDEXX BioResearch Vet Med Labor GmbH.

[0352] Results and Discussion As shown in Figure 5, in this mouse model, none of the tested substances (anti-PAF, anti-IL-6, antihistamine, and leukotriene antagonist) were able to prevent IRR associated with AT-130-2 administration. This suggests that only corticosteroids as pretreatment can provide the protective effect described in Example 1. This finding is surprising considering that all of these substances are commonly used clinically to treat IRR associated with other therapeutic antibodies.

[0353] Example 3 overview Intravenous administration of BI-1206 is frequently associated with IRR, thrombocytopenia, and transient cytokine spikes, and, less frequently but in the most severe cases, is clearly associated with increased liver enzymes (Figure 6). Therefore, it is advantageous if a drug regimen can be used that can prevent or mitigate these adverse effects. It is also clear that in patients with non-Hodgkin lymphoma, FcγRIIb receptor occupancy leads to B cell depletion (which correlates with in vivo data from mouse models), and therefore sustained receptor saturation is important for sustained B lymphocyte depletion, but achieving such sustainably high receptor occupancy necessary for therapeutic benefit from intravenous injection is associated with high levels of IRR (Figure 7).

[0354] Materials and methods Platelet count, ALT concentration, and IRR grading Platelet counts, ALT concentrations, and IRR grading were obtained from clinical settings, analyzed and reported according to local standard procedures. All data described from clinical trials are preliminary, partially quality-controlled, and should be considered as representing the pharmacodynamic effects and tolerability associated with BI-1206.

[0355] FcgRIIb receptor occupancy Human FcgRIIb receptor occupancy and hFcgRIIb transgenic mice were analyzed using flow cytometry. Whole blood was incubated with either 005-C05 antibody (targeting hFcgRIIb) or anti-hCD32-AF647 antibody. 005-C05 binds to the same epitope as BI-1206, but with much lower affinity. For the analysis, the geometric mean (Geo Mean) of mAbs (005-C05 and anti-human CD32), respectively, was obtained for the CD19+ cell population. Receptor occupancy (RO) was calculated using the following formula: RO(%) = ((Total receptors - Normalized free receptors) * 100) / Total receptors. Then, all replicas of the 005-C05 geometric mean in CD19+ cells were multiplied by a normalization factor.

[0356] Cytokine analysis For cytokine concentrations, frozen plasma samples were thawed and diluted 2-fold and 8-fold. Cytokines were analyzed in two parallel sets: a pro-inflammatory assay (MesoScale Discovery (MSD) #K15049) containing IL-6, IL-8, TNF-α, IFN-γ, IL-10, IL-2, and IL-4, and a chemokine assay (MSD #K15067) containing MIP-1β, IL-1β, IL-23, IL-12p70, TARC, and VEGF. The assays followed the manufacturer's protocol, as briefly outlined below: 50 μL of sample and calibration standard was added to a suitable MSD plate and incubated. After washing, 25 μL of SULFO-TAG detection antibody mixture was added to each well of the corresponding plate. The plates were analyzed using a QuickPlex SQ120 reader instrument (MSD), and cytokine concentrations were calculated using MSD software (Discovery Workbench, 2013; version LSR-4-0-12).

[0357] B cell depletion in hFcgRIIb transgenic mice B cell depletion in hFcgRIIb transgenic mice was analyzed using flow cytometry with commercially available anitobodies.

[0358] Results and Discussion As shown in Figure 6, intravenous administration of BI-1206 is clearly associated with increased IRR, thrombocytopenia, transient spikes in cytokines, and, less frequently but in the most severe cases, increased liver enzymes. As shown in Figure 7, achieving such persistently high receptor occupancy, necessary for therapeutic benefit, is associated with high levels of IRR.

[0359] Example 4 In Examples 4A and 4B, an antibody designated BI-1206 is used. This antibody has the following light and heavy chains. Light chain: QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYADDHRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCASWDDSQRAVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS(Sequence ID 1) Heavy chain: EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWMAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELYDAFDIWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(Sequence ID 2)

[0360] In the modified form of BI-1206, the glycosylation site at N297 (marked in bold above) is mutated to Q (marked in bold below) (i.e., the N297Q mutation), resulting in the following heavy chain. EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWMAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELYDAFDIWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(Sequence ID 195)

[0361] As surrogate and control antibodies, the anti-mouse CD32B antibody AT130-2 as the IgG2a isotype and the control antibody AT130-2 N297A as the IgG1 isotype are used below. AT130-2 as the IgG2a isotype is commercially available, for example, from ThermoFisher Scientific (as catalog number 12-0321-82), but since #12-0321-82 is a PE conjugate, the antibody needs to be modified to be non-conjugated. AT130-2 N297A as the IgG1 isotype can be produced by any known method, which involves substituting the N at position 297 (as identified above) with A.

[0362] Example 4A - Target: FcγRIIB background BioInvent International AB has developed BI-1206, a therapeutic monoclonal antibody with antitumor activity, which can be used as monotherapy or in combination with anti-CD20 targeted therapies or other clinically validated checkpoint inhibitors. BI-1206 binds with high specificity to CD32B (FcγRIIB) and is currently being evaluated in two Phase I / IIa clinical trials, CRUKD / 16 / 001 and 17-BI-1206-02, to treat patients with chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (B-cell NHL). All data below from clinical trials are preliminary, partially quality-controlled, and should be considered as indicating the pharmacodynamic effects and tolerability associated with BI-1206. Some data are based on personal communications with individual principal investigators.

[0363] To date, BI-1206 at doses up to 100 mg has been administered to 24 human subjects, either as monotherapy or in combination with rituximab. 100 mg of BI-1206 induced transient receptor saturation on peripheral B cells, maintaining 100% or near-100% receptor occupancy for up to 48 hours (Figure 8). Correspondingly, transient depletion of peripheral B lymphocytes was observed, recovering within approximately 7 days (Figure 8). This is consistent with preclinical in vivo models using hFcγRIIB mice, where sustained receptor saturation has been demonstrated to achieve sustained B lymphocyte depletion.

[0364] Frequent infusion-related reactions (IRRs) were observed during BI-1206 infusion in human subjects (Figure 7A). Administration of BI-1206 at doses of 50 mg or higher was also associated with a transient decrease in platelets (Figure 9). The thrombocytopenia was not severe and was not associated with bleeding, and most episodes resolved within one week. There appeared to be a correlation between the decrease in platelets and elevated transaminases (i.e., alanine transaminases (ALT) and aspartate transaminases (AST)), with increases in ALT and AST being significant in 3 out of 16 subjects who received BI-1206 at doses of 70 mg or higher (Figure 9).

[0365] Furthermore, transient cytokine release was observed in 5 out of 5 subjects who received 70 mg or more of BI-1206, for which plasma or serum was available for analysis. Cytokine release included macrophage inflammatory protein (MIP)-1β, tumor necrosis factor (TNF)-α, interleukin (IL)-10, IL-8, IL-6, and IL-4, with peaks observed immediately after infusion, and cytokine levels consistently normalized within 24 hours (Figure 10). Cytokine release was not associated with clinical symptoms.

[0366] In clinical trial 17-BI-1206-02, 16 subjects received BI-1206 at doses ranging from 70 to 100 mg, totaling 58 doses at these levels. 46 of these doses were administered after the implementation of in vivo protective corticosteroid-based premedication regimens identified in animal models (Figures 7C and 7H). Clinical implementation of premedication regimens identified in in vivo animal models resulted in a statistically significant reduction in the severity and frequency of IRR in human cancer patients (Figures 7D and 7H).

[0367] Subjects 501-001 and 503-002 received 12 mg and 4 mg of dexamethasone, respectively, in the evening prior to the third dose of BI-1206 (70 mg) during induction therapy, and another 20 mg of dexamethasone 30 minutes prior. After this premedication regimen using these two doses of dexamethasone, neither subject experienced an IRR (Internal Rate of Reaction). However, during the two preceding infusions with BI-1206, where dexamethasone (20 mg) was administered just 30 minutes prior to the infusion, subjects 501-001 and 503-002 experienced no or minimal thrombocytopenia after premedication with two doses of dexamethasone, and no increase in ALT / AST was observed after BI-1206 administration (Figure 11). The third group (201-003) received nine doses of 30 mg of BI-1206 (four doses in the induction phase and five doses in the maintenance phase) and repeatedly experienced IRRs. For the tenth dose of BI-1206, two doses of dexamethasone were used as premedication, and the IRR improved to grade 1. No thrombocytopenia or increase in ALT / AST was observed in group 201-003, which received the low dose of BI-1206 (30 mg). Importantly, consistent with FcgRIIB receptor saturation, which determines treatment efficacy, treatment efficacy was maintained after the implementation of the clinical premedication regimen. Both complete and partial responses were observed in patients after the premedication regimen was incorporated into the clinical protocol (Figure 7H).

[0368] Materials and methods Test substance and control substance Anti-mouse CD32B IgG2a clone AT130-2 and a control antibody (AT130-2 N297A) were transiently expressed in HEK293 cells. Specificity of the purified study batch was demonstrated by luminescence-based enzyme-linked immunosorbent assay (ELISA) or flow cytometry analysis. The antibody endotoxin levels were found to be <0.1 IU / mL, as determined by the LAL-amebocytocyte assay. [Table 6]

[0369] mouse Female C57 / BL6 mice aged 6-8 weeks (17-20g) were obtained from Taconic. The mice were injected intravenously (iv), intraperitoneally (ip), or subcutaneously (sc) with mouse anti-CD32B AT-130-2 IgG2a at doses ranging from 1 μg to 400 μg / mouse.

[0370] Premedication For corticosteroid treatment, Betapred (betamethasone, VNR: 008938, Alfasigma SPA) or dexamethasone (catalog number: S1322, batch number: 02, Selleckchem) was used. For antihistamine treatment, Zyrlex (10 mg / ml, VNR: 523084, MACURE PHARMA ApS), Zantac (25 mg / ml, VNR: 077875, GlaxoSmithKline AB), or Aeurius (0.5 mg / ml, VNR: 097288, Merck Sharp & Dohme BV) was used.

[0371] Animal monitoring Mice were monitored after injection for behavioral changes such as isolation, motility, and fur condition, as well as macroscopic symptoms. A macroscopic IRR scoring system of 0–2 was established based on the following observations. [Table 7]

[0372] Blood sample Blood samples were collected from the saphenous vein for immediate blood cell count analysis. For serum AT130-2 concentration, liver enzyme, and cytokine analysis, mice were given blood samples from the aorta under isoflurane anesthesia immediately before euthanasia.

[0373] Serum concentration of AT130-2 Serum concentrations of AT130-2 mAb were quantified using sandwich ELISA. Recombinant CD32B protein (Sino Biological #50030-M08H) was used as a coating. Diluted samples were added to ELISA plates, incubated, and washed, followed by detection via HRP-conjugated polyclonal donkey anti-mouse IgG Ab (Jackson #715-035-151). Subsequently, plates were read using a Tecan Ultra microplate reader with a picochemiluminescent substrate (ThermoFisher #37069).

[0374] Platelet count Platelet counts in fresh blood were analyzed using Vetscan (Vetscan HM5 Abaxis, Triolab).

[0375] Transaminase Transaminases were analyzed by shipping frozen serum samples to IDEXX BioResearch Vet Med Labor GmbH.

[0376] Cytokine To study the potential contribution of injection-related responses (IRRs) in mice, cytokine release associated with intraperitoneal injection of AT-130-2 mAb was evaluated at selected time points. Once frozen, serum samples were thawed and diluted 2-fold or 4-fold. Cytokines were analyzed using the V-plex pro-inflammatory panel 1 mouse kit (MesoScale Discovery #K15048D), which includes the analytes interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, KC / GRO, and tumor necrosis factor (TNF)-α. The assay followed the manufacturer's protocol, as briefly outlined below: 50 μL of sample and calibration standard was added to an MSD plate and incubated. After washing, 25 μL of SULFO-TAG detection antibody mixture was added to each well of the corresponding plate. The plates were analyzed using a QuickPlex SQ120 reader instrument (MSD), and cytokine concentrations were calculated using MSD software (Discovery Workbench, 2013; version LSR-4-0-12).

[0377] result Macroscopic symptoms after mouse surrogate anti-CD32b IgG2a (AT-130-2) administration. A mouse surrogate anti-CD32b (AT-130-2 IgG2a) was injected into wild-type C57 / BL6 mice via three different injection routes: intravenous (iv), intraperitoneal (ip), or subcutaneous (sc). At a dose of 200 μg (corresponding to 10 mg / kg), a rapid onset of infusion-related reactions (IRRs) was observed 5–7 minutes after intravenous injection. These IRRs included isolation, decreased activity, balance disturbances, piloerection, kyphosis, and subsequent unnatural postures. Blood sampling from these mice showed decreased blood pressure. 10–15 minutes after the onset of IRRs, these mice began to recover, and no macroscopic symptoms were observed 1 hour after injection.

[0378] When intravenous doses were titrated, the same timing and severity of macroscopic symptoms were observed up to 10 μg (0.5 mg / kg). However, no internal rate of response (IRR) was observed at 1 μg (0.05 mg / kg) (Figure 12).

[0379] When the same dose of 200 μg (10 mg / kg) was administered intraperitoneally, an IRR (Internal Reaction Rate) appeared 20-30 minutes after injection, indicating a delay in the onset of IRR. In contrast to the intravenous injection route, all mice in this group did not show IRR, and in some mice, the IRR was milder (Figure 12).

[0380] However, when the intraperitoneal dose was increased to 400 μg (20 mg / kg), the onset of IRR was still delayed compared to the intravenous injection route, but all mice exhibited IRR to the same degree and grade as with the 200 μg intravenous administration (Figure 12). All mice had fully recovered one hour after injection.

[0381] Finally, when 200 μg was administered subcutaneously to mice, no macroscopic symptoms were observed (up to 24 hours after injection). Increasing the subcutaneous dose to 400 μg did not affect the mice (Figure 12).

[0382] Intravenous administration of AT-130-2 IgG1 N297A, an Fc-null version of AT-130-2, did not result in an internal response rate (IRR), indicating that Fc binding is necessary to induce symptoms associated with AT-130-2.

[0383] The pharmacokinetic profile of AT-130-2 was evaluated for intravenous, intraperitoneal, and subcutaneous injection (Figure 13).

[0384] Comparing pharmacokinetics (PK) and estimated receptor occupancy (RO, based on separate experiments not shown herein that demonstrated 10 μg / ml gave 100% receptor saturation) with the onset, severity, and duration of IRR, it is clear that there is a correlation between high and rapid exposure to AT-130-2, rather than the saturation time of FcγRIIB. Tolerability shows a clear pattern of subcutaneous > intraperitoneal > intravenous, with RO being maintained for a long period after IRR recovery (Figure 14).

[0385] Platelets, transaminases, cytokines To investigate whether the IRR observed in these mice was associated with other parameters observed in clinical trials of BI-1206 mice, blood was collected at the time of IRR onset and analyzed for blood cell counts, clinical chemistry parameters, and cytokines. In the case of subcutaneous injection, no IRR occurred, and blood was collected from mice at different time points after injection. A decrease in platelet count (PLT) was observed simultaneously with the onset of IRR after injection of AT-130-2 via both intravenous and intraperitoneal administration routes (Figure 15A). In the case of subcutaneous administration, only a moderate decrease was observed 10 hours after injection (Figure 15A). In all cases, the decrease in PLT was transient and recovered to within the normal range within 8 hours after injection (data for 200 μg of AT-130-2 administered intraperitoneally is shown in Figure 16A). Subcutaneous administration of AT-130-2 IgG2a avoids the increase in transaminases observed after intravenous injection. For intravenous administration, an increase in transaminase (AST) was observed one hour after the onset of macroscopic symptoms (this was previously established as the point at which the peak value of transaminase was reached). However, no macroscopic symptoms were observed with subcutaneous administration. More specifically, as shown in Figure 15B, no increase in transaminase was observed 11 hours after injection (one hour after the saturation time of FcγRIIB by PK (10 hours)).

[0386] Regarding clinical chemistry parameters, the only parameters affected by AT-130-2 injection were the increase in transaminases (AST and ALT), which peaked one hour after injection. These increases were similar to the transient decrease in PLT (Figure 16B). The same transient increase was observed when AT-130-2 was administered intravenously. No increase in transaminases was detected when AT-130-2 was administered subcutaneously.

[0387] A panel of cytokines, including the analytes IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, KC / GRO, and TNF-α, was analyzed at different time points after 200 μg intraperitoneal injection. Of all the cytokines analyzed, IL-5, IL-6, IL-10, KC / GRO, and TNF-α showed transient increases 1–3 hours after injection, with the exception of IL-5 (Figure 16C). IL-5 showed a delayed peak 3–8 hours after injection (Figure 16C). These were the same cytokines that had been shown to increase in some patients in clinical trials using BI-1206.

[0388] Premedication To investigate whether corticosteroid premedication could inhibit the IRR and associated toxicity of AT-130-2, mice were premedicated with 40 mg / kg betamethasone 16–24 hours and 1 hour prior to AT-130-2 injection. Both the IRR and thrombocytopenia observed with AT-130-2 were completely inhibited by premedication (Figures 17A–B). Furthermore, the increase in hepatic transaminase and cytokine release was not significantly severe (Figure 17C and data not shown). The same effect was observed when evaluating another corticosteroid, dexamethasone (data not shown).

[0389] To evaluate the importance of the dose of corticosteroid treatment, the following experiment reduced the betamethasone dose from 40 mg / kg to 10 mg / kg (Figure 18). At 10 mg / kg, both IRR and platelet count reductions were observed in half of the mice, indicating that high doses of corticosteroids are required to completely block IRR and associated toxicity (Figure 18).

[0390] Furthermore, the importance of two doses of corticosteroid treatment was investigated by comparing the protective effects of premedication administered only early (1 hour before injection) or only late (24 hours before injection) with two doses of corticosteroid treatment. Premedication administered 1 hour before injection failed to suppress the decrease in IRR or platelet count (Figure 19). Premedication administered 24 hours before injection reduced IRR and platelet count, but did not completely block these symptoms (Figure 19). This indicates that two doses of corticosteroid are necessary to completely block IRR.

[0391] Finally, the effect of antihistamines, a standard premedication in clinical trials, was evaluated. Premedication with antihistamines alone did not inhibit IRR or thrombocytopenia. The protective effect was maintained when antihistamine premedication was combined with two doses of corticosteroid treatment (Figure 20). These results were confirmed for three different types of antihistamines (Zyrlex, Zantac, and Aeurius).

[0392] conclusion Our data demonstrate an in vivo model using intravenous (iv) or intraperitoneal (ip) administration of anti-FcγRIIB mIgG2a surrogate (AT-130-2) in wild-type mice, replicating the tolerability profile observed in BI-1206, including decreased IRR, decreased platelet count, elevated transaminases (i.e., ALT and AST), and transient cytokine release. The IRR appears 5–20 minutes after AT-130-2 injection and is accompanied by macroscopic symptoms including isolation, decreased activity, balance disturbances, piloerection, kyphosis, unnatural posture, and decreased blood pressure. The visual and physical reactions are transient, and the animals recover completely 1 hour after antibody administration. The macroscopic symptoms are accompanied by decreased platelet count and elevated transaminases, which normalize within 8 hours. Cytokine release is acute and transient, including IL-6, IL-5, IL-10, TNFα, and KC / GRO (a rodent homolog of human IL-8). The cytokine profile and kinetics are comparable to those observed after BI-1206 in human subjects. In mouse models, there is a clear correlation between high and rapid exposure to IRR, rather than FcγRIIB saturation time, and subcutaneous (sc) administration of AT-130-2 is better tolerated than intraperitoneal and intravenous administration. The timing of symptom onset correlates with the serum concentration at which receptor saturation is achieved. However, when antibody doses that achieve receptor saturation for more than 6 days are administered, animals recover from all symptoms within 24 hours. Sustained FcγRIIB blockade itself does not appear to be the cause of IRR.

[0393] In this model, premedication with two doses of corticosteroids (dexamethasone or betamethasone) inhibits macroscopic IRR, as well as thrombocytopenia and elevated transaminases. The two doses are administered subcutaneously 30-60 minutes before antibody administration and intravenously 16-24 hours before antibody administration. Prevention of macroscopic symptoms in mice by corticosteroids is dose-dependent, and importantly, the timing of premedication is crucial. A dose administered 16-24 hours before antibody administration is essential to achieve protective effects. When corticosteroids are administered only 30-60 minutes before antibody administration, no protective effect on macroscopic symptoms is observed, but a dose administered 16-24 hours before antibody administration alone partially improves tolerability. When both doses are administered, inhibition of macroscopic symptoms, thrombocytopenia, elevated transaminases, and cytokine release is achieved.

[0394] The administration of corticosteroid-based regimens to human patients, as identified in mouse models, protected them from IRRs and allowed for higher doses, which is likely related to the stronger antitumor activity of the studied anti-FcgRIIB antibodies.

[0395] Example 4B - Other Targets Materials and methods Test substance and control substance Anti-mouse CD32b clones were transiently expressed in HEK293 cells. Batch specificity was demonstrated by luminescence-based enzyme-linked immunosorbent assay (ELISA) or flow cytometry analysis. The antibody endotoxin levels were found to be <0.1 IU / mL, as determined by the LAL-amebocytocyte assay. Anti-mouse CD40, EGFR, and CSFR1 antibodies were purchased from BioXcell or Absolute Antibody (see table below), and the anti-mouse FcγRIII antibody AT154-2 was donated by the University of Southampton. Alternatively, AT154-2 may be purchased as a rat IgG2b isotype from, for example, BioRad, Argio Biolaboratories (ARG23942), or LSBio (LS-C745656), and then converted to the IgG2a form using any known method. [Table 8]

[0396] mouse Female C57 / BL6 mice aged 6-8 weeks (17-20g) were obtained from Taconic. The mice were intravenously injected with 200 μg / mouse doses of different antibodies.

[0397] Premedication For corticosteroid treatment, Betapred (betamethasone, VNR: 008938, Alfasigma SPA) or dexamethasone (catalog number: S1322, batch number: 02, Selleckchem) was used.

[0398] Animal monitoring Mice were monitored after injection for behavioral changes such as isolation, motility, and fur condition, as well as macroscopic symptoms. A macroscopic IRR scoring system of 0–2 was established based on the following observations. [Table 9]

[0399] Blood sample Blood samples were collected from the saphenous vein for immediate blood cell count analysis.

[0400] Platelet count Platelet counts in fresh blood were analyzed using Vetscan (Vetscan HM5 Abaxis, Triolab).

[0401] conclusion This example demonstrates that the model described herein can distinguish between antibody molecules that induce tolerability issues and those that do not. It further demonstrates that premedication can inhibit IRRs associated with different antibodies and targets.

[0402] This embodiment also demonstrates that antibodies that induce IRR also induce thrombocytopenia. It further shows that premedication can inhibit thrombocytopenia associated with different antibodies and targets.

[0403] Embodiments of the present invention Specific embodiments of the present invention are described with reference to the following numbered paragraphs.

[0404] 1. A therapeutic system for improving the tolerance of antibody molecules that specifically bind to FcyRllb in a target, (i) An antibody molecule that specifically binds to FcyRllb, wherein the antibody molecule is administered to a subject in at least a first dose and a second dose, (ii) corticosteroids and, The first dose of the antibody molecule is lower than the maximum therapeutic dose of the antibody molecule. A therapeutic system in which corticosteroids are administered to the target before the first dose of the antibody molecule.

[0405] 2. A combination comprising an antibody molecule and a corticosteroid for use in a drug regimen to improve the tolerance of the antibody molecule that specifically binds to FcyRllb in a target, wherein the drug regimen comprises the following steps: (i) The step of administering a corticosteroid before administering the first dose of the antibody molecule, (ii) The step of administering a first dose of an antibody molecule that specifically binds to FcyRllb, which is lower than the maximum therapeutic effective dose, (iii) A combination comprising the step of administering a second dose of an antibody molecule that specifically binds to FcyRllb, wherein a first dose of the antibody molecule is administered before the second dose.

[0406] 3. (i) An antibody molecule that specifically binds to FcyRllb, (ii) Use of corticosteroids, In the manufacture of a pharmaceutical product for improving the tolerability of an antibody molecule that specifically binds to FcyRllb in a target, the pharmaceutical product comprises at least a first dose and a second dose of the antibody molecule, The first dose of the antibody molecule is lower than the maximum therapeutic dose of the antibody molecule. Corticosteroids are administered before the first dose of the antibody molecule.

[0407] 4. A method for improving the tolerance of an antibody molecule that specifically binds to FcyRllb in a target, (i) Before administering the first dose of the antibody molecule, administer a corticosteroid, (ii) Administering a first dose of an antibody molecule that specifically binds to FcyRllb, which is lower than the maximum therapeutic dose. (iii) A method comprising administering a second dose of an antibody molecule that specifically binds to FcyRllb, wherein a first dose of the antibody molecule is administered before the second dose.

[0408] 5. The systems, combinations for use, uses, or methods described in paragraphs 1-4, further comprising the administration of one or more therapeutic antibodies for the treatment of cancer in a subject.

[0409] 6. The system, combination for use, use, or method described in paragraph 5, wherein the therapeutic antibody is selected from rituximab, pembrolizumab, nivolumab, semiprimab, camrelizumab, dostallimab, obinutuzumab, ofatumumab, and their biosimilars or equivalents.

[0410] 7. The system, combination for use, use, or method described in paragraphs 1-6, wherein a corticosteroid is administered to the subject 10 minutes to 48 hours prior to the first dose of an antibody molecule that specifically binds to FcyRllb.

[0411] 8. The system, combination for use, use, or method described in paragraph 7, wherein a corticosteroid is administered to the subject 10 minutes to 24 hours prior to the first dose of an antibody molecule that specifically binds to FcyRllb.

[0412] 9. The system, combination for use, use, or method described in paragraphs 1-6, wherein a corticosteroid is administered as a first dose and a second dose, the first dose of the corticosteroid being administered 16 to 48 hours prior to the first dose of the antibody molecule that specifically binds to FcyRllb, and the second dose of the corticosteroid being administered 10 minutes to 2 hours prior to the first dose of the antibody molecule that specifically binds to FcyRllb.

[0413] 10. The system, combination for use, use, or method described in paragraph 9, wherein an additional dose of corticosteroid is administered 16 to 48 hours prior to a second dose of an antibody molecule that specifically binds to FcyRllb.

[0414] 11. The system, combination for use, use, or method described in paragraphs 1-10, wherein a first dose of an antibody molecule that specifically binds to FcyRllb is administered 1 to 24 hours prior to a second dose of an antibody molecule that specifically binds to FcyRllb.

[0415] 12. The system, combination for use, use, or method described in paragraphs 1-10, wherein a first dose of an antibody molecule that specifically binds to FcyRllb is administered approximately one hour before a second dose of an antibody molecule that specifically binds to FcyRllb.

[0416] 13. The system, combination for use, use, or method described in paragraphs 1-10, wherein a first dose of an antibody molecule that specifically binds to FcyRllb is administered approximately 24 hours before a second dose of an antibody molecule that specifically binds to FcyRllb.

[0417] 14. The system, combination for use, use, or method described in paragraphs 1 to 10, wherein a first dose of an antibody molecule that specifically binds to FcyRllb is administered 24 to 48 hours prior to a second dose of an antibody molecule that specifically binds to FcyRllb.

[0418] 15. A system, combination for use, use, or method of use described in paragraphs 1-14, in which a corticosteroid is administered in a dose of 4 mg or more.

[0419] 16. A system, combination for use, use, or method of use described in paragraphs 1 to 15, wherein a corticosteroid is administered in a dose of 12 mg or more.

[0420] 17. The systems, combinations for use, uses, or methods described in paragraphs 1 to 14, in which corticosteroids are administered in doses of 4 mg to 20 mg.

[0421] 18. The system, combination for use, use, or method of use described in paragraph 17, wherein corticosteroids are administered in doses of 12 mg to 20 mg.

[0422] 19. The system, combination for use, use, or method of use described in paragraph 17, wherein corticosteroids are administered in doses of 4 mg to 12 mg.

[0423] 20. The systems, combinations for use, uses, or methods described in paragraphs 1 to 19, wherein the corticosteroid is dexamethasone or betamethasone, or a combination of dexamethasone and betamethasone.

[0424] 21. A system, combination for use, use, or method described in paragraphs 1-20, wherein the first dose of an antibody molecule that specifically binds to FcyRllb is lower than the maximum permissible therapeutic dose.

[0425] 22. A system, combination for use, use, or method described in paragraphs 1-21, wherein the first dose of an antibody molecule that specifically binds to FcyRllb is at least 50% lower than the maximum therapeutically effective dose.

[0426] 23. The system, combination for use, use, or method described in paragraphs 1 to 22, wherein the first dose of an antibody molecule that specifically binds to FcyRllb is administered at a dose of 0.2 mg / kg to 0.6 mg / kg.

[0427] 24. The system, combination for use, use, or method described in paragraph 23, wherein the first dose of an antibody molecule that specifically binds to FcyRllb is administered at a dose of 0.3 mg / kg to 0.5 mg / kg.

[0428] 25. The system, combination for use, use, or method described in paragraphs 1 to 24, wherein the first dose of an antibody molecule that specifically binds to FcyRllb is administered in doses of 20 mg to 40 mg.

[0429] 26. The system, combination for use, use, or method described in paragraph 25, wherein a first dose of an antibody molecule that specifically binds to FcyRllb is administered at a dose of approximately 30 mg.

[0430] 27. The system, combination for use, use, or method described in paragraphs 1-26, wherein a second dose of an antibody molecule that specifically binds to FcyRllb is the therapeutically effective dose.

[0431] 28. The system, combination for use, use, or method described in paragraphs 1 to 27, wherein the second dose of the antibody molecule that specifically binds to FcyRllb is the maximum permissible therapeutic dose or the maximum administerable therapeutic dose.

[0432] 29. A system, combination for use, use, or method described in paragraphs 1-27, wherein a second dose of an antibody molecule that specifically binds to FcyRllb is lower than the therapeutically effective dose.

[0433] 30. The system, combination for use, use, or method described in paragraphs 1-29, wherein a second dose of an antibody molecule specifically binding to FcyRllb is administered to the subject, followed by a further additional dose of an antibody molecule specifically binding to FcyRllb.

[0434] 31. The systems, combinations for use, uses, or methods described in paragraphs 1-30, wherein injection-related reactions associated with the administration of an antibody molecule that specifically binds to FcyRllb are reduced or eliminated.

[0435] 32. A system, combination for use, use, or method described in paragraphs 1 to 31, wherein changes in the subject's body temperature and / or platelet count and / or blood levels of liver enzymes are reduced (preferably to an acceptable level) at least 24 hours after administration of a second dose of an antibody molecule that specifically binds to FcyRllb.

[0436] 33. The system, combination for use, use, or method described in paragraphs 1 to 32, wherein an antibody molecule that specifically binds to FcyRllb can bind to one or more Fcγ receptors via its Fc region.

[0437] 34. The system, combination for use, use, or method described in paragraphs 1 to 33, wherein the antibody molecule that specifically binds to FcyRllb has the light chain sequence of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2.

[0438] 35. The system, combination for use, use, or method described in paragraphs 1 to 34, wherein first and second doses of an antibody molecule specifically binding to FcyRllb are formulated for intravenous delivery to a subject.

[0439] 36. A system, combination for use, use, or method of use described in paragraphs 1 to 35, wherein a corticosteroid is formulated for intravenous or oral delivery to a subject.

[0440] 37. It is a kit, (i) an antibody molecule that specifically binds to FcyRllb, optionally an antibody molecule as defined in paragraphs 33 and / or 34, (ii) Corticosteroids, optionally, one of the corticosteroids defined in paragraphs 15-20, (iii) optionally including instructions for use, A kit comprising an antibody molecule provided as a first dose and a second dose, wherein the first dose of the antibody molecule is lower than the maximum therapeutically effective dose of the antibody molecule, and optionally, the first dose is as defined in paragraphs 11-14 and 21-26, and optionally, the second dose is as defined in paragraphs 27-29.

[0441] 38. The kit described in paragraph 37, wherein the kit is for improving the tolerance of antibody molecules in a subject.

[0442] 39. The kit according to paragraph 37 or 38, wherein a corticosteroid is provided in a dose defined in any one of paragraphs 12-17.

[0443] 40. The kit described in paragraphs 37-39, wherein the kit further comprises one or more therapeutic antibodies.

[0444] 41. The kit described in paragraph 40, wherein the therapeutic antibody is selected from rituximab, pembrolizumab, nivolumab, semiprimab, camrelizumab, dostallimab, obinutuzumab, ofatumumab, and their biosimilars or equivalents.

[0445] 42. The kit described in paragraph 40 or 41, wherein the kit is intended for use in the treatment of cancer in a subject.

[0446] 43. Systems, combinations for use, uses, methods, or kits substantially described herein, with reference to the description and drawings.

[0447] 44. A method for predicting whether a therapeutic antibody molecule that specifically binds to a human target is associated with tolerability issues related to intravenous administration to humans, comprising the following steps: (i) In the case of cross-reactivity with mouse target or surrogate antibodies, a step of administering a therapeutic antibody molecule intravenously or intraperitoneally to a mouse, and observing the mouse during the period immediately following the administration of the therapeutic antibody or surrogate antibody, wherein the presentation of isolated macroscopic symptoms and decreased activity during the period following the recovery of the mouse's condition to a normal state indicates that intravenous administration of the therapeutic antibody molecule to humans would be associated with tolerability issues; The process also includes the step of predicting whether prophylactic or therapeutic measures, changes in the route of administration, and / or modifications of the therapeutic antibody molecule can prevent or mitigate tolerance issues associated with the intravenous administration of a therapeutic antibody molecule that specifically binds to a human target to humans, In addition to (i) above, the following steps: (ii) A step of administering a prophylactic or therapeutic agent to a mouse, and concurrently administering a therapeutic antibody or surrogate antibody intravenously or intraperitoneally to the mouse, and observing the mouse during the period immediately following the administration of the therapeutic antibody or surrogate antibody, wherein the presentation of macroscopic symptoms is reduced compared to the macroscopic symptoms presented by the mouse in (i), or the absence of macroscopic symptoms during that period indicates that the administration of the therapeutic antibody molecule to humans in combination with pretreatment with the prophylactic or therapeutic agent can prevent or mitigate tolerance issues, or otherwise be associated with intravenous administration of the therapeutic antibody molecule to humans; (iii) a step of administering a therapeutic antibody or surrogate antibody to a mouse by a route of administration other than intravenous or intraperitoneal administration, and observing the mouse during the period immediately following the administration of the therapeutic antibody or surrogate antibody, wherein the presentation of macroscopic symptoms is reduced compared to the macroscopic symptoms presented by the mouse in (i), or the absence of macroscopic symptoms during that period indicates that other routes of administration can be used for the administration of the therapeutic antibody molecule to humans in order to prevent or mitigate tolerability issues that may be associated with the intravenous administration of the therapeutic antibody molecule to humans, and / or (iv) A method comprising the step of intravenously or intraperitoneally administering a modified form of a therapeutic antibody or surrogate antibody to a mouse by a route of administration other than intravenous or intraperitoneal administration, and observing the mouse during the period immediately following the administration of the therapeutic antibody or surrogate antibody, the observation that the presentation of macroscopic symptoms is reduced compared to the macroscopic symptoms presented by the mouse in (i), or that there is no presentation of macroscopic symptoms during that period, can be used to prevent or mitigate tolerability issues that may be associated with intravenous administration of the therapeutic antibody molecule to humans.

[0448] 45. The method of paragraph 44, wherein the presentation of (i) of one to three additional macroscopic symptoms selected from (i) balance disorders, piloerection, and kyphosis, followed by unnatural postures, during the period (i) after the mouse has recovered to a normal state, further reinforces the indicator that intravenous administration of therapeutic antibody molecules to humans would be associated with tolerability issues.

[0449] 46. ​​The method according to paragraph 44 or 45, wherein the period during which macroscopic symptoms are presented in (i) begins 5 to 10 minutes after administration of the therapeutic antibody or surrogate antibody and ends 45 to 90 minutes after administration of the therapeutic antibody or surrogate antibody, and the observation periods in (ii), (iii), and / or (iv) are of the same length.

[0450] 47. The following additional parameters: ● Lowering blood pressure ●Decreased platelet count, and / or ● Elevated liver enzymes (AST / ALT), at least one of which is: The method described in any one of paragraphs 44-46, wherein observations made during the period of (i) further reinforce the indicator that intravenous administration of therapeutic antibody molecules to humans would be associated with tolerability issues.

[0451] 48. A method for predicting whether a prophylactic or therapeutic treatment can prevent or mitigate tolerance issues associated with the intravenous administration of a therapeutic antibody molecule specifically bound to a human target according to any one of claims 1 to 4, comprising at least steps (i) and (ii), wherein the pretreatment is the administration of a corticosteroid to a mouse used in (ii), prior to the injection of the therapeutic antibody or surrogate antibody.

[0452] 49. The method according to paragraph 48, wherein the pretreatment comprises two doses of corticosteroid, one administered 10 to 48 hours before administration of the therapeutic antibody or surrogate antibody, and the other administered 5 minutes to 5 hours before administration of the therapeutic antibody or surrogate antibody.

[0453] 50. The method according to paragraph 49, wherein the corticosteroid is dexamethasone or betamethasone.

[0454] 51. A method for predicting whether a change in the route of administration can prevent or mitigate tolerability issues associated with the intravenous administration of a therapeutic antibody molecule that specifically binds to a human target as described in any one of paragraphs 44-50, comprising at least steps (i) and (iii), wherein the route of administration used in (iii) is subcutaneous administration.

[0455] 52. A method for predicting whether a modification of a therapeutic antibody molecule can prevent or mitigate tolerance issues associated with the intravenous administration of a therapeutic antibody molecule that specifically binds to a human target as described in any one of paragraphs 44 to 51, comprising at least steps (i) and (iv), wherein the modified form of the therapeutic antibody or surrogate antibody used in (iv) is a modification that results in a reduction or loss of Fc receptor involvement.

[0456] 53. The method according to any one of paragraphs 44-52, wherein the human target is selected from the group consisting of FcγRIIB, FcγRIIA, and CD40.

[0457] 54. The method according to paragraph 53, wherein the therapeutic antibody molecule is a human anti-FcγRIIB antibody capable of binding to human FcγR via its Fc domain, and the mouse surrogate antibody is an anti-FcγRIIb antibody capable of binding to mouse FcγR via its Fc domain.

[0458] 55. The method according to paragraph 54, wherein the therapeutic antibody molecule is a human anti-FcγRIIb IgG1 antibody and the mouse surrogate antibody is anti-FcγRIIb mIgG2a.

[0459] 56. Corticosteroids for use in drug regimens to prevent or mitigate tolerability issues associated with intravenous administration of therapeutic antibody molecules to a target, It is predicted that therapeutic antibody molecules, when administered intravenously to humans using the methods described in any one of paragraphs 44-56, will be associated with tolerance issues, and / or that administration of therapeutic antibody molecules to humans in combination with corticosteroid pretreatment will prevent or mitigate tolerance issues, otherwise it is predicted that intravenous administration of therapeutic antibody molecules to humans using the methods described in any one of paragraphs 48-50, or, if referring to any one of paragraphs 48-50, the methods described in any one of paragraphs 53-55, Corticosteroids for use, comprising the administration of corticosteroids to the subject in at least two doses prior to the intravenous administration of the therapeutic antibody molecule, with one dose of corticosteroid administered 10 to 48 hours before the initiation of administration of the therapeutic antibody molecule ("first dose"), and another dose of corticosteroid administered 5 minutes to 5 hours before the initiation of administration of the therapeutic antibody molecule ("second dose").

[0460] 57. Corticosteroids for use in drug regimens to prevent or mitigate tolerability issues associated with intravenous administration of therapeutic antibody molecules to a target, The therapeutic antibody molecule is the anti-FcγRIIB antibody. Corticosteroids for use, comprising the administration of corticosteroids to the subject in at least two doses prior to the intravenous administration of the therapeutic antibody molecule, with one dose of corticosteroid administered 10 to 48 hours before the initiation of administration of the therapeutic antibody molecule ("first dose"), and another dose of corticosteroid administered 5 minutes to 5 hours before the initiation of administration of the therapeutic antibody molecule ("second dose").

[0461] 58. A corticosteroid for use as described in paragraph 56 or 57, wherein the first dose is administered 6 to 36 hours before the start of administration of the therapeutic antibody molecule, and the second dose is administered 15 to 120 minutes before the start of administration of the therapeutic antibody molecule.

[0462] 59. A corticosteroid for use as described in paragraphs 56-58, the first dose of which is administered 16-24 hours before the initiation of administration of the therapeutic antibody molecule.

[0463] 60. A corticosteroid for use as described in any one of paragraphs 56-59, wherein the second dose is administered 30-60 minutes before the initiation of administration of the therapeutic antibody molecule.

[0464] 61. Corticosteroids for use as described in any one of paragraphs 56-60, wherein the drug regimen includes administering at least two doses of corticosteroids before each infusion of antibodies during the course of antibody therapy.

[0465] 62. A corticosteroid for use as described in any one of paragraphs 56-61, wherein the corticosteroid is dexamethasone or betamethasone, or a combination of dexamethasone and betamethasone.

[0466] 63. Corticosteroid for use as described in any one of paragraphs 56-62, wherein the corticosteroid is dexamethasone, and the first dose is 4-20 mg and the second dose is 4-25 mg.

[0467] 64. Corticosteroids for use as described in paragraph 63, wherein the first dose is 10-12 mg and the second dose is 20 mg.

[0468] 65. A corticosteroid for use as described in any one of paragraphs 56-62, wherein the corticosteroid is betamethasone, and the first dose is 3.2-16 mg and the second dose is 3.2-20 mg.

[0469] 66. Corticosteroids for use as described in paragraph 65, wherein the first dose is 8-9.6 mg and the second dose is 16 mg.

[0470] 67. Corticosteroids for use as described in any one of paragraphs 56 to 66, wherein the drug regimen further comprises the administration of an antihistamine 10 minutes to 24 hours prior to the commencement of administration of the therapeutic antibody molecule.

[0471] 68. A corticosteroid for use as described in any one of paragraphs 56-67, wherein the therapeutic antibody is an Fc receptor-binding antibody.

[0472] 69. A corticosteroid for use as described in any one of paragraphs 56-68, wherein the therapeutic antibody is an anti-FcγRIIB antibody.

[0473] 70. An anti-FcγRIIB antibody is an antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2, for use as described in paragraph 69 of a corticosteroid.

[0474] 71. A therapeutic antibody molecule for use in the treatment of cancer, wherein the therapeutic antibody molecule is expected to be associated with tolerance issues related to intravenous administration to humans using the method described in any one of paragraphs 44-55, and / or a subcutaneous administration route of the therapeutic antibody molecule to humans is expected to prevent or mitigate tolerance issues, and otherwise be associated with intravenous administration of the therapeutic antibody molecule to humans using the method described in paragraph 51, or, if referring to paragraph 51, the method described in any one of paragraphs 53-55. A therapeutic antibody molecule, which is formulated for subcutaneous administration.

[0475] 72. The therapeutic antibody molecule for use as described in paragraph 71, wherein the therapeutic antibody is an anti-FcγRIIB antibody.

[0476] 73. A therapeutic antibody molecule for use as described in paragraph 72, wherein the anti-FcγRIIB antibody is an antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2.

[0477] 74. A modified form of therapeutic antibody molecule for use in the treatment of cancer, wherein the therapeutic antibody molecule is expected to be associated with tolerability issues related to intravenous administration to humans using the method described in any one of paragraphs 44-55, and / or administration of the modified form of therapeutic antibody molecule to humans is expected to prevent or mitigate tolerability issues, and otherwise be associated with intravenous administration of the therapeutic antibody molecule to humans using the method described in paragraph 52, or, if referring to paragraph 52, the method described in any one of paragraphs 53-55. A modified therapeutic antibody molecule is an Fc receptor-binding antibody, and the modified form is an antibody that has the same Fv variable sequence, but in which the FcγR binding is impaired or inactivated compared to the therapeutic antibody molecule.

[0478] 75. A modified form of the therapeutic antibody molecule for use as described in paragraph 74, wherein the therapeutic antibody is an anti-FcγRIIB antibody.

[0479] 76. A modified form of therapeutic antibody molecule for use as described in paragraph 75, wherein the modified form of anti-FcγRIIB antibody is an antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 295.

[0480] 77. Methods for preventing or mitigating tolerability issues associated with the intravenous administration of therapeutic antibody molecules to a subject, including corticosteroid drug regimens, It is predicted that therapeutic antibody molecules, when administered intravenously to humans using the methods described in any one of paragraphs 44-56, will be associated with tolerance issues, and / or that administration of therapeutic antibody molecules to humans in combination with corticosteroid pretreatment will prevent or mitigate tolerance issues, otherwise it is predicted that intravenous administration of therapeutic antibody molecules to humans using the methods described in any one of paragraphs 48-50, or, if referring to any one of paragraphs 48-50, the methods described in any one of paragraphs 53-56, A drug regimen comprising administering corticosteroids to a subject in at least two doses prior to intravenous administration of a therapeutic antibody molecule, wherein one dose of corticosteroids is administered 10 to 48 hours before the start of administration of the therapeutic antibody molecule ("first dose"), and another dose of corticosteroids is administered 5 minutes to 5 hours before the start of administration of the therapeutic antibody molecule ("second dose").

[0481] 78. The method according to paragraph 77, wherein the first dose is administered 6 to 36 hours before the start of administration of the therapeutic antibody molecule, and the second dose is administered 15 to 120 minutes before the start of administration of the therapeutic antibody molecule.

[0482] 79. The method according to paragraph 77 or 78, wherein the first dose is administered 16 to 24 hours before the start of administration of the therapeutic antibody molecule.

[0483] 80. The method according to any one of paragraphs 77-79, wherein the second dose is administered 30-60 minutes before the start of administration of the therapeutic antibody molecule.

[0484] 81. The method according to any one of paragraphs 77-80, wherein the drug regimen includes administering at least two doses of corticosteroids before each infusion of antibody during the course of antibody therapy.

[0485] 82. The method according to any one of paragraphs 77-81, wherein the corticosteroid is dexamethasone or betamethasone, or a combination of dexamethasone and betamethasone.

[0486] 83. The method according to any one of paragraphs 77-82, wherein the corticosteroid is dexamethasone, the first dose is 4-20 mg, and the second dose is 4-25 mg.

[0487] 84. The method according to paragraph 83, wherein the first dose is 10-12 mg and the second dose is 20 mg.

[0488] 85. The method according to any one of paragraphs 77-82, wherein the corticosteroid is betamethasone, the first dose is 3.2-16 mg, and the second dose is 3.2-20 mg.

[0489] 86. The method according to paragraph 85, wherein the first dose is 8-9.6 mg and the second dose is 16 mg.

[0490] 87. The method according to any one of paragraphs 77 to 86, wherein the drug regimen further comprises the administration of an antihistamine 10 minutes to 24 hours before the initiation of administration of a therapeutic antibody molecule.

[0491] 88. The method according to any one of paragraphs 76-86, wherein the antibody is an Fc receptor-binding antibody.

[0492] 89. The method according to any one of paragraphs 77-88, wherein the antibody is an anti-FcγRIIB antibody.

[0493] 90. The method according to paragraph 89, wherein the anti-FcγRIIB antibody is an antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2.

[0494] 91. A method for the treatment of cancer, comprising subcutaneously administering a therapeutically effective dose of a therapeutic antibody molecule, which is expected to be associated with tolerance issues related to intravenous administration to a human, using the method described in any one of paragraphs 44 to 56, and / or the subcutaneous administration route of the therapeutic antibody molecule to a human is expected to prevent or mitigate tolerance issues, and otherwise be associated with intravenous administration of the therapeutic antibody molecule to a human using the method described in paragraph 51, or, if referring to paragraph 51, the method described in any one of paragraphs 53 to 56.

[0495] 92. The method according to paragraph 91, wherein the antibody is an anti-FcγRIIB antibody.

[0496] 93. The method according to paragraph 92, wherein the anti-FcγRIIB antibody is an antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2.

[0497] 94. A method for treating cancer, comprising administering a therapeutically active amount of a modified form of a therapeutic antibody, wherein the therapeutic antibody molecule is expected to be associated with tolerability issues related to intravenous administration to humans using the method described in any one of paragraphs 44-56, and / or administration of the modified form of the therapeutic antibody molecule to humans is expected to prevent or mitigate tolerability issues, otherwise it will be associated with intravenous administration of the therapeutic antibody molecule to humans using the method described in paragraph 52, or, if referring to paragraph 52, the method described in any one of paragraphs 53-56. A method in which the therapeutic antibody molecule is an Fc receptor-binding antibody, and the modified form is an antibody that has the same Fv variable sequence, but in which the FcγR binding is impaired or inactivated compared to the therapeutic antibody molecule.

[0498] 95. The method according to paragraph 94, wherein the antibody is an anti-FcγRIIB antibody.

[0499] 96. The method according to paragraph 95, wherein the anti-FcγRIIB antibody is an antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2, and the heavy chain has the N297Q mutation.

[0500] 97. A therapeutic antibody molecule for use in the treatment of cancer, autoimmune diseases, inflammatory diseases, immune diseases, and / or infectious diseases, wherein the therapeutic antibody molecule is an anti-FcγRIIB antibody, and the therapeutic antibody molecule is formulated for subcutaneous administration.

[0501] 98. Use of a therapeutic antibody molecule in the manufacture of a pharmaceutical product for use in the treatment of cancer, autoimmune diseases, inflammatory diseases, immune diseases, and / or infectious diseases, wherein the therapeutic antibody molecule is an anti-FcγRIIB antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2, and the pharmaceutical product is formulated for subcutaneous administration.

[0502] 99. A pharmaceutical preparation comprising a therapeutic antibody molecule, wherein the therapeutic antibody molecule is an anti-FcγRIIB antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2, and the pharmaceutical preparation comprises a pharmaceutically acceptable diluent or excipient and is formulated for subcutaneous administration.

[0503] 100. A therapeutic antibody molecule for use as described in paragraph 97, a therapeutic antibody molecule for use as described in paragraph 98, or a pharmaceutical preparation as described in paragraph 99, wherein the therapeutic antibody is an Fc receptor-binding antibody.

[0504] 101. A therapeutic antibody molecule for use as described in paragraph 97 or 100, a therapeutic antibody molecule for use as described in paragraph 98 or 100, or a pharmaceutical preparation as described in paragraph 99 or 100, wherein the therapeutic antibody is an anti-FcγRIIB antibody.

[0505] 102. A therapeutic antibody molecule for use as described in paragraph 101, the use of a therapeutic antibody molecule as described in paragraph 101, or a pharmaceutical preparation as described in paragraph 101, wherein the therapeutic antibody has the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2.

[0506] 103. A therapeutic antibody molecule for use as described in paragraph 101 or 102, use of a therapeutic antibody molecule as described in paragraph 101 or 102, or a pharmaceutical preparation as described in paragraph 101 or 102, for the treatment of cancer.

[0507] 104. A pharmaceutical preparation described in any one of paragraphs 99 to 103, wherein the therapeutic antibody is present at a concentration of approximately 90 mg / mL to approximately 220 mg / mL.

[0508] 105. A pharmaceutical preparation according to any one of paragraphs 99 to 104, further comprising approximately 5 mM to approximately 20 mM acetate, and / or approximately 50 mM to approximately 250 mM NaCl, and / or approximately 0.05% polysorbate 20, and / or having a pH of approximately 5.0 to approximately 5.8.

[0509] 106. The formulation, - Therapeutic antibody at a concentration of -150 mg / mL, -5 mM acetate, -110 mM NaCl, Contains -0.05% (w / v) polysorbate 20, - A pharmaceutical preparation as described in any one of paragraphs 99 to 105, wherein the preparation has a pH of 5.8.

[0510] 107. A method for treating cancer, autoimmune disease, inflammatory disease, immune disease, and / or infectious disease in a subject, comprising the step of administering a therapeutic antibody molecule to the subject, wherein the therapeutic antibody molecule is an Fc receptor-binding antibody, and the therapeutic antibody molecule is formulated for subcutaneous administration.

[0511] 108. The method according to paragraph 107, wherein the Fc receptor-binding antibody is an anti-FcγRIIB antibody.

[0512] 109. The method according to paragraph 107 or 108, wherein the Fc receptor-binding antibody is an anti-FcγRIIB antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2.

[0513] 110. A method for treating cancer, autoimmune disease, inflammatory disease, immune disease, and / or infectious disease in a subject, comprising the step of subcutaneously administering a pharmaceutical preparation as defined in any one of paragraphs 99 to 106.

[0514] 111. The method described in paragraph 109 or 110 for the treatment of cancer.

Claims

1. The use of a therapeutic antibody molecule in the manufacture of a pharmaceutical product for use in the treatment of cancer, autoimmune diseases, inflammatory diseases, immune diseases, and / or infectious diseases, wherein the therapeutic antibody molecule is an anti-FcγRIIB antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2, and the pharmaceutical product is formulated for subcutaneous administration. The aforementioned pharmaceuticals are intended for use in the treatment of cancer, autoimmune diseases, inflammatory diseases, immunological diseases, and / or infectious diseases in patients. The patient is a patient for whom it is desirable to reduce and / or prevent infusion-related reactions associated with the administration of the therapeutic antibody molecule. The therapeutic antibody molecule is present at a concentration of 90 mg / mL to 220 mg / mL. Use of a therapeutic antibody molecule comprising 5 mM to 20 mM acetate and / or 50 mM to 250 mM NaCl and / or 0.05% polysorbate 20, and / or the pharmaceutical preparation having a pH of 5.0 to 5.

8.

2. Use of the therapeutic antibody molecule according to claim 1 in the manufacture of a pharmaceutical product for use in the treatment of cancer.

3. A pharmaceutical preparation comprising a therapeutic antibody molecule, wherein the therapeutic antibody molecule is an anti-FcγRIIB antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2, and the pharmaceutical preparation comprising a pharmaceutically acceptable diluent or excipient, and formulated for subcutaneous administration. It is intended for use in the treatment of cancer, autoimmune diseases, inflammatory diseases, immunological diseases, and / or infectious diseases in patients. The aforementioned patient is a patient for whom it is desirable to reduce and / or prevent infusion-related reactions associated with the administration of the therapeutic antibody molecule. The therapeutic antibody molecule is present at a concentration of 90 mg / mL to 220 mg / mL. A pharmaceutical preparation further comprising 5 mM to 20 mM acetate, and / or 50 mM to 250 mM NaCl, and / or 0.05% polysorbate 20, and / or the pharmaceutical preparation having a pH of 5.0 to 5.

8.

4. A pharmaceutical preparation according to claim 3, for use in the treatment of cancer.

5. The pharmaceutical preparation according to claim 3, wherein the therapeutic antibody molecule is administered subcutaneously, thereby reducing and / or preventing injection-related reactions associated with the administration of the therapeutic antibody molecule.

6. The aforementioned pharmaceutical preparation, - The therapeutic antibody molecule at a concentration of -150 mg / mL, -5 mM acetate, -110 mM NaCl, - Contains 0.05% (w / v) polysorbate 20, - The pharmaceutical preparation according to any one of claims 3 to 5, wherein the pharmaceutical preparation has a pH of 5.

8.

7. A pharmaceutical preparation comprising a therapeutic antibody molecule, wherein the therapeutic antibody molecule is an anti-FcγRIIB antibody having the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2, and the pharmaceutical preparation comprising a pharmaceutically acceptable diluent or excipient, and formulated for subcutaneous administration. It is intended for use in the treatment of cancer, autoimmune diseases, inflammatory diseases, immunological diseases, and / or infectious diseases in patients. By administering the therapeutic antibody molecule subcutaneously, the tolerance issues associated with intravenous administration of the therapeutic antibody molecule are reduced and / or prevented. The therapeutic antibody molecule is present at a concentration of 90 mg / mL to 220 mg / mL. A pharmaceutical preparation further comprising 5 mM to 20 mM acetate, and / or 50 mM to 250 mM NaCl, and / or 0.05% polysorbate 20, and / or the pharmaceutical preparation having a pH of 5.0 to 5.8.

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