A composition

Abstract

The present invention relates to a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: IgG3 and / or IgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease.

Description

[0001] A composition

[0002] The present invention provides a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease.

[0003] Background

[0004] In general, autoimmune diseases involve target cells displaying autoantigens, to which autoantibodies bind via their Fab portion, leaving the Fc portion free to engage with NK cells, macrophages, or complement system components. This binding activates cell death through granzyme and perforin release by NK cells, phagocytosis by macrophages, and complement system activation, leading to the formation of the membrane attack complex and subsequent cell lysis. While these systems are useful in combating pathogens, autoimmune diseases result when target cells are one’s own.

[0005] Several different methods for treating autoimmune diseases are known. One such method is intravenous immunoglobulin (IVIg) therapy, which is increasingly being used. I Vlg therapy is typically administered intravenously to a patient to help modulate the immune response by blocking the action of undesirable autoantibodies. IVIg is a sterile, purified immunoglobulin product that is manufactured from pooled human plasma, wherein more than 95% of the total immunoglobulins are IgG, with trace amounts of IgA and / or IgM. An example of an IVIg therapeutic that is used for treating autoimmune diseases is GamunexS^C.

[0006] Another method for treating autoimmune diseases is subcutaneous immunoglobulin therapy (SCIg). SCIg infusions are given by slowly injecting purified immunoglobulin into fatty tissue just underneath the skin. This method is most commonly an option for patients with an immunodeficiency who need treatment to replace missing antibodies. However, it is also becoming increasingly available for neurology, dermatology, and rheumatology (immunomodulatory) patients who have an overactive immune system and need high doses of immunoglobulin.

[0007] New methods for treating autoimmune diseases are needed.

[0008] Brief summary of the disclosure

[0009] The inventors have surprisingly found that, despite only being a minor fraction of total human IgG found in plasma (and in commercial IVIg and SCIg products), lgG3 has excellent therapeutic efficacy in patients with autoimmunity. lgG3 is shown herein to inhibit the antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and / or complement-dependent cytotoxicity (CDC) effects of autoimmune diseases caused by pathogenic antibodies. The efficacy of lgG3 in the treatment of autoimmune diseases represents a novel approach that has not been assessed to date.

[0010] Therapeutic antibodies in I Vlg and SCIg therapy have been found to block Fc receptors to prevent the activation of immune cells (e.g., NK cells and macrophages) in autoimmune diseases. Monomeric antibodies (not bound to their antigen) normally bind to Fc receptors, but with lower affinity compared to when they form immune complexes. One of the proposed mechanisms of I Vlg and SCIg therapy for autoimmune diseases is that, at very high doses, the therapeutic antibodies saturate the Fc receptors.

[0011] The invention has been demonstrated using compositions comprising a minimum therapeutic threshold of lgG3. The Fc region of the lgG3 binds to and blocks C1q and Fc receptors, thereby modulating the complement system and immune cells, and consequently decreasing the effect of the pathogenic antibodies. The invention therefore applies equally to lgG3 antibodies and lgG3 fragments, provided that they comprise the lgG3 Fc region. Such lgG3 fragments are therefore encompassed herein.

[0012] The inventors have shown that lgG3 (lgG3 antibodies and lgG3 fragments) has a higher affinity for Fc receptors and C1q than other subclasses (lgG1, lgG2, lgG4). This means a composition enriched for lgG3 will have a higher affinity for Fc receptors and C1 q than a composition with lower content of lgG3. Therefore, compositions enriched for lgG3 can treat autoimmune diseases (i.e. limit or decrease the effect of pathogenic antibodies causing autoimmune diseases) at lower doses. Administering lower doses can reduce the incidence and severity of dose-dependent adverse effects, improving overall tolerability for patients. Lower dosage regimens also decrease systemic exposure, which can minimize long-term safety risks while maintaining therapeutic efficacy. In addition, lower doses may enhance patient adherence by reducing side-effects and simplifying treatment management. Lower doses may also reduce IVIg infusion volumes, infusion times and infusion rates required, overall enhancing patients’ quality of life.

[0013] The invention has been demonstrated using a composition having a minimum therapeutic threshold of at least 10% lgG3 of the total immunoglobulins present in the composition. Other compositions comprising the minimum therapeutic threshold of lgG3 provided herein will also provide the therapeutic efficacy described herein (as the efficacy is provided by the level of lgG3 per se). Accordingly, any composition comprising the minimum therapeutic threshold of lgG3 provided herein is encompassed herein.In one aspect the invention provides a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease. In other words, the invention provides a composition comprising immunoglobulins, wherein at least 10% of the immunoglobulins in the composition are lgG3 and / or lgG3 fragments comprising the Fc region, wherein the lgG3 and / or fragments thereof are for use in preventing and / or treating an autoimmune disease.

[0014] The invention also provides a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in a method of preventing and / or treating an autoimmune disease. In other words, the invention provides a composition comprising immunoglobulins, wherein at least 10% of the immunoglobulins in the composition are lgG3 and / or lgG3 fragments comprising the Fc region, wherein the lgG3 and / or fragments thereof are for use in a method of preventing and / or treating an autoimmune disease.

[0015] Suitably, the immunoglobulins may comprise at least about 50%, at least about 80%, or at least about 90% lgG3 and / or lgG3 fragments comprising the Fc region.

[0016] Suitably, the autoimmune disease may be selected from the group consisting of: Immune Thrombocytopenia Purpura (ITP), Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Myasthenia Gravis (MG), Guillain-Barre Syndrome (GBS), Kawasaki’s Disease, Graves ophthalmopathy (Thyroid Eye Disease), Systemic Lupus Erythematosus, Dermatomyositis, Multifocal Motor Neuropathy, Autoimmune Encephalitis, Sjogren Syndrome, Pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS), Paraproteinemic neuropathy, Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD), Autoimmune hemolytic anemia / Evan syndrome, Antineutrophil Cytoplasmic Antibodies disease (ANCA-vasculitis), Bullous Pemphigus, Autoimmune Uveitis, Narcolepsy with cataplexy, and Antiphospholipid Syndrome.

[0017] Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may bind to Fc receptors and / or bind C1q to prevent and / or treat the autoimmune disease.

[0018] Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may modulate the complement system (e.g. by binding to C1q) to prevent and / or treat the autoimmune disease. Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may inhibit antibodydependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and / or complement-dependent cytotoxicity (CDC) to prevent and / or treat the autoimmune disease.Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may be human lgG3 and / or lgG3 fragments (comprising the Fc region).

[0019] Suitably, the immunoglobulins may comprise lgG1, lgG2, lgG4, IgA and / or IgM; or fragments thereof.

[0020] Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may be from blood or ascites. Suitably, the immunoglobulins in the composition may be from blood or ascites. Suitably, the composition may be from blood or ascites.

[0021] Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may be from blood plasma. Suitably, the immunoglobulins in the composition may be from blood plasma. Suitably, the composition may be from blood plasma.

[0022] Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may be recombinant and / or synthetic. Suitably, they may be recombinant lgG3 and / or lgG3 fragments (comprising the Fc region). Suitably, they may be synthetic lgG3 and / or lgG3 fragments (comprising the Fc region).

[0023] Suitably, the immunoglobulin may be administered (e.g. to a human) at a dosage amount of at least 0.01 g / kg, 0.05 g / kg, 0.1 g / kg, 0.15 g / kg, 0.2 g / kg, 0.25 g / kg, 0.3 g / kg, 0.35 g / kg, 0.4 g / kg, 0.45 g / kg, 0.5 g / kg, 0.55 g / kg, 0.6 g / kg, 0.65 g / kg, 0.7 g / kg, 0.75 g / kg, 0.8 g / kg, 0.85 g / kg, 0.9 g / kg, 0.95 g / kg, 1 g / kg, 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg or 10 g / kg, optionally wherein the dosage amount is in the range of 0.01 g / kg to 2 g / kg.

[0024] Suitably, the lgG3 and / or lgG3 fragment (comprising the Fc region) may be administered (e.g. to a human) at a dosage amount of at least 0.01 g / kg, 0.05 g / kg, 0.1 g / kg, 0.15 g / kg, 0.2 g / kg, 0.25 g / kg, 0.3 g / kg, 0.35 g / kg, 0.4 g / kg, 0.45 g / kg, 0.5 g / kg, 0.55 g / kg, 0.6 g / kg, 0.65 g / kg, 0.7 g / kg, 0.75 g / kg, 0.8 g / kg, 0.85 g / kg, 0.9 g / kg, 0.95 g / kg, 1 g / kg, 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg or 10 g / kg, optionally wherein the dosage amount is in the range of 0.01 g / kg to 2 g / kg.

[0025] Suitably, the composition may further comprise and / or be used in combination with one or more additional therapeutic agents selected from: corticosteroids, anti-inflammatory, painkilling medication, immunosuppressant drugs, FcRn inhibitors, Fc-multimers, FcyR inhibitors, antibody-drug conjugates, check point agonist / inhibitors, and / or complement inhibitors.

[0026] Suitably, the composition may further comprise an adjuvant, diluent and / or excipient.

[0027] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps.Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0028] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

[0029] Various aspects of the invention are described in further detail below.

[0030] Brief description of the Figures

[0031] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which:

[0032] Figure 1 shows results from an in vitro study demonstrating that immunoglobulins enriched for lgG3 are more effective than commercial therapeutic IgG at inhibiting ADCC (antibodydependent cellular cytotoxicity) (A) ADCC induction expressed as a percentage normalized to the saline-treated condition. Product concentration before test dilution in all cases is 5 mg / mL, (product final concentration is 1 mg / mL) and anti-CD20 is at 0.02 pg / mL. Data are shown as mean ± SD, with triplicates for each condition. (B) lgG3 inhibition effectiveness compared to a commercial IgG product expressed in percentages. (C) ADCC induction expressed as a percentage normalized to the saline-treated condition. Product concentrations before test dilution are shown in brackets in mg / mL (for the final concentration in the test, these values must be divided by 5). Anti-CD20 concentration is 1 pg / mL. Commercial IgG encompasses 2% of lgG3 while lgG3 enriched product encompasses > 80% of lgG3. Data are shown as mean ± SD, with 2-4 replicates for each condition.

[0033] Figure 2 shows results from an in vitro study demonstrating that immunoglobulins enriched for lgG3 are more effective than commercial therapeutic IgG at inhibiting ADCP (antibodydependent cellular phagocytosis) (A) ADCP induction expressed as a percentage normalized to the saline-treated condition (I Vlg excipients). Product concentration before test dilution in all cases is 30 mg / mL (product final concentration is 6 mg / mL) and anti-CD20 concentration is 0.03 pg / mL. Data are shown as mean ± SD, with triplicates for each condition. (B) lgG3 inhibition effectiveness compared to a commercial IgG product expressed in percentages. (C)ADCP induction expressed as a percentage normalized to the saline-treated condition. Product concentrations before test dilution are shown in brackets in mg / mL (for the final concentration in the test, these values must be divided by 5). Anti-CD20 concentration is 0.8 pg / mL. Commercial IgG encompasses 2% lgG3 while lgG3 enriched product encompasses > 80% lgG3. Data are shown as mean ± SD, with 2-4 replicates for each condition.

[0034] Figure 3 shows results from an in vitro study demonstrating that immunoglobulins enriched for lgG3 are more effective than therapeutic IgG at inhibiting CDC (complement-dependent cytotoxicity) (A) Cell lysis caused by CDC activation expressed as a percentage normalized to digitonin treatment (100% lysis). Target cells incubated with anti-CD20 and human serum but without any additional treatment were used as the Complement control. Product concentration before test dilution in all cases is 10 mg / mL (product final concentration is 3.33 mg / mL) and anti-CD20 concentration is 2.3 pg / mL. Data are shown as mean ± SD, with triplicates for each condition. (B) lgG3 inhibition effectiveness compared to a commercial IgG product expressed in percentages. (C) Cell lysis caused by CDC activation expressed as a percentage normalized to digitonin treatment (100% lysis). Target cells incubated with anti-CD20 and human serum but without any additional treatment were used as the Complement control. Product concentrations before test dilution are shown in brackets in mg / mL (for the final concentration in the test, these values must be divided by 3). Anti-CD20 concentration is 2.33 pg / mL. Commercial IgG encompasses 2% lgG3 while lgG3 enriched product encompasses > 80% lgG3. Data are shown as mean ± SD, with 2-4 replicates for each condition.

[0035] Figure 4 shows that immunoglobulins enriched for lgG3 (“lgG3-enriched”) exhibit higher levels of binding to C1q compared to commercial IgG. (A) “lgG3 enriched” (> 80% lgG3 content) products exhibit superior efficacy in binding to C1q compared to commercial IgG (2% lgG3 content). Data are shown as mean ± SD, with 3 replicates for each condition for two independent assays using independent batches (#A and #B) of lgG3-enriched and commercial IgG in each assay. (B) IC50 values (in nM) obtained for each condition and batch (#A and #B). Data were fitted to a four-parameter logistic regression equation to calculate IC50 values.

[0036] Figure 5 shows an in vivo study on the efficacy of lgG3 in mitigating platelet drop in Idiopathic Thrombocytopenic Purpura (ITP) disease model rats. (A) shows the details about the experimental groups and study design in which rats were intravenously (IV) administered with commercial IgG (2% content of lgG3) at a dose of 1000 mg / kg or “lgG3 enriched” (content > 80% lgG3) at doses of 50, 100 mg / kg or 200 mg / kg. n=6 animals per treatment group. “TA”refers to therapeutic antibody. Blood was collected at various time points including before administration of TA, pre-induction of ITP with anti-serum and at 1, 3, 6, 24, 48, 72 and 96 hours post-induction of ITP. (B) shows a schematic for the study. (C) Platelet count expressed as a percentage of the pre-antiserum injection values. A reduction in the percentage of platelet drop was observed compared to saline solution in a dose-dependent manner, when “lgG3 enriched” at 50 mg / kg, 100 mg / kg or 200 mg / kg were administered to ITP disease model rats. A grey shaded area shows 100% of the baseline platelet count ± 20%. Data are shown as mean ± SEM (n=5-6 animals per treatment group). (D) Area under the curve of platelet count changes in each experimental group during different phases of the study (from 0 to 48h, from 0 to 72h and from 0 to 96h post-induction of the disease). Data are shown as mean ± SEM (n=5-6 animals per treatment group).

[0037] The patent, scientific and technical literature referred to herein establish knowledge that was available to those skilled in the art at the time of filing. The entire disclosures of the issued patents, published and pending patent applications, and other publications that are cited herein are hereby incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference. In the case of any inconsistencies, the present disclosure will prevail.

[0038] Various aspects of the invention are described in further detail below.

[0039] Detailed Description

[0040] Composition

[0041] In one aspect the invention provides a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease.

[0042] The invention also provides a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in a method of preventing and / or treating an autoimmune disease.

[0043] The invention further provides a method of preventing and / or treating an autoimmune disease, comprising administering a therapeutically effective amount of a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region to a subject in need thereof.The term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in a clinical improvement of disease.

[0044] Also provided herein is the use of a composition comprising immunoglobulins for the manufacture of a medicament for preventing and / or treating an autoimmune disease, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region.

[0045] The compositions provided herein comprise immunoglobulins. They may be immunoglobulin compositions (also referred to as immunoglobulin therapies). In one example they may be an intravenous immunoglobulin composition, or an intravenous immunoglobulin therapy. In another example they may be a subcutaneous immunoglobulin composition, or a subcutaneous immunoglobulin therapy.

[0046] The invention therefore also provides an immunoglobulin composition, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease. In other words, the invention provides an immunoglobulin composition, wherein at least 10% of the immunoglobulins in the composition are lgG3 and / or lgG3 fragments comprising the Fc region, wherein the lgG3 and / or fragments thereof are for use in preventing and / or treating an autoimmune disease. In one example, the composition is an intravenous immunoglobulin composition. In another example, the composition is a subcutaneous immunoglobulin composition.

[0047] The invention also provides an immunoglobulin composition, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in a method of preventing and / or treating an autoimmune disease. In other words, the invention provides an immunoglobulin composition, wherein at least 10% of the immunoglobulins in the composition are lgG3 and / or lgG3 fragments comprising the Fc region, wherein the lgG3 and / or fragments thereof are for use in a method of preventing and / or treating an autoimmune disease. In one example, the composition is an intravenous immunoglobulin composition. In another example, the composition is a subcutaneous immunoglobulin composition.

[0048] The invention further provides a method of preventing and / or treating an autoimmune disease, comprising administering a therapeutically effective amount of an immunoglobulincomposition, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region to a subject in need thereof. In other words, the invention provides a method of preventing and / or treating an autoimmune disease, comprising administering a therapeutically effective amount of an immunoglobulin composition, wherein at least 10% of the immunoglobulins in the composition are lgG3 and / or lgG3 fragments comprising the Fc region. In one example, the composition is an intravenous immunoglobulin composition. In another example, the composition is a subcutaneous immunoglobulin composition.

[0049] Also provided herein is the use of an immunoglobulin composition for the manufacture of a medicament for preventing and / or treating an autoimmune disease, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region. In other words, the use of an immunoglobulin composition for the manufacture of a medicament for preventing and / or treating an autoimmune disease is provided, wherein at least 10% of the immunoglobulins in the composition are lgG3 and / or lgG3 fragments comprising the Fc region. In one example, the composition is an intravenous immunoglobulin composition. In another example, the composition is a subcutaneous immunoglobulin composition.

[0050] The term “immunoglobulin” (also referred to as an antibody) is used herein in the broadest sense. The term “immunoglobulin” as used herein encompasses full-length antibodies, antibody conjugates, antibody fragments and antibody fragment conjugates.

[0051] In some embodiments, the immunoglobulins are antibody fragments.

[0052] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g. E. coli or phage).

[0053] In some embodiments, the immunoglobulins are full length immunoglobulins (full length antibodies).

[0054] The terms “full length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure.For the sake of clarity, the terms “antibody” and “immunoglobulin” may be used interchangeably herein. Immunoglobulins are glycoproteins produced by plasma cells. In the case of human immunoglobulins, light chains are classified as kappa and lambda light chains. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the immunoglobulin's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.

[0055] Immunoglobulin G (IgG) is synthesized mostly in the secondary immune response to pathogens. It can activate the classical pathway of the complement system, and can play a protective role. IgG represents approximately 75% of serum antibodies in humans and is the most common type of antibody found in blood circulation. Pharmaceutical formulations of immunoglobulin G type (IgG) are widely used to treat a variety of immunodeficiency, inflammatory, autoimmune and neurological conditions.

[0056] IgG is a polypeptide belonging to the class of immunoglobulins that are substantially encoded by a recognized immunoglobulin gamma gene. Full-length IgGs have two identical pairs of two immunoglobulin chains, each pair having one light and one heavy chain, each light chain comprising immunoglobulin domains VL and CL, and each heavy chain comprising immunoglobulin domains VH, Cy1 (also called CH1), Cy2 (also called CH2), and Cy3 (also called CH3).

[0057] IgG comprises several different subclasses: lgG1, lgG2, lgG3, and lgG4. This numbering reflects the abundance of the subclass in human serum: lgG1 constitutes around 66% of total IgG; lgG2 is around 23%; lgG3 around 7% and lgG4 around 4%.

[0058] The four subclasses, lgG1, lgG2, lgG3, and lgG4, are highly conserved, and differ in their constant region, particularly in their hinges and upper CH2 domains. These regions are involved in binding to both IgG-Fc receptors (FcyR) and C1q. As a result, the different subclasses have different effector functions, both in terms of triggering FcyR-expressing cells, resulting in phagocytosis or antibody-dependent cell-mediated cytotoxicity, and activating complement. These differences in effector function give rise to different immune functions of the IgG subclasses.

[0059] In particular, it is recognized that lgG3 has enhanced antigen neutralization, high Fc-mediated activity and complement activation, and is a potent mediator of effector functions (ADCC, ADCP and CDC).I gG3 fragments are immunoglobulin fragments (or antibody fragments) that are specifically of the lgG3 type i.e. have an lgG3 specific heavy chain constant domain.

[0060] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions.

[0061] “lgG3 fragments comprising the Fc region” are lgG3 fragments that must include at least an Fc region and may include further parts of the full-length lgG3 antibody. In the context of the invention, and therefore as used herein, the term “lgG3 fragments comprising the Fc region” may be abbreviated to “the lgG3 fragments” herein (unless the context specifically indicates otherwise).

[0062] In the present invention, the immunoglobulins (that are present in the composition) comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region. In other words, of the total immunoglobulins in the composition, at least 10% are lgG3 and / or lgG3 fragments comprising the Fc region.

[0063] In some embodiments, the immunoglobulins comprise at least 10% of lgG3. In other words, of the total immunoglobulins in the composition, at least 10% are lgG3.

[0064] In some embodiments, the immunoglobulins comprise at least 10% of lgG3 fragments comprising the Fc region. In other words, of the total immunoglobulins in the composition, at least 10% are lgG3 fragments comprising the Fc region.

[0065] In some embodiments, the immunoglobulins comprise at least 10% of lgG3 and lgG3 fragments comprising the Fc region. In other words, of the total immunoglobulins in the composition, at least 10% are a mix of lgG3 and lgG3 fragments comprising the Fc region.

[0066] In some embodiments, the immunoglobulins may comprise at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% of lgG3 and / or lgG3 fragments comprising the Fc region. In other words, of the total immunoglobulins in the composition, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% may be lgG3 and / or lgG3 fragments comprising the Fc region.

[0067] In some embodiments, the immunoglobulins may comprise at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or atleast 90% of lgG3 and / or lgG3 fragments comprising the Fc region. In other words, of the total immunoglobulins in the composition, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% may be lgG3 and / or lgG3 fragments comprising the Fc region.

[0068] In some embodiments, the immunoglobulins may comprise at least 50%, at least 80%, or at least 90% of lgG3 and / or lgG3 fragments comprising the Fc region. In other words, of the total immunoglobulins in the composition, at least 50%, at least 80%, or at least 90% may be lgG3 and / or lgG3 fragments comprising the Fc region.

[0069] In some embodiments, the immunoglobulins may comprise more than 50%, more than 80%, or more than 90% of lgG3 and / or lgG3 fragments comprising the Fc region. In other words, of the total immunoglobulins in the composition, more than 50%, more than 80%, or more than 90% may be lgG3 and / or lgG3 fragments comprising the Fc region.

[0070] In some embodiments, the immunoglobulins may consist of lgG3 and / or lgG3 fragments comprising the Fc region. In other words, all of the immunoglobulins in the composition may be lgG3 and / or lgG3 fragments comprising the Fc region.

[0071] The compositions described herein may be referred to as “lgG3-enriched”. The term “lgG3-enriched” as used herein refers to a composition where the abundance of lgG3 as a proportion of total IgG is more than that which is naturally occurring in blood, particularly human blood.

[0072] In a composition enriched for lgG3 and / or lgG3 fragments comprising the Fc region, preferably more than 7% of the total immunoglobulins are lgG3. Preferably, more than 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the total immunoglobulins are lgG3. The immunoglobulins may comprise between 70% and 100% of lgG3 and / or lgG3 fragments comprising the Fc region.

[0073] In some embodiments, the immunoglobulins are not anti-RhD (also known as anti-D) immunoglobulins. In some embodiments, the immunoglobulins are not anti-RhD (also known as anti-D) IgG.

[0074] In some embodiments, the immunoglobulins are polyclonal immunoglobulins.

[0075] In some embodiments, the immunoglobulins are human polyclonal immunoglobulins.In some embodiments, the immunoglobulins are monoclonal immunoglobulins.

[0076] The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies in the antibody population are identical and / or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being well known in the art.

[0077] In some embodiments, the composition comprising immunoglobulins may be substantially composed of immunoglobulins. For instance, the composition may be at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% composed of immunoglobulins. For example, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the proteins in the composition (w / w) may be immunoglobulins. In other words, in this example, of the total protein content of the composition, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% (w / w) may be immunoglobulins.

[0078] In some embodiments, the composition comprising immunoglobulins may be substantially composed of lgG3 and / or lgG3 fragments comprising the Fc region. For instance, the composition may be at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% composed of lgG3 and / or lgG3 fragments comprising the Fc region. For example, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the proteins in the composition (w / w) may be lgG3 and / or lgG3 fragments comprising the Fc region. In other words, in this example, of the total protein content of the composition, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% (w / w) may be lgG3 and / or lgG3 fragments comprising the Fc region.In some embodiments, the composition comprising immunoglobulins may consist of immunoglobulins.

[0079] In some embodiments, the composition is an immunoglobulin composition. In some embodiments, an immunoglobulin composition may be a composition wherein at least 70%, at least 80%, or at least 90% of the proteins in the composition (w / w) are immunoglobulins.

[0080] In some embodiments, the composition is an IgG composition. In some embodiments, an IgG composition may be a composition wherein at least 70%, at least 80%, or at least 90% of the proteins in the composition (w / w) are IgG.

[0081] In some embodiments, the composition is an lgG3 composition (comprising lgG3 and / or lgG3 fragments comprising the Fc region). In some embodiments, an lgG3 composition may be a composition wherein at least 70%, at least 80%, or at least 90% of the proteins in the composition (w / w) are lgG3 and / or lgG3 fragments comprising the Fc region.

[0082] The invention further provides lgG3 and / or lgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease.

[0083] The invention further provides lgG3 and / or lgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease, wherein the lgG3 and / or lgG3 fragments are present in an immunoglobulin composition, wherein the lgG3 and / or lgG3 fragments are at least 10% of the immunoglobulin composition.

[0084] In another aspect the invention provides a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, wherein the lgG3 and / or lgG3 fragments comprising the Fc region are for use in preventing and / or treating an autoimmune disease.

[0085] As described herein, throughout the description, the lgG3 and / or lgG3 fragments comprising the Fc region are the components of the composition comprising immunoglobulins that are therapeutically active (i.e. they are the active agent) in preventing and / or treating an autoimmune disease.

[0086] In some embodiments, the lgG3 and / or lgG3 fragments comprising the Fc region are not lgG3 pi adrenergic receptors (AR) autoantibodies.

[0087] UseIn the present invention, the composition is for use in preventing and / or treating an autoimmune disease.

[0088] Autoimmune diseases are a diverse group of conditions characterized by aberrant B cell and T cell reactivity to normal constituents of the host. These diseases occur widely and affect individuals of all ages, especially women. Among these diseases, the most prominent immunological manifestation is the production of autoantibodies, which provide valuable biomarkers for diagnosis, classification and disease activity. In general, autoimmune disease results from an interplay between a genetic predisposition and environmental factors. Genetic predisposition to autoimmunity is complex and can involve multiple genes that regulate the function of immune cell populations.

[0089] Autoimmunity is a complex process and the exact mechanism of damage can vary depending on the specific disease. Some autoimmune diseases can be caused by pathogenic antibodies activating the immune system via Fc-mediated effector functions, leading to enhanced ADCC and opsonophagocytosis amongst other functions, such as complement activation.

[0090] lgG3 immunoglobulins exhibit high Fc-mediated activity and complement activation, and are potent mediators of effector functions (ADCC, ADCP and CDC). However, as demonstrated herein, to the surprise of the inventors, lgG3 actually inhibits the ADCC, ADCP and CDC effects of autoimmune diseases caused by pathogenic antibodies. It appears that lgG3 blocks Fc receptors and complement activation, due to its higher affinity compared to other IgG subclasses, and thus limits or decreases the effect of pathogenic antibodies causing autoimmune diseases.

[0091] An “autoimmune disease” as used herein refers to a disease in which the immune system mistakenly identifies native cells as being foreign and attacks them. There are a wide range of autoimmune diseases that affect a wide range of body parts. In the context of the present invention the autoimmune disease may be selected from the following list: Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Myasthenia Gravis (MG), Guillain-Barre Syndrome (GBS), Kawasaki’s Disease, Graves ophthalmopathy (Thyroid Eye Disease), Immune Thrombocytopenia Purpura (ITP), Systemic Lupus Erythematosus, Dermatomyositis, Multifocal Motor Neuropathy, Autoimmune Encephalitis / Meningoencephalitis / Encephalomyelitis, Neuralgic Amyotrophy, Proximal Diabetic Neuropathy - Diabetic Amyotrophy, Autoimmune diabetes mellitus - LADA, Type 1 , Post-Polio Syndrome (PPS), Stiff Person Syndrome, IgM anti-MAG paraprotein-associated peripheral neuropathy, Intractable childhood epilepsy, Paraproteinemic neuropathy (apart from anti-MAG), Autoimmune hemolytic anemia / Evan syndrome, Autoimmune uveitis (Birdshot Retinochoroidopathy),Autoimmune optic neuropathy (optic neuritis), Acute idiopathic dysautonomia, Severe Juvenile idiopathic arthritis, Crohn's disease, Ulcerative Colitis, Acute disseminated encephalomyelitis, Multiple Sclerosis (e.g., relapsing remitting, primary / secondary progressive), Lambert-Eaton Myasthenic Syndrome (LEMS), Necrotizing autoimmune myositis inc statin associated (SRP, HMG-CoA, Jo-1, other myositis Abs), Severe Rheumatoid Arthritis (RA), Fetal / Neonatal Alloimmune Thrombocytopenia (FAIT / NAIT), Asthma steroid dependant (severe, refractory), Graft vs. Host Disease, Pediatric HIV, Post-Bone Marrow Transplant (BMT) / SID, Polymyositis, Stevens-Johnson syndrome, Rasmussen syndrome, Post-transfusion purpura, Autoimmune bullous diseases (pemphigus, epidermolysis bullosa), Generalised recalcitrant morphea, Eosinophilic fasciitis, Alloimmune hemolytic disease of the fetus (treatment), Thrombotic thrombocytopenic purpura, Autoimmune neutropenia, Immune tolerance induction (ITI) in Hemophilia B, Celiac disease, Felty syndrome, Adult-onset Still disease, Macrophage activation syndrome, Haemophagocytic syndrome (Haemophagocytic lymphohistiocytosis or HLH) , Alzheimer’s Disease, Immune mediated autonomic disorders, POTS with evidence of autoimmunity, COVID-POTS and / or COVID-Small Fiber Neuropathy, CRPS, Narcolepsy with cataplexy, Limbic encephalitis, Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis, Immunoglobulin A vasculitis (IgAV; formerly called Henoch-Schdnlein purpura [HSP]), Polyarteritis nodosa, Autism, Inclusion Body Myositis (IBM), Small Fiber Neuropathy, Antiphospholipid antibody syndrome in pregnancy, Neonatal sepsis, Chronic Fatigue Syndrome, Lennox Gastaut Syndrome, Sjogren related small fiber and / or sensory neuropathy, Blood-Related Autoimmune Disorders (Hematology / Oncology), Hemolytic transfusion reactions, Hyperhemolytic crisis in individuals with sickle cell disease who have received transfusions, Digestive Autoimmune Disorders, Endocrine Autoimmune Disorders, Rheumatologic Autoimmune Disorders, Sjogren in general without neurological manifestations, Nervous System Autoimmune Disorders / Muscular disorders, Epilepsy, Pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS) and associated disorders, Neuromyelitis Optica, Spectrum Disorder (NMOSD), Refractory Optic Neuritis, Transverse myelitis, Parkinson’s Disease, Amyotrophic lateral sclerosis, Checkpoint inhibitor associated neurologic syndromes (myasthenia, Al DP, Cl DP, Autonomic neuropathy, encephalitis, transverse myelitis), Myelin oligodendrocyte glycoprotein (mog) antibody disorder, Opsoclonus myoclonus syndrome, Paraneoplastic cerebellar degeneration, Paraneoplastic sensory neuronopathy, Neuromyotonia (Isaac's syndrome), POEMS syndrome, Skin Autoimmune Disorders / Vasculitis / Ophthalmic, Autoimmune Chronic urticaria, Other Autoimmune Disorders / lnfectious, Infection prophylaxis, Autoimmune hepatitis, Non-CF bronchiectasis Transplant, Antibody mediated rejection, Chronic Transplant Rejection, Acute Graft Rejection, Pre-transplant Desensitization, Solid Organ Transplant, Chronic immunosuppression, Membranous nephropathy.In some embodiments, the autoimmune disease may be selected from the group consisting of: Immune Thrombocytopenia Purpura (ITP), Chronic Inflammatory Demyelinating Polyneuropathy (Cl DP), Myasthenia Gravis (MG), Guillain-Barre Syndrome (GBS), Kawasaki’s Disease, Graves ophthalmopathy (Thyroid Eye Disease), Systemic Lupus Erythematosus, Dermatomyositis, Multifocal Motor Neuropathy, Autoimmune Encephalitis, Sjogren Syndrome, Pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS), Paraproteinemic neuropathy, Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD), Autoimmune hemolytic anemia / Evan syndrome, Antineutrophil Cytoplasmic Antibodies disease (ANCA-vasculitis), Bullous Pemphigus, Autoimmune Uveitis, Narcolepsy with cataplexy, and Antiphospholipid Syndrome.

[0092] In some embodiments, the autoimmune disease is Immune Thrombocytopenia Purpura (ITP). ITP is an autoimmune blood disorder characterized by a reduced number of platelets.

[0093] In some embodiments, the autoimmune disease is Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). CIDP is an autoimmune disease characterized by inflammation of nerve roots and peripheral nerves and destruction of the myelin sheath around peripheral nerves.

[0094] Myasthenia gravis (MG) is an autoimmune disease which blocks, alters, or destroys the receptors for acetylcholine, such as acetylcholine receptors and / or muscle-specific kinase proteins, at the neuromuscular junction which prevents the muscle from contracting.

[0095] Guillain-Barre Syndrome (GBS) is an autoimmune disease that targets peripheral nerves characterized by rapid-onset muscle weakness.

[0096] Kawasaki’s Disease, also known as mucocutaneous lymph node syndrome, is a disease that causes inflammation is blood vessels throughout the body, including coronary arteries.

[0097] Graves ophthalmopathy (Thyroid Eye Disease) is an autoimmune inflammatory disorder of the orbit and periorbital tissues.

[0098] Systemic lupus erythematosus (SLE), also known as ‘lupus’, is a chronic autoimmune disease which occurs when the immune system attacks its own tissues. SLE causes inflammation and tissue damage in connective tissues, such as cartilage and the lining of blood vessels.Dermatomyositis is a long-term inflammatory disorder which affects the skin and the muscles. Its symptoms are generally a skin rash and worsening muscle weakness over time.

[0099] Multifocal motor neuropathy (MMN) is a rare immune-mediated motor neuropathy characterized by asymmetric weakness that preferentially affects distal upper limb muscles.

[0100] Autoimmune Encephalitis: This is a group of conditions where the immune system mistakenly attacks the brain, causing inflammation. Symptoms can include memory loss, changes in behavior, seizures, and psychiatric symptoms.

[0101] Sjogren Syndrome: An autoimmune disease that primarily affects the glands that produce saliva and tears, leading to dry mouth and dry eyes. It can also cause joint pain, swelling, and fatigue.

[0102] Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS): This condition occurs in children and is characterized by the sudden onset of obsessive-compulsive disorder (OCD) or tic disorders following a streptococcal infection like strep throat. Symptoms can include anxiety, mood changes, and motor or vocal tics.

[0103] Paraproteinemic Neuropathy: A type of neuropathy associated with the presence of abnormal proteins (paraproteins) in the blood. It can cause symptoms like muscle weakness, numbness, and pain, often related to conditions like multiple myeloma or monoclonal gammopathy of undetermined significance (MGLIS).

[0104] Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD): An autoimmune condition where the immune system attacks the myelin sheath covering nerve fibers in the central nervous system. Symptoms can include vision loss, muscle weakness, and coordination problems.

[0105] Autoimmune Hemolytic Anemia / Evan Syndrome: A rare disorder where the immune system destroys red blood cells, leading to anemia. Evans syndrome is a combination of autoimmune hemolytic anemia and immune thrombocytopenia, where both red blood cells and platelets are attacked. The most common type of autoimmune hemolytic anemia, is Warm Autoimmune Hemolytic Anemia (wAIHA) the where antibodies attack red blood cells at body temperature, leading to their premature destruction. Symptoms include fatigue, pallor, and jaundice.Antineutrophil Cytoplasmic Antibodies disease (ANCA-associated vasculitis): These are autoantibodies that target neutrophils, a type of white blood cell. ANCA-associated vasculitis is a group of autoimmune diseases that cause inflammation of blood vessels, leading to organ damage.

[0106] Bullous Pemphigus: An autoimmune blistering disorder affecting the skin and mucous membranes. It causes large, fluid-filled blisters that can be painful and prone to infection.

[0107] Autoimmune Uveitis: Inflammation of the uvea, the middle layer of the eye, caused by an autoimmune response. Symptoms include eye pain, redness, blurred vision, and light sensitivity.

[0108] Narcolepsy with Cataplexy: A chronic sleep disorder characterized by excessive daytime sleepiness and sudden loss of muscle tone (cataplexy). It is believed to be an autoimmune condition.

[0109] Antiphospholipid Syndrome: An autoimmune disorder where the immune system mistakenly attacks normal proteins in the blood, leading to increased risk of blood clots. It can cause complications like deep vein thrombosis, stroke, and pregnancy-related issues.

[0110] In some embodiments, the autoimmune disease is not cardiac disease and / or systemic sclerosis.

[0111] Cardiac disease or Cardiovascular disease (CVD) is a general term for conditions affecting the heart or blood vessels.

[0112] Scleroderma, also known as systemic sclerosis, is a group of rare diseases that involve the hardening and tightening of the skin. Scleroderma also may cause problems in the blood vessels, internal organs and digestive tract.

[0113] As used herein the terms “treat”, “treating” or “treatment” refer to a clinical improvement of a disease. A clinical improvement may be demonstrated by an improvement of the pathology and / or symptoms associated with the disease.

[0114] In some embodiments, effective treatment may be demonstrated by slowing or halting the progression of the disease in the subject, or reversing the disease. Suitably, the disease maybe reversed partially, or completely. In some embodiments, complete reversal of the disease may be sufficient to result in curing of the disease.

[0115] The terms “preventing and / or treating” include preventing or protecting against the disease or disorder. This may include causing clinical symptoms not to develop; inhibiting the disease or disorder (such as arresting or suppressing the development of clinical symptoms); and / or relieving the disease or disorder i.e. causing the regression of clinical symptoms.

[0116] Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may bind to Fc receptors and / or C1 q to prevent and / or treat the autoimmune disease.

[0117] Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may modulate the complement system to prevent and / or treat the autoimmune disease.

[0118] In some embodiments, the Fc receptors are FcyR receptors.

[0119] An Fc receptor is an antibody receptor involved in antigen recognition which is located at the membrane of certain immune cells including B lymphocytes.

[0120] The complement system plays a crucial role in the innate defense against common pathogens. Activation of complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the pathogen as well as in the generation of the classical inflammatory response through the production of potent proinflammatory molecules. Modulation of the complement system can affect the entire host immune response.

[0121] In some embodiments, the lgG3 and / or lgG3 fragments (comprising the Fc region) may bind to 01 q and / or modulate the complement system to prevent and / or treat the autoimmune disease.

[0122] C1 q (also called complement 01 q) is the first component of the 01 complex in the classical pathway of complement activation. lgG3 has higher affinity for C1q than other subclasses (lgG1, lgG2, lgG-4), so a composition enriched for lgG3 will have higher affinity for 01 q than a composition with lower content of lgG3.

[0123] Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may inhibit antibodydependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and / or complement-dependent cytotoxicity (GDC) to prevent and / or treat the autoimmune disease.In antibody-dependent cellular cytotoxicity (ADCC), an Fey receptor (FcyR or FCGR) on the surface of an immune effector cell binds to the Fc region of an antibody, which specifically binds to a target cell. Cells that can mediate ADCC are non-specific cytotoxic cells such as natural killer cells, macrophages, monocytes, and eosinophils. When FCGR binds to the antibody, the FCGR ITAM is phosphorylated, which triggers the activation of effector cells and the secretion of various substances (lyase, perforin, granzyme, TNF) that mediate target cell destruction.

[0124] Antibody-dependent cellular phagocytosis (ADCP) is a key mechanism of action for many antibody therapies. It is defined as a highly regulated process in which an antibody eliminates binding target and initiates phagocytosis by linking its Fc domain to a specific receptor on the phagocytic cell. Unlike ADCC, ADCP can mediate monocytes, macrophages, neutrophils and dendritic cells via FcyRlla, FcyRI and FcyRllla, where FcyRlla (CD32a) on macrophages represents the major pathway.

[0125] In complement-dependent cytotoxicity (CDC), C1q binds to antibodies, which triggers the complement cascade, resulting in the formation of a membrane attack complex (MAC) (C5b to C9) on the surface of target cells, and further resulting in a classical pathway of complement activation.

[0126] Also provided herein is the use of lgG3 and / or lgG3 fragments (comprising the Fc region) for preventing and / or treating an autoimmune disease.

[0127] Also provided herein is the use of lgG3 and / or lgG3 fragments (comprising the Fc region) for inhibiting antibody-dependent cellular cytotoxicity (ADCC) in a subject with an autoimmune disease.

[0128] Also provided herein is the use of lgG3 and / or lgG3 fragments (comprising the Fc region) for inhibiting antibody-dependent cellular phagocytosis (ADCP) in a subject with an autoimmune disease.

[0129] Also provided herein is the use of lgG3 and / or lgG3 fragments (comprising the Fc region) for inhibiting complement-dependent cytotoxicity (CDC) in a subject with an autoimmune disease.

[0130] Further provided herein is a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising theFc region, for use in inhibiting antibody-dependent cellular cytotoxicity (ADCC) in a subject with an autoimmune disease.

[0131] Further provided herein is a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in inhibiting antibody-dependent cellular phagocytosis (ADCP) in a subject with an autoimmune disease.

[0132] Further provided herein is a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in inhibiting complement-dependent cytotoxicity (CDC).

[0133] lgG3 and / or lgG3 fragments

[0134] Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may be human lgG3 and / or lgG3 fragments.

[0135] Suitably, the immunoglobulins (in the composition described herein) may comprise lgG1, lgG2, lgG4, IgA and / or IgM; or fragments thereof.

[0136] In some embodiments, the lgG3 and / or lgG3 fragments (comprising the Fc region) are in an lgG3 enriched intravenous immunoglobulin (I Vlg) composition.

[0137] In some embodiments, the composition comprising immunoglobulins is an I Vlg composition.

[0138] In one aspect the invention provides an I Vlg composition comprising at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease. The IVIg composition may be referred to as an lgG3 enriched IVIg composition.

[0139] In some embodiments, the lgG3 and / or lgG3 fragments (comprising the Fc region) are in an lgG3 enriched subcutaneous immunoglobulin (SCIg) composition.

[0140] In some embodiments, the composition comprising immunoglobulins is an SCIg composition.

[0141] In one aspect the invention provides an SCIg composition comprising at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease. The SCIg composition may be referred to as an lgG3 enriched SCIg composition.Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may be from blood or ascites.

[0142] Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may be from human blood or ascites.

[0143] Suitably, the immunoglobulins may be human immunoglobulins.

[0144] Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may be from blood plasma.

[0145] Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may be from human blood plasma.

[0146] “Blood” includes a blood sample and / or blood-derived sample, such as plasma or serum. The term “blood plasma” or “plasma” refers to the liquid portion of blood and lymphatic fluid. Plasma generally accounts for about half of the blood volume (e.g. about 50% to 60% by volume). There are substantially no cells in the plasma. Plasma may contain coagulation factors, in particular fibrinogen, and water. Plasma components include electrolytes, lipid metabolites, biomarkers such as markers for infection or tumor, enzymes, substrates, proteins, and additional molecular components. As used herein, the term “serum” refers to the fluid and solute component of blood which does not play a role in clotting. It may be defined as blood plasma without fibrinogen. These materials are readily available commercially, for example from donor centers widely located globally or from commercial suppliers of laboratory reagents.

[0147] Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may be recombinant and / or synthetic lgG3 and / or lgG3 fragments.

[0148] Suitably, the lgG3 and / or lgG3 fragments (comprising the Fc region) may be human lgG3 and / or lgG3 fragments.

[0149] Synthetic antibodies are affinity reagents generated entirely in vitro, thus completely eliminating animals from the production process. Synthetic antibodies include recombinant antibodies, nucleic acid aptamers and non-immunoglobulin protein scaffolds. As a consequence of their in vitro manufacturing method the antigen recognition site of synthetic antibodies can be engineered to any desired target and may extend beyond the typical immune repertoire offered by natural antibodies.Recombinant antibodies are monoclonal antibodies generated in vitro using synthetic genes. Recombinant antibody technology involves recovering the antibody genes from the source cells, amplifying and cloning the genes into an appropriate vector, introducing the vector into a host, and achieving expression of adequate amounts of functional antibody. Recombinant antibodies can be cloned from any species of antibody-producing animal, if the appropriate oligonucleotide primers or hybridization probes are available. The ability to manipulate the antibody genes make it possible to generate new antibodies and antibody fragments, such as Fab fragments, scFv and Fc fragments in vitro. This can be done at the level of the whole combining site by making new combinations of H and L chains. It can also be done by mutating individual CDRs. Display libraries, commonly expressed in phage or yeast, can be analysed to select for desirable characteristics arising from such changes in antibody sequence

[0150] The term “recombinant” refers to proteins that result from the expression of recombinant DNA within living cells. Recombinant DNA is the general name for a piece of DNA that has been created by the combination of at least two separate segments of DNA.

[0151] Preparation

[0152] Methods for the preparation of compositions comprising immunoglobulins from starting materials (such as blood or plasma) are known in the art.

[0153] For example, a caprylate / chromatography manufacturing process can be used. In brief, caprylic acid is used to precipitate immunoglobulins from plasma followed by chromatographic purification with an ion exchange or hydrophobic matrix. Once prepared, various methods can be used to provide a composition comprising immunoglobulins, wherein the immunoglobulins are enriched for lgG3 (i.e. where the abundance of lgG3 as a proportion of total IgG is more than that which is naturally occurring in blood, particularly human blood).

[0154] For example, a typical process to prepare a composition comprising blood-derived immunoglobulin is the use of affinity chromatography. Affinity chromatography (also called affinity purification) makes use of specific binding interactions between molecules. The term “affinity chromatography” as used herein, refers to a mode of chromatography where a target substance (such as a target protein e.g., IgG) to be separated is isolated by its interaction (affinity) with a molecule (e.g., IgG binding affinity ligand) which specifically interacts with the target substance, wherein the molecule is stationary due to be being bound to the chromatographic solid support (also known as a stationary phase). A particular ligand is chemically immobilized or “coupled” to a solid support so that when an immunoglobulin-containing sample comes into contact with the stationary phase, those molecules in theimmunoglobulin-containing sample having specific binding affinity to the ligand become bound. After other sample components are washed away, the bound molecule is stripped from the chromatographic solid support, resulting in its purification from the original sample. Alternatively, it may be the flow-through material that is the material of interest, i..e. the bound molecule (having specific binding affinity to the ligand coupled to the solid support) is removed from the immunoglobulin-containing sample, thereby purifying the sample and producing a flow-through material of interest. Affinity chromatography described herein may be affinity column chromatography, meaning the stationary phase is immobilized as part of the column.

[0155] One example of a particular ligand used in such an affinity chromatography process is protein A. This ligand is well known in the field of immunoglobulin purification and suitable chromatography stationary phases containing this ligand can be obtained from many commercial suppliers of laboratory equipment and reagents. Examples of suitable and commercially available protein A stationary phases include MabSelect PrismA Protein A chromatography resin, Purolite DurA Cycle A50 (ECOI-AB), Amsphere A+ (JSR Life Sciences), TOYOPEARL Super A and TOYOPEARL AF-rProtein A HC-650F (Tosoh Bioscience), MabCaptureC High Capacity (Thermo Scientific), and KanCapA 3G (Kaneka). It is known the protein A is preferably bound by lgG1, lgG2 and lgG4 isoforms of IgG. Hence when material containing all found isotypes of IgG is passed through a protein A column, then the flow-through material will be substantially enriched for lgG3, while the eluent from the affinity chromatography column will be substantially deficient in lgG3. By preparing these two samples of IgG containing material, it is possible to adjust the quantity of lgG3 relative to the other IgG so as to prepare compositions enriched for lgG3 at the desired amount. Conditions for the preparation of flow-through material substantially enriched for lgG3 and an eluent substantially deficient in lgG3 are well known in the art, including the choice of loading buffer, wash buffer and elution buffers, for example conditions described by the manufacturers of protein A stationary phases may be used where appropriate.

[0156] The term "Protein A" as used herein refers to the 42 kDa Staphylococcus aureus cell wall Protein A. Similar results may be achieved with natural forms, recombinant forms, modified (for example truncated) forms, engineered forms, and derivatives of protein A.

[0157] In some embodiments, the compositions comprising immunoglobulins are enriched for lgG3 (and / or lgG3 fragments comprising the Fc region) in vitro. In other words, the composition comprising immunoglobulins is enriched for lgG3 (and / or lgG3 fragments comprising the Fc region) in vitro.In some embodiments, the compositions comprising immunoglobulins are depleted for lgG1, I gG2, and / or lgG4 or fragments thereof in vitro. In other words, the composition comprising immunoglobulins is depleted for lgG1, lgG2, and / or lgG4 or fragments thereof in vitro.

[0158] In some embodiments, the compositions comprising immunoglobulins are enriched for lgG3 (and / or lgG3 fragments comprising the Fc region) using affinity chromatography. In other words, the composition comprising immunoglobulins is enriched for lgG3 (and / or lgG3 fragments comprising the Fc region) using affinity chromatography.

[0159] In some embodiments, the compositions comprising immunoglobulins are depleted for lgG1, lgG2, and / or lgG4 or fragments thereof using affinity chromatography. In other words, the composition comprising immunoglobulins is depleted for I gG 1 , 1 gG2, and / or lgG4 or fragments thereof using affinity chromatography.

[0160] In some embodiments, the affinity chromatography uses a stationary phase containing protein A.

[0161] The affinity chromatography produces a flow-through material. In some embodiments, the flow-through material is a composition comprising immunoglobulins enriched for lgG3.

[0162] In some embodiments, the flow-through material is a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region.

[0163] In some embodiments, the flow-through material is a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 50%, at least 80%, or at least 90% lgG3 and / or lgG3 fragments comprising the Fc region.

[0164] In some embodiments, the flow-through material is a composition comprising immunoglobulins, wherein the immunoglobulins comprise more than 50%, more than 80%, or more than 90% lgG3 and / or lgG3 fragments comprising the Fc region.

[0165] In some embodiments, the compositions comprising immunoglobulins are enriched for lgG3 using protein A. In other words, the composition comprising immunoglobulins enriched for lgG3 (i.e. the lgG3-enriched product) is obtained from protein A purification.In some embodiments, the compositions comprising immunoglobulins are enriched for lgG3 using protein A affinity chromatography. In other words, the composition comprising immunoglobulins enriched for lgG3 (i.e. the lgG3-enriched product) is obtained from a chromatographic process using a stationary phase comprising protein A.

[0166] In some embodiments, the immunoglobulins are blood-derived immunoglobulins.

[0167] In some embodiments, the immunoglobulins are from blood plasma.

[0168] In some embodiments, the immunoglobulins are recombinant or synthetic.

[0169] In some embodiments, the affinity chromatography comprises adding blood plasma or a blood plasma-derived sample to a chromatography column containing protein A. In other words, the immunoglobulin-containing sample (which contacts the stationary phase) is blood plasma or a blood plasma-derived sample.

[0170] In some embodiments, the immunoglobulin-containing sample (which contacts the stationary phase) is a commercial IgG product (IVIg). The commercial IgG product (I Vlg) is enriched for lgG3 by being processed through a protein A column that presents minimal lgG3 binding. Hence, the flow-through material is a composition comprising immunoglobulins enriched for lgG3 e.g. an lgG3-enriched fraction or product.

[0171] In some embodiments the lgG3-enriched fraction undergoes further processing prior to administration. This further processing may include polishing steps, buffer exchange steps, further affinity chromatography steps, size exclusion chromatography steps, and dilution / concentration.

[0172] As can be appreciated by the skilled person, a composition comprising polyclonal immunoglobulins enriched for lgG3 can be obtained from a blood-derived sample and can comprise a combination of different polyclonal immunoglobulins which bind to different antigens.

[0173] A composition comprising polyclonal immunoglobulins enriched for lgG3 may alternatively be prepared using a combination of recombinant monoclonal immunoglobulins. Methods of preparing recombinant monoclonal immunoglobulins are well known in the art.

[0174] In general, recombinant immunoglobulins are monoclonal immunoglobulins that are produced in vitro by using known antibody coding genes. The coding sequences of the heavy and light

[0175] 1chain of an antibody can be obtained for example by hybridoma sequencing. The sequences are cloned into an expression vector and are transfected into a mammalian host cell line for immunoglobulin expression. Stably transfected cell clones can be generated and the expression can be adapted and optimized.

[0176] The term “recombinant” refers to proteins that result from the expression of recombinant DNA within living cells. Recombinant DNA is the general name for a piece of DNA that has been created by the combination of at least two separate segments of DNA.

[0177] Used herein the term “effluent” has the same meaning as eluate, i.e. the fluid obtained when the stationary phase is contacted with the eluent. As such the effluent may comprise the elution buffer and any immunoglobulins formerly bound to the stationary phase.

[0178] Used herein the term “eluent” refers to a substance which is applied to a stationary phase to remove compounds bound to the stationary phase.

[0179] Used herein the term “flow through” refers to the fluid obtained when a sample in loading buffer is contacted with the stationary phase. As such the flow through may comprise the loading buffer and any immunoglobulins which have not bound to the stationary phase. Optionally the flow through may comprise components other than the loading buffer and any immunoglobulins which have not bound to the stationary phase, for example the flow through may comprise wash buffer, and / or additional loading buffer used to wash the stationary phase following the stationary phase being contacted with the sample.

[0180] Used herein the term “stationary phase” has its usual meaning in chromatography, a non-fluid substance to which components of the sample bind to preferentially relative to the mobile phase. Stationary phase is used in contrast to mobile phase. Mobile phase refers to fluids used in chromatography such as the loading buffer, wash buffers and elution buffers.

[0181] In the context of the present disclosure the term “contacting” means bringing a sample into sufficient proximity to the stationary phase to allow binding of substances in the sample having affinity for the stationary phase to the stationary phase. Suitably, the step of “contacting” may occur within an affinity chromatography column.

[0182] AdministrationThe composition of the invention can be administered by any suitable route including, for example, injection, intravenous infusion, intradermal, subcutaneous, percutaneous, intramuscular, intra-arterial, intraperitoneal, intraarticular, intraosseous, intravesicular, transdermally, intradermally, orally, topically, intranasal, inhaled, ocular or other appropriate administration routes. Administration can be "parenteral administration" meaning modes of administration other than enteral and topical administration, usually by injection. Alternatively, the composition of the invention can be administered via a non-parenteral route. Administration may be systemic or local. Local administration includes peritumoral, juxtatumoral, intratumoral, intralesional, perilesional, intra cavity infusion, intravesicle administration, subcutaneous and inhalation.

[0183] Preferably, the administration is by subcutaneous and / or intravenous routes or infusion.

[0184] In some embodiments, the composition is administered by a subcutaneous route.

[0185] In some embodiments, the composition is administered by an intravenous route.

[0186] In some embodiments, the composition is administered as a subcutaneous immunoglobulin (SCIg) therapy.

[0187] In some embodiments, the composition is administered as an intravenous immunoglobulin (IVIg) therapy.

[0188] In some embodiments, the composition is formulated for administration by a subcutaneous route.

[0189] In some embodiments, the composition is formulated for administration by an intravenous route.

[0190] In some embodiments, the composition is formulated for administration as a subcutaneous immunoglobulin (SCIg) therapy.

[0191] In some embodiments, the composition is formulated for administration as an intravenous immunoglobulin (IVIg) therapy.

[0192] The administration may be subcutaneous administration. As used herein “subcutaneous” refers to the administration of the composition of the invention by subcutaneous injection. Asubcutaneous injection may be administered as a bolus or infusion into the subcutis, the layer of skin directly below the dermis and epidermis, collectively referred to as the cutis. The volume injected may be, e.g., in the range of 0.1 - 1000 ml, such as, 1 - 700 ml.

[0193] The administration may be intravenous. As used herein “intravenous” refers to the administration of the composition of the invention by injection of a medication or another substance into a vein and directly into the bloodstream. It allows for the controlled administration of medicaments with minimal delay and can have patient comfort benefits over subcutaneous or other forms of administration.

[0194] A suitable dosage of a composition of the invention of the invention may be determined by a skilled medical practitioner. Actual dosage levels of a composition of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular antibody employed, the route of administration, the time of administration, the rate of excretion of the antibody, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0195] In some embodiments, the immunoglobulin may be administered at a dosage amount of at least 0.01 g / kg, 0.05 g / kg, 0.1 g / kg, 0.15 g / kg, 0.2 g / kg, 0.25 g / kg, 0.3 g / kg, 0.35 g / kg, 0.4 g / kg, 0.45 g / kg, 0.5 g / kg, 0.55 g / kg, 0.6 g / kg, 0.65 g / kg, 0.7 g / kg, 0.75 g / kg, 0.8 g / kg, 0.85 g / kg, 0.9 g / kg, 0.95 g / kg, 1 g / kg, 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg or 10 g / kg, optionally wherein the dosage amount is in the range of 0.01 g / kg to 5 g / kg. A suitable dose of the immunoglobulin may be, for example, in the range of from about 0.01 g / kg to about 5 g / kg body weight of the subject to be treated. In some embodiments, the immunoglobulin is administered at a dosage amount of 0.01 g / kg - 2 g / kg.

[0196] In other words, in this embodiment, the composition is administered to the subject at a dosage amount that equates to at least 0.01 g / kg, 0.05 g / kg, 0.1 g / kg, 0.15 g / kg, 0.2 g / kg, 0.25 g / kg, 0.3 g / kg, 0.35 g / kg, 0.4 g / kg, 0.45 g / kg, 0.5 g / kg, 0.55 g / kg, 0.6 g / kg, 0.65 g / kg, 0.7 g / kg, 0.75 g / kg, 0.8 g / kg, 0.85 g / kg, 0.9 g / kg, 0.95 g / kg, 1 g / kg, 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg or 10 g / kg (wherein the dose is g of immunoglobulin per kg of the subject). Optionally, the composition is administered to the subject at a dosage amount that equates to a range of 0.01 g / kg to 5 g / kg (wherein the dose is g of immunoglobulin per kg of the subject).A suitable dose of the immunoglobulin may be, for example, in the range of from about 0.01 g / kg to about 5 g / kg body weight of the subject to be treated. In some embodiments, the composition is administered to the subject at a dosage amount that equates to a range of 0.01 g / kg - 2 g / kg (wherein the dose is g of immunoglobulin per kg of the subject).

[0197] In some embodiments, the lgG3 and / or lgG3 fragment may be administered at a dosage amount of at least 0.01 g / kg, 0.05 g / kg, 0.1 g / kg, 0.15 g / kg, 0.2 g / kg, 0.25 g / kg, 0.3 g / kg, 0.35 g / kg, 0.4 g / kg, 0.45 g / kg, 0.5 g / kg, 0.55 g / kg, 0.6 g / kg, 0.65 g / kg, 0.7 g / kg, 0.75 g / kg, 0.8 g / kg, 0.85 g / kg, 0.9 g / kg, 0.95 g / kg, 1 g / kg, 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg or 10 g / kg, optionally wherein the dosage amount is in the range of 0.01 g / kg to 5 g / kg. A suitable dose of the lgG3 and / or lgG3 fragment may be, for example, in the range of from about 0.01 g / kg to about 5 g / kg body weight of the subject to be treated. In some embodiments, the lgG3 and / or lgG3 fragment is administered at a dosage amount of 0.01 g / kg - 2 g / kg.

[0198] In other words, in this embodiment, the composition is administered to the subject at a dosage amount that equates to at least 0.01 g / kg, 0.05 g / kg, 0.1 g / kg, 0.15 g / kg, 0.2 g / kg, 0.25 g / kg, 0.3 g / kg, 0.35 g / kg, 0.4 g / kg, 0.45 g / kg, 0.5 g / kg, 0.55 g / kg, 0.6 g / kg, 0.65 g / kg, 0.7 g / kg, 0.75 g / kg, 0.8 g / kg, 0.85 g / kg, 0.9 g / kg, 0.95 g / kg, 1 g / kg, 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg or 10 g / kg (wherein the dose is g of the lgG3 and / or lgG3 fragment per kg of the subject). Optionally, the composition is administered to the subject at a dosage amount that equates to a range of 0.01 g / kg to 5 g / kg (wherein the dose is g of the lgG3 and / or lgG3 fragment per kg of the subject). A suitable dose of the lgG3 and / or lgG3 fragment may be, for example, in the range of from about 0.01 g / kg to about 5 g / kg body weight of the subject to be treated. In some embodiments, the composition is administered to the subject at a dosage amount that equates to a range of 0.01 g / kg - 2 g / kg (wherein the dose is g of the lgG3 and / or lgG3 fragment per kg of the subject).

[0199] In one aspect the invention provides a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease, wherein the composition is administered as an intravenous immunoglobulin (IVIg), wherein the immunoglobulin is administered at a dosage amount of 0.01 g / kg - 2 g / kg.

[0200] In another aspect the invention provides a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease, wherein thecomposition is administered as an intravenous immunoglobulin (IVIg), wherein the lgG3 and / or lgG3 fragment is administered at a dosage amount of 0.01 g / kg - 2 g / kg.

[0201] In a further aspect the invention provides a composition comprising immunoglobulins, wherein the immunoglobulins comprise lgG3 and / or lgG3 fragments comprising the Fc region administered at a dosage amount of 0.01 g / kg - 2 g / kg, for use in preventing and / or treating an autoimmune disease, wherein the composition is administered as an intravenous immunoglobulin (IVIg).

[0202] In one aspect the invention provides a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease, wherein the composition is administered as a subcutaneous immunoglobulin (SCIg), wherein the immunoglobulin is administered at a dosage amount of 0.01 g / kg - 2 g / kg.

[0203] In another aspect the invention provides a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease, wherein the composition is administered as a subcutaneous immunoglobulin (SCIg), wherein the lgG3 and / or lgG3 fragment is administered at a dosage amount of 0.01 g / kg - 2 g / kg.

[0204] In a further aspect the invention provides a composition comprising immunoglobulins, wherein the immunoglobulins comprise lgG3 and / or lgG3 fragments comprising the Fc region administered at a dosage amount of 0.01 g / kg - 2 g / kg, for use in preventing and / or treating an autoimmune disease, wherein the composition is administered as a subcutaneous immunoglobulin (SCIg).

[0205] In some embodiments, the immunoglobulin may be administered at a dosage amount of at most 0.01 g / kg, 0.05 g / kg, 0.1 g / kg, 0.15 g / kg, 0.2 g / kg, 0.25 g / kg, 0.3 g / kg, 0.35 g / kg, 0.4 g / kg, 0.45 g / kg, 0.5 g / kg, 0.55 g / kg, 0.6 g / kg, 0.65 g / kg, 0.7 g / kg, 0.75 g / kg, 0.8 g / kg, 0.85 g / kg, 0.9 g / kg, 0.95 g / kg, 1 g / kg, 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg or 10 g / kg. A suitable dose of the immunoglobulin may be, for example, in the range of from about 0.01 g / kg to about 0.14 g / kg body weight of the subject to be treated. In some embodiments, the immunoglobulin is administered at a dosage amount of at most 0.14 g / kg, at most 0.13 g / kg, at most 0.12 g / kg, at most 0.11 g / kg, at most 0.1 g / kg, at most 0.05 g / kg, or at most 0.01 g / kg.In other words, in this embodiment, the composition is administered to the subject at a dosage amount that equates to at most 0.01 g / kg, 0.05 g / kg, 0.1 g / kg, 0.15 g / kg, 0.2 g / kg, 0.25 g / kg, 0.3 g / kg, 0.35 g / kg, 0.4 g / kg, 0.45 g / kg, 0.5 g / kg, 0.55 g / kg, 0.6 g / kg, 0.65 g / kg, 0.7 g / kg, 0.75 g / kg, 0.8 g / kg, 0.85 g / kg, 0.9 g / kg, 0.95 g / kg, 1 g / kg, 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg or 10 g / kg (wherein the dose is g of immunoglobulin per kg of the subject). A suitable dose of the immunoglobulin may be, for example, in the range of from about 0.01 g / kg to about 0.14 g / kg body weight of the subject to be treated. In some embodiments, the immunoglobulin is administered at a dosage amount of at most 0.14 g / kg, at most 0.13 g / kg, at most 0.12 g / kg, at most 0.11 g / kg, at most 0.1 g / kg, at most 0.05 g / kg, or at most 0.01 g / kg (wherein the dose is g of immunoglobulin per kg of the subject).

[0206] In some embodiments, the lgG3 and / or lgG3 fragment may be administered at a dosage amount of at most 0.01 g / kg, 0.05 g / kg, 0.1 g / kg, 0.15 g / kg, 0.2 g / kg, 0.25 g / kg, 0.3 g / kg, 0.35 g / kg, 0.4 g / kg, 0.45 g / kg, 0.5 g / kg, 0.55 g / kg, 0.6 g / kg, 0.65 g / kg, 0.7 g / kg, 0.75 g / kg, 0.8 g / kg, 0.85 g / kg, 0.9 g / kg, 0.95 g / kg, 1 g / kg, 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg or 10 g / kg. A suitable dose of the lgG3 and / or lgG3 fragment may be, for example, in the range of from about 0.01 g / kg to about 0.14 g / kg body weight of the subject to be treated. In some embodiments, the lgG3 and / or lgG3 fragment is administered at a dosage amount of at most 0.14 g / kg, at most 0.13 g / kg, at most 0.12 g / kg, at most 0.11 g / kg, at most 0.1 g / kg, at most 0.05 g / kg, or at most 0.01 g / kg.

[0207] In other words, in this embodiment, the composition is administered to the subject at a dosage amount that equates to at most 0.01 g / kg, 0.05 g / kg, 0.1 g / kg, 0.15 g / kg, 0.2 g / kg, 0.25 g / kg, 0.3 g / kg, 0.35 g / kg, 0.4 g / kg, 0.45 g / kg, 0.5 g / kg, 0.55 g / kg, 0.6 g / kg, 0.65 g / kg, 0.7 g / kg, 0.75 g / kg, 0.8 g / kg, 0.85 g / kg, 0.9 g / kg, 0.95 g / kg, 1 g / kg, 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg or 10 g / kg (wherein the dose is g of the lgG3 and / or lgG3 fragment per kg of the subject). A suitable dose of the lgG3 and / or lgG3 fragment may be, for example, in the range of from about 0.01 g / kg to about 0.14 g / kg body weight of the subject to be treated. In some embodiments, the lgG3 and / or lgG3 fragment is administered at a dosage amount of at most 0.14 g / kg, at most 0.13 g / kg, at most 0.12 g / kg, at most 0.11 g / kg, at most 0.1 g / kg, at most 0.05 g / kg, or at most 0.01 g / kg (wherein the dose is g of the lgG3 and / or lgG3 fragment per kg of the subject).

[0208] Administration of any given dose may occur daily, weekly, monthly, or annually. The composition of the invention may be administered on multiple occasions to the same subject. Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus or infusion may be administered, or themethod may comprise several divided doses administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation, provided the required interval. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0209] In one embodiment, the subject to be treated is human.

[0210] Additional agents

[0211] Suitably, the composition may further comprise and / or be used in combination with one or more additional therapeutic agents selected from: corticosteroids, anti-inflammatory, painkilling medication, immunosuppressant drugs, FcRn inhibitors, Fc-multimers, FcyR inhibitors , antibody-drug conjugates, check point agonist / inhibitors, and / or complement inhibitors.

[0212] The term “corticosteroids” as used herein refers to a medicament selected without limitation from the following: Dexamethasone, Methylprednisolone, Prednisolone, Betamethasone, Hydrocortisone, Triamcinolone, Budesonide, Deflazacort, Clobetasol, Fluticasone and Pulmicort.

[0213] The term “anti-inflammatory” refers to a drug or substance that reduces inflammation (redness, swelling, and pain) in the body. Anti-inflammatory agents block certain substances in the body that cause inflammation. They are used to treat many different conditions. Examples include ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, indomethacin and aspirin.

[0214] The term “pain-killing medication” refers to medications known as analgesics, also called painkillers. These are medications that relieve different types of pain — from headaches to injuries to arthritis. Anti-inflammatory analgesics reduce inflammation.

[0215] The term “immunosuppressant drugs” as used herein refers to a medicament selected without limitation from the following: Azathioprine, Cyclosporine, Ciclosporin, Mycophenolic acid, Tacrolimus, Methotrexate, mTOR inhibitors, Sirolimus, Everolimus, Leflunomide, Omalizumab, Alemtuzumab, Antibodies, Antithymocyte globulin (rabbit), ATGAM, Antimetabolites, Basiliximab, Muromonab, Rituximab, Tocilizumab.The term “FcRn inhibitors” as used herein refers to a medicament selected without limitation from the following: Efgartigimod, Rozanolixizumab, Batoclimab, Nipocalimab, Orilanolimab.

[0216] An “Fc multimer” is a multimer of Fc polypeptides or fragments.

[0217] “FcyR inhibitors” refers to agents that block the activity of Fc gamma receptors (FcyRs) preventing the activation of the immune cells and minimizing inflammation and tissue damage.

[0218] The term "antibody-drug conjugate" as used herein refers to antibody-based conjugates that are configured to deliver a drug to a cell. A “drug” or “therapeutic” is any chemical substance that affects the functioning of living things and the organisms (such as bacteria, fungi, and viruses) that infect them. A “toxic drug” is a drug that is toxic to target cells and kills them.

[0219] A checkpoint inhibitor or agonist targets and blocks key reference point receptors, produced by immune and cancer cells. For example, the checkpoint inhibitor may inhibit at least one of CTLA4, PD-1, PD-L1, TIM-3 or LAG-3.

[0220] The term “complement inhibitors” as used herein refers to a medicament selected without limitation from the following: Cinryze, Berinert, Ruconest, Sutimlimab, Pegcetacoplan, Eculizumab, Ravulizumab, Avacincaptad pegol, Pozelimab, Zilucoplan, Iptacopan, Avacopan.

[0221] The present invention also contemplates the use of supplementary therapeutic agents in combination with composition of the invention. The supplementary therapeutic agents can be co-formulated with composition of the invention as a unit dosage form, i.e. as a physically discrete unit intended as a unitary dosage for the subject to be treated.

[0222] Alternatively, the supplementary therapeutic agents can be presented as a kit-of-parts, and: administered separately to composition of the invention, in a phased or sequential dosing pattern; or co-administered simultaneously from different dosage forms.

[0223] The composition of the invention described herein may be a pharmaceutical composition or part of a pharmaceutical composition. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is part of a pharmaceutical composition.

[0224] In other words, in one aspect the invention provides a pharmaceutical composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / orlgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease. In another aspect, the invention provides a pharmaceutical composition comprising a composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease.

[0225] As used herein, “pharmaceutical composition” refers to a composition comprising one or more compounds that is formulated for administration to a subject. Pharmaceutical compositions typically comprise one or more active ingredients (e.g. in this case a composition of the invention) and one or more pharmaceutically acceptable materials. The pharmaceutical compositions described herein may therefore comprise composition of the invention and one or more other components. For example, the pharmaceutical composition may comprise a composition of the invention and a pharmaceutically acceptable excipient, diluent and / or carrier. Pharmaceutical compositions may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, supplementary immune potentiating agents such as adjuvants and optionally other therapeutic agents or compounds.

[0226] As used herein, "pharmaceutically acceptable" refers to a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected compound (e.g. composition of the invention) without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

[0227] In some embodiments, the composition may further comprise an adjuvant, diluent and / or excipient.

[0228] An “adjuvant” is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. It is an ingredient in a medicine that increases or modifies the activity of the other ingredients.

[0229] Diluents are diluting agents. Pharmaceutically acceptable diluents are well known in the art. A suitable diluent is therefore easily identifiable by one of ordinary skill in the art.

[0230] Excipients are natural or synthetic substances formulated alongside an active ingredient included for the purpose of bulking-up the formulation or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption orsolubility. Excipients can also be useful in the manufacturing process, to aid in the handling of the active substance concerned such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation over the expected shelf life. Pharmaceutically acceptable excipients are well known in the art. A suitable excipient is therefore easily identifiable by one of ordinary skill in the art. By way of example, suitable pharmaceutically acceptable excipients include water, saline, aqueous dextrose, glycerol, ethanol, and the like. For example, the pharmaceutical compositions may include formulations used in commercial products (e.g. glycine, proline, polysorbate, sorbitol, alanine).

[0231] Unless defined otherwise herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. For example, Singleton and Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d Ed., John Wiley and Sons, NY (1994); and Hale and Marham, The Harper Collins Dictionary of Biology, Harper Perennial, NY (1991) provide those of skill in the art with a general dictionary of many of the terms used in the invention. Although any methods and materials similar or equivalent to those described herein find use in the practice of the present invention, the preferred methods and materials are described herein. Accordingly, the terms defined immediately below are more fully described by reference to the Specification as a whole. Also, as used herein, the singular terms "a", "an," and "the" include the plural reference unless the context clearly indicates otherwise. Unless otherwise indicated, nucleic acids are written left to right in 5' to 3' orientation; amino acid sequences are written left to right in amino to carboxy orientation, respectively. It is to be understood that this invention is not limited to the particular methodology, protocols, and reagents described, as these may vary, depending upon the context they are used by those of skill in the art.

[0232] Aspects of the invention are demonstrated by the following non-limiting examples.

[0233] Examples

[0234] Materials and Methods

[0235] Material:

[0236] Commercial IgG product (I VI g) is processed through a Protein A column that presents minimal lgG3 binding, obtaining an effluent that contains mostly a mix of lgG1, lgG2 and lgG4 (<1% of lgG3) and a flowthrough mainly containing lgG3 (lgG3-enriched fraction). Characterization of I Vlg and lgG3-enriched products have been conducted. Percentages below 2% and over80% of lgG3 have been detected in commercial IVIg and lgG3-enriched products, respectively.

[0237] To conduct in vitro studies, mixtures commercial IgG (< 2% content of lgG3) and lgG3-enriched (> 80% content of lgG3) products were prepared in order to obtain the desired percentage of lgG3 content. This resulted in products with varying lgG3 percentages: 10%, 50% and 75%. The 2% lgG3 product corresponds to commercial human IgG, while the 80% lgG3 product corresponds to lgG3-enriched product obtained from Protein-A purification.

[0238] Methods:

[0239] To assess the therapeutic potential of non-pathogenic lgG3 in autoimmune diseases, its ability to block immune cell Fey receptors and modulate complement system has been evaluated using both in vitro and in vivo studies. In vitro assessment has included multiple assays to measure ADCC (antibody-dependent cellular cytotoxicity), ADCP (antibody-dependent cellular phagocytosis) and CDC (complement-dependent cytotoxicity). In all these assays, cells expressing CD20 in their surface and anti-CD20 antibodies have been used in order to mimic autoimmune conditions in vitro. Specifically, we used cells expressing CD20 on their surface as an autoantigen and anti-CD20 antibodies as autoantibodies to simulate target cells. Using this autoimmune disease context in vitro, we assessed the efficacy of products with different percentages of lgG3 in inhibiting FcyRllla activation through the ADCC assay, FcyRlla activation using the ADCP assay and complement system activation thorough the CDC assay. Moreover, efficacy of lgG3 treating autoimmune diseases has been confirmed in vivo in a dose-response study using the immune thrombocytopenia (ITP) rat model.

[0240] ADCC assay

[0241] ADCC evaluation assays evaluate the ability of a product to interfere with the interaction of autoantibodies with FcyRllla receptors leading to the activation of NK cells (effector cells). Raji target cells are CD20-expressing cells (mimicking autoantigens) that in combination with anti-CD20 antibodies (mimicking autoantibodies) can activate Jurkat effector cells. These effector cells contain a luciferase reporter gene driven by an NFAT response element (NFAT-RE). Therefore, their activation is detected by an increase in the bioluminescent signal observed. In this case, we take advantage of this assay to evaluate the efficacy of products with different percentages of lgG3 to inhibit NK cells activation.

[0242] ADCP assay

[0243] ADCP activation assays assess the ability of a product to interfere with the interaction of autoantibodies with FcyRlla-H receptors triggering the activation of for example macrophagesand consequently cell phagocytosis in an autoimmune disease context in vitro. Raji target cells are CD20-expressing cells (mimicking autoantigens) that treated with anti-CD20 antibodies (mimicking autoantibodies) can activate effector cells. As these effector cells contain a luciferase reporter gene driven by an NFAT response element, their activation is detected by an increase in the bioluminescent signal observed. In this case, we take advantage of this assay to evaluate the efficacy of products with different percentages of lgG3 to inhibit macrophages activation.

[0244] CDC assay

[0245] CDC activation assays assess the ability of a product to limit the interaction of autoantibodies with serum complement system components triggering the formation of the membrane attack complex (MAC) on the surface of target cells and subsequent cell lysis. In order to emulate an autoimmune disease context in vitro, human serum containing the components of the complement system is used, together with Ramos cells expressing CD20 on their surface (mimicking autoantigens; target cells) and anti-CD20 antibodies (mimicking autoantibodies). This model allows the assessment of the capacity of a product to activate or inhibit the complement system and subsequent cell lysis, which is measured using a luminescent cytotoxicity assay. Specifically, this assay measures the extracellular activity of multiple intracellular proteases that are released from membrane-compromised cells and correlates with the percentage of cell lysis. In this case, we take advantage of this assay to evaluate the efficacy of products with different percentages of lgG3 to inhibit complement system activation.

[0246] In vivo ITP model and platelet drop counting

[0247] In the rat model of ITP, male Wistar-Han rats are intravenously (IV) administered with rabbit anti-rat thrombocyte anti-serum which causes a rapid and significant decrease of circulating platelets. The drop of platelet counts could reach as low as 20-30% of the baseline level, effectively simulating the clinical manifestations of ITP. Blood samples were collected at different time points to perform a complete blood cell count (CBC) to determine the blood platelet levels. The effectiveness of lgG3 was evaluated by monitoring the platelet drop count in these animals.

[0248] Results

[0249] ADCC

[0250] The increased percentage of lgG3 significantly reduced ADCC induction in a dose-dependent manner, increasing the inhibition with the percentage of lgG3 (Figure 1A). >80% lgG3 enriched product achieved a 66% inhibition of ADCC relative to the saline condition, whereascommercial IgG, which contains 2% lgG3, only achieved a 25% inhibition (Figure 1A). These results enabled the calculation of the improvement in the effectiveness of lgG3 to inhibit ADCC compared to commercial IgG products (2% lgG3 condition), as shown in Figure 1B. >80% lgG3 enriched product achieved a 54% increase in ADCC inhibition effectiveness compared to the commercial IgG containing 2% lgG3. Figure 1C illustrates the dose-dependent inhibition of ADCC. As the concentration of the lgG3-enriched product increases, there is a corresponding enhancement in ADCC inhibition, demonstrating superior performance compared to the commercial IgG product.

[0251] ADCP

[0252] The use of lgG3 also led to a significant dose-dependent reduction in ADCP induction, where higher percentages of lgG3 resulted in greater inhibition (Figure 2A). >80% lgG3 enriched product was able to induce a 97% inhibition of ADCP relative to the saline condition (corresponding to excipients), whereas commercial IgG, which contains a 2% lgG3, only achieved a 30% inhibition. These results enabled the calculation of the improvement in the effectiveness of lgG3 to inhibit ADCP compared to commercial IgG products (2% lgG3 condition), as shown in Figure 2B. >80% lgG3 enriched product attained a 96% increase in ADCP inhibition effectiveness compared to the commercial IgG containing 2% lgG3. Figure 2C illustrates the dose-dependent inhibition of ADCP. As the concentration of the lgG3-enriched product increases, there is a corresponding enhancement in ADCP inhibition, demonstrating superior performance compared to the commercial IgG product

[0253] CDC

[0254] lgG3 was able to reduce CDC induction, with inhibition increasing with the percentage of lgG3. An inhibition of CDC and consequently of cell lysis was observed as the percentage of lgG3 increased from 2% to 10% content of lgG3 (Figure 3A). Above 10% lgG3 a plateau effect is observed regarding the inhibitory effect of lgG3 (Figure 3A). >80% lgG3 enriched product led to a 36% reduction in cell lysis compared to non-treated conditions (control complement), whereas commercial IgG, which contains 2% lgG3, only achieved a 16% reduction (Figure 3A). These results enabled the calculation of the improvement in the effectiveness of lgG3 to inhibit CDC compared to commercial IgG products (2% lgG3 condition), as shown in Figure 3B. >80% lgG3 product achieved a 51% increase in CDC inhibition effectiveness compared to the commercial IgG containing 2% lgG3. Figure 3C illustrates the dose-dependent inhibition of CDC. As the concentration of the lgG3-enriched product increases, there is a corresponding enhancement in CDC inhibition, demonstrating superior performance compared to the commercial IgG productITP in vivo model

[0255] Different doses of lgG3-enriched product were evaluated in vivo using a model of autoimmune disease, specifically in an immune thrombocytopenia (ITP) model in rats. The products were administered intravenously (IV) and blood samples were obtained at various time points to run a complete blood count (CBC) to determine blood platelet levels (Figures 5A and 5B). The three tested doses of lgG3-enriched product (50, 100 and 200 mg / kg) effectively mitigated the decline in platelet count, observing a dose-response effect (Figure 5C). Commercial IgG-treated animals, serving as the positive control, demonstrated a robust improvement in platelet counts at clinical dose of 1000 mg / kg (Figure 5C). Importantly, the lgG3-enriched product at all three tested doses restored platelet count to over > 80% within 48-72h post-induction of the disease (Figure 5C).

[0256] Conclusion

[0257] lgG3-enriched product exhibits a potent modulation of immune system activation in the context of autoimmune diseases both in vitro and in vivo:

[0258] Products containing 10% lgG3 are already 4% and 5% more effective at inhibiting ADCC and ADCP and 49% more effective at inhibiting CDC compared to commercial human IgG products, respectively. Moreover, this inhibitory effect increases with higher lgG3 content.

[0259] lgG3-enriched product with higher percentages of lgG3 exhibit a significant inhibition of NK cells, macrophages and complement system activation compared to products with lower lgG3 content.

[0260] lgG3-enriched products are able to mitigate platelet reduction in an ITP model in rats. This beneficial effect is observed in a dose-dependent manner and demonstrates 5- 10 times more potency than current commercial human IgG products.

[0261] Our findings show that higher percentages of lgG3 exhibit a superior efficacy in inhibiting ADCC, ADCP and CDC activation compared to IgG commercial products. Moreover, an lgG3-enriched product demonstrates higher efficacy in mitigating platelet drop in an in vivo ITP rat model than commercial IgG at current clinical dose.

[0262] Therefore, the utilization of these lgG3-enriched products could significantly decrease patient dosage compared to actual commercial IgG products, mitigating side effects linked to high IgG doses, and potentially shortening infusion times, overall enhancing patients’ quality of life.The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

[0263] All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive.

[0264] Each feature disclosed in this specification (including any accompanying claims, abstract and drawings), may be replaced by alternative features serving the same, equivalent, or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

[0265] The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

Claims

Claims1. A composition comprising immunoglobulins, wherein the immunoglobulins comprise at least 10% (w / w) of: lgG3 and / or lgG3 fragments comprising the Fc region, for use in preventing and / or treating an autoimmune disease.

2. The composition for use according to claim 1 , wherein the immunoglobulins comprise at least 50%, at least 80%, or at least 90% lgG3 and / or lgG3 fragments comprising the Fc region.

3. The composition for use according to any one of the previous claims, wherein the autoimmune disease is selected from the group consisting of: Immune Thrombocytopenia Purpura (ITP), Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Myasthenia Gravis (MG), Guillain-Barre Syndrome (GBS), Kawasaki’s Disease, Graves ophthalmopathy (Thyroid Eye Disease), Systemic Lupus Erythematosus, Dermatomyositis, Multifocal Motor Neuropathy, Autoimmune Encephalitis, Sjogren Syndrome, Pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS), Paraproteinemic neuropathy, Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD), Autoimmune hemolytic anemia / Evan syndrome, Antineutrophil Cytoplasmic Antibodies disease (A NCA- vasculitis), Bullous Pemphigus, Autoimmune Uveitis, Narcolepsy with cataplexy, and Antiphospholipid Syndrome.

4. The composition for use according to any one of the previous claims, wherein the lgG3 and / or lgG3 fragments bind to Fc receptors and / or binds to C1q to prevent and / or treat the autoimmune disease.

5. The composition for use according to any one of the previous claims, wherein the lgG3 and / or lgG3 fragments inhibit antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and / or complement-dependent cytotoxicity (CDC) to prevent and / or treat the autoimmune disease.

6. The composition for use according to any one of the previous claims, wherein the lgG3 and / or lgG3 fragments are human lgG3 and / or lgG3 fragments.

7. The composition for use according to any one of the previous claims, wherein the immunoglobulins comprise lgG1, lgG2, lgG4, IgA and / or IgM or fragments thereof.

8. The composition for use according to any one of the previous claims, wherein the lgG3 and / or lgG3 fragments are from blood or ascites.

9. The composition for use according to any one of the previous claims, wherein the lgG3 and / or lgG3 fragments are from blood plasma.

10. The composition for use according to any one of the previous claims, wherein the lgG3 and / or lgG3 fragments are recombinant and / or synthetic lgG3 and / or lgG3 fragments.

11. The composition for use according to any one of the previous claims, wherein the immunoglobulin is administered at a dosage amount of at least 0.01 g / kg, 0.05 g / kg, 0.1 g / kg, 0.15 g / kg, 0.2 g / kg, 0.25 g / kg, 0.3 g / kg, 0.35 g / kg, 0.4 g / kg, 0.45 g / kg, 0.5 g / kg, 0.55 g / kg, 0.6 g / kg, 0.65 g / kg, 0.7 g / kg, 0.75 g / kg, 0.8 g / kg, 0.85 g / kg, 0.9 g / kg, 0.95 g / kg, 1 g / kg, 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg or 10 g / kg, optionally wherein the dosage amount is in the range of 0.01 g / kg to 2 g / kg.

12. The composition for use according to any one of the previous claims, wherein the lgG3 and / or lgG3 fragment is administered at a dosage amount of at least 0.01 g / kg, 0.05 g / kg, 0.1 g / kg, 0.15 g / kg, 0.2 g / kg, 0.25 g / kg, 0.3 g / kg, 0.35 g / kg, 0.4 g / kg, 0.45 g / kg, 0.5 g / kg, 0.55 g / kg, 0.6 g / kg, 0.65 g / kg, 0.7 g / kg, 0.75 g / kg, 0.8 g / kg, 0.85 g / kg, 0.9 g / kg, 0.95 g / kg, 1 g / kg, 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg or 10 g / kg, optionally wherein the dosage amount is in the range of 0.01 g / kg to 2 g / kg.

13. The composition for use according to any one of the previous claims, wherein the composition further comprises and / or is used in combination with one or more additional therapeutic agents selected from: corticosteroids, anti-inflammatory, pain-killing medication, immunosuppressant drugs, FcRn inhibitors, Fc-multimers, FcyR inhibitors, antibody-drug conjugates, check point agonist / inhibitors, and / or complement inhibitors.

14. The composition for use according to any one of the previous claims, wherein the composition further comprises an adjuvant, diluent and / or excipient.

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