WO2011097527A2 - Immunoprotection de fractions thérapeutiques avec des régions fc améliorées - Google Patents

Immunoprotection de fractions thérapeutiques avec des régions fc améliorées Download PDF

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WO2011097527A2
WO2011097527A2 PCT/US2011/023813 US2011023813W WO2011097527A2 WO 2011097527 A2 WO2011097527 A2 WO 2011097527A2 US 2011023813 W US2011023813 W US 2011023813W WO 2011097527 A2 WO2011097527 A2 WO 2011097527A2
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antibody
protein
fcyrllb
variant
fusion
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PCT/US2011/023813
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WO2011097527A9 (fr
WO2011097527A3 (fr
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John Desjarlais
Gregory L. Moore
Holly M. Horton
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Xencor, Inc.
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Publication of WO2011097527A3 publication Critical patent/WO2011097527A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70535—Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6056—Antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/53—Hinge
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/72—Increased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • the present application relates to therapeutic moieties displaying reduced immunogen response, particularly for therapeutic purposes.
  • BCR B cell antigen receptor
  • BCR B cell receptor
  • Iga signaling components
  • CD79b Ig3
  • immunoreceptor tyrosine-based activation motifs within CD79a and CD79b, initiating a cascade of intracellular signaling events that recruit downstream molecules to the membrane and stimulate calcium mobilization. This leads to the induction of diverse B cell responses including cell survival, proliferation, and differentiation (1-3).
  • Other components of the BCR coreceptor complex enhance (e.g., CD19, CD21 , and CD81 ) or suppress (e.g., CD22 and CD72) BCR activation signals (4, 5). In this way the immune system maintains multiple BCR regulatory mechanisms to ensure that B cell responses, including antibody production and antigen presentation, are tightly controlled.
  • FcyRllb ITIM This inhibitory effect occurs through phosphorylation of the FcyRllb ITIM, which recruits Src homology region 2-containing inositol polyphosphate 5-phosphatase (SHIP) to neutralize ITAM-induced intracellular calcium mobilization (3, 10, 1 1 ).
  • SHIP inositol polyphosphate 5-phosphatase
  • FcyRllb dysregulation has also been associated with human autoimmune disease; for example, alleles of polymorphisms in the promoter (18, 19) and transmembrane domain (20-22) of FcyRllb have been linked with increased prevalence of systemic lupus erythematosus (SLE). SLE patients also show reduced FcyRllb surface expression on B cells (23, 24) and, as a consequence, exhibit dysregulated signaling (23). The pivotal role of FcyRllb in regulating B cells, supported by mouse models and clinical evidence, makes it an attractive target for controlling immune response and treating autoimmune and inflammatory disorders (3, 25, 26).
  • the present invention provides methods of reducing a B-cell mediated immune response to a protein comprising administering to a patient in need thereof a fusion composition comprising a first domain comprising the protein and a second domain comprising an Fc variant of a human wild-type Fc region that binds the FcyRllb receptor with a Kd of less than about 100 nM.
  • the protein can be a a therapeutic protein, an autoantigen, and/or an allergen.
  • the invention provides methods of reducing a B-cell mediated immune response to a therapeutic antibody comprising administering to a patient in need thereof a variant therapeutic antibody, wherein the Fc domain of said therapeutic antibody comprises an Fc variant of a human wild-type Fc region that binds the FcyRllb receptor Kd of less than about 100 nM.
  • the invention provides fusion compositions comprising a first fusion protein comprising a protein selected from the group consisting of an autoantigen, an allergen and a non-antibody therapeutic protein and a second fusion protein comprising an Fc variant of a human wild-type Fc region that binds the FcyRllb receptor with a Kd of less than about 100 nM.
  • the Fc variants above comprises an amino acid substitution selected from the group consisting of 234D, 234E, 234W, 235D, 235F, 235R, 235Y, 236D, 236N, 237D, 237N, 239D, 239E, 266M, 267D, 267E, 268D, 268E, 327D, 327E, 328F, 328W, 328Y, and 332E, wherein numbering is according to the EU index.
  • the Fc variant comprises an amino acid substitution selected from the group consisting of 235Y, 236D, 239D, 266M, 267E, 268D, 268E, 328F, 328W, and 328Y wherein numbering is according to the EU index.
  • the Fc variant comprises an amino acid substitutions selected from the group consisting of 235Y/267E, 236D/267E, 239D/268D, 239D/267E, 267E/268D, 267E/268E, and 267E/328F, wherein numbering is according to the EU index.
  • the invention provides methods of treating a B-cell mediated autoimmune disease comprising administering to a patient in need thereof a fusion composition comprising an autoantigen first protein associated with said autoimmune disease and a second protein comprising an Fc variant of a human wild-type Fc region that binds the FcyRllb receptor Kd of less than about 100 nM.
  • a method of treatment comprising the administration of a therapeutic antibody to a patient in need thereof, the improvement comprising administering a variant therapeutic antibody wherein the Fc region of said antibody is an Fc variant of a human wild-type Fc region that binds the FcyRllb receptor with a Kd of less than about 100 nM.
  • a method of treatment comprising the administration of a therapeutic protein to a patient in need thereof, the improvement comprising administering a fusion therapeutic protein comprising the therapeutic protein and an Fc variant of a human wild-type Fc region that binds the FcyRllb receptor with a Kd of less than about 100 nM.
  • FIG. 1 Immunoprotection mechanism for therapeutic proteins.
  • a critical step in immune response to an administered therapeutic protein (TP) is engagement of the B cell receptor (BCR) and subsequent activation of B cells.
  • FIG. 3 Adalimumab elicits a strong immune response in mice.
  • the data show the time course of anti-drug antibody (ADA) response in four C57BL/6 mice following single dose 2 mg/kg intravenous administration of adalimumab lgG1 .
  • the top panel shows the ADA response for individual mice and the bottom panel shows the group mean average and standard error.
  • the outpoint of the ADA assay was approximately 200 RFU (relative fluorescence units).
  • the mean RFU for the four mice on the final day of the study (day 14) was 12302. This level is 62-fold relative to outpoint, representing quantitatively the immune response
  • the outpoint of the ADA assay was approximately 200 RFU (relative fluorescence units).
  • the mean RFU's for the five mice for the lgG1 and llbE groups on the final day of the study (day 14) were thus 283-fold and 29-fold relative to outpoint respectively.
  • FIG. 7 Immunoprotective Fc region (llbE) inhibits ADA response to adalimumab relative to a native lgG1 Fc region in mice transgenic for human FcyRllb (hCD32b+ tg mice) but not in genetically matched mice lacking human FcyRllb (hCD32b- tg mice).
  • the data show the time course of anti-drug antibody (ADA) response in transgenic mice either containing (hCD32b+ tg) or lacking (hCD32b- tg) human FcyRllb.
  • Mice were adminstered a single 10 mg/kg dose of antibody intravenously.
  • the top panel shows the ADA response for individual mice and the bottom panel shows the group mean average and standard error.
  • ADA response on the final day of the study (day 24) for the hCD32b+ tg mice was 218478 for lgG1 and 92092 for llbE.
  • the outpoint of the ADA assay was approximately 200 RFU (relative fluorescence units).
  • the mean RFU's for the five mice for the lgG1 and llbE groups on the final day were thus 1092-fold and 460-fold relative to outpoint respectively.
  • FIG. 8 Amino acid sequences of the Fc regions of the native human IgG isotypes and the Fc-engineered 267E/328F llbE lgG1 version described in the Examples.
  • FIG. 9 Immunoprotection mechanism for application to reducing the immune response to autoantigens and allergens.
  • An important step in the pathology of many autoimmune and allergic disease is activation of B cells by autoantigen (A) or allergen (A) via engagement of the B cell receptor (BCR). Fusion of the autoantigen or allergen to an Fc region enhanced in affinity (with high affinity) for FcyRllb (llbE), but not to a native (weak affinity) Fc region, is able to inhibit B cell activation and immune response.
  • FIG. 10 Amino acid sequences of MOG and MOG peptide Fc fusions with native, FcyRI lb-enhanced (llbE), and FcyR-knockout (KO) Fc regions.
  • FIG. 1 Binding of human MOG-Fc fusions to human FcyRllb, human V158 FcyRllla, and anti-MOG antibody as measured by Biacore.
  • Fc regions of the MOG-Fc fusions contained either native lgG1 , an FcyRI Ib-enhanced (llbE) variant 267E/328F, or a knockout (KO) variant 236R/328R.
  • FIG. 12 Affinities of Fc variant antibodies for human FcyRs as determined by Biacore surface plasmon resonance.
  • Figure 13 Fold affinities of Fc variant antibodies for human FcyRs as determined by Biacore surface plasmon resonance.
  • BCR B cell antigen receptor
  • B-cell receptor (BCR) induced B cell proliferation can lead to unwanted immune responses, particularly humoral immune responses.
  • BCR B-cell receptor
  • the administration of a number of therapeutic drugs, including proteinaceous therapeutic drugs as are more fully described below can lead to immune responses to the drug itself, leading to both a loss of drug efficacy as well as the potential for significant side effects.
  • this same immune response can be seen to autoantigens in autoimmune diseases.
  • the present invention is drawn to the use of the FcyRI lb-mediated inhibitory mechanism to reduce the immune response to a therapeutic protein, autoantigens, and/or allergen.
  • Our novel approach illustrated in Figures 1 and 9, mimics the inhibitory effects of immune complex by high- affinity coengagement of FcyRllb and the BCR coreceptor complex on human B cells.
  • a key step in immune response to a protein is engagement with anti-immunogen specific BCR on B cells followed by activation, internalization, and presentation to T cells. Fusion of the proteinto the IgG Fc region enables interaction with the inhibitory receptor FcyRllb.
  • native IgG's bind FcyRllb with weak (uM) affinity
  • FcyRI lb-mediated inhibition occurs in response only to immune complexed but not monomeric IgG Fc.
  • FcyRllb-enhanced (llbE) Fc domains to immunogens such as therapeutic proteins, autoantigens, and/or allergens utilizes the natural inhibitory pathway to inhibit the B cell response to the fusion partner.
  • immunogens such as therapeutic proteins, autoantigens, and/or allergens
  • Enhanced affinity of the protein-Fc fusion for the inhibitory FcyRllb prevents anti-therapeutic protein, anti-autoantigen, and/or anti-allergen B cells from activation and differentiation into immunoglobulin-producing plasma cells.
  • the present invention is directed in some aspects to the coupling of an immunogen to a variant Fc region that has been engineered to bind with increased binding affinity to the FcyRllb receptor to result in significant "immunoprotection", such that the administration of the previously immunogenic moiety, e.g. the immunogen, reduces or prevents the production of antibodies.
  • the addition of the variant Fc domain forces a "tolerization" of the immunogen to which it is attached, thus silencing the response.
  • the immunogen to which the variant Fc domain is attached can be an exogenous immunogen, such as a therapeutic drug, including therapeutic proteins and antibodies or allergens, or an endogenous immunogen such as an autoantigen, as are further described below.
  • B cells are important in adaptive immunity because BCR-antigen complex internalization is the first step in antigen presentation. Because FcyRllb coengagement inhibits BCR-dependent antigen internalization and processing, the activities of the NbE variants presented here may also suppress T cell-mediated adaptive immunity.
  • an application of the NbE Fc domain is as a fusion with an immunogenic therapeutic protein. Such a fusion will suppress differentiation, survival, and proliferation only of B cell populations possessing BCRs specific for epitopes of the immunogen. This strategy thus selectively eliminates only drug-reactive B cells, and thus mitigates potential immunogenicity concerns arising from the clinical use of therapeutic proteins.
  • NbE Fc regions have therapeutic applications by selectively eliminating only immunogen-reactive B cells.
  • FcyRllb-enhanced Fc domains Coupling of FcyRllb-enhanced Fc domains to therapeutic proteins has several clinical benefits.
  • Second, the Fc domain also generally serves to improve the pharmacokinetic properties of the therapeutic protein, a strategy that has been applied successfully with a variety of agents.
  • this same mechanism finds use for other immunogens in addition to therapeutic proteins (including antibodies).
  • fusions of the variant Fc domain with either autoantigens or allergens can be made. Both of these types of molecules can cause unwanted immune effects.
  • an immunogen that causes unwanted effects e.g. autoimmune disease or inflammation/allergic responses, the response to the immunogen is reduced.
  • the endogenous Fc domain of the therapeutic antibody is altered to contain the amino acid substitutions that result in increased FcyRllb, as is described below. Alteration of one or more specific amino acids in the Fc domain of the Fc region to significantly increase the binding of the variant Fc domain to the FcyRllb receptor, can result in the reduction and/or elimination of humoral antibodies to the therapeutic antibody.
  • the therapeutic drug is not an antibody but a therapeutic protein
  • the therapeutic protein is fused to the variant Fc domain.
  • This fusion can occur in a number of ways, including but not limited to a genetic linkage, a chemical conjugation or the fusion of the N-terminus of one component (e.g. the variant Fc domain) to the C-terminus of the other component (e.g. the therapeutic protein), or vice versa, either directly or through the use of traditional linkers as is described below.
  • the immunogen that is fused to an immunoprotective Fc domains may be an autoantigen or allergen that plays a role in a disease.
  • the adminstered biotherapeutic may mimic the suppressive effects of cognate immune complex on activated B cells. Because FcyRllb coengagement inhibits BCR-dependent antigen internalization and processing, the activities of the NbE variants presented here may also suppress T cell-mediated adaptive immunity, thereby inhibiting the underlying biology of the disease.
  • the present invention provides methods of preventing a B-cell mediated immune response to a number of different types of proteins.
  • a B-cell mediated immune response herein is meant the antigen-specific B cell activation by engagement of the B cell antigen receptor on mature B cells which results in an intracellular signaling cascade, including calcium mobilization, that leads to cell proliferation and differentiation.
  • assays there are a variety of assays to assess the presence or absence of a B- cell mediated immune response. As is described in the examples, one assay is the anti-drug antibody (ADA) assay which can be run in either mice or non-human primates such as
  • a B-cell mediated immune response is determined to occur when the level of pre-clinical (for example mouse or monkey) or clinical (human) anti-drug antibody is greater than the outpoint of an ADA assay.
  • An ADA response may for example be 2-fold above outpoint, although preferably it is greater than 10- fold above outpoint.
  • immune response to an antigen or allergen is determined as the observation of disease in a pre-clinical model of the disease, for example in mice or monkeys, when the animals are administered the antigen or allergen. In this case immune response is typically measured using some disease score that may reflect incidence, severity, or other metrics, and will vary depending on the disease and pre-clinical model as is established in the art.
  • the invention provides for the prevention of B-cell mediated immune responses.
  • prevention herein is meant a reduction in the B-cell mediated immune response.
  • Reduction in immune response may be a reduction in ADA response where the application is to reduce immunogenicity of a biotherapeutic, or may be a reduction in disease score in a preclinical model of the disease or in humans who suffer from the disease. Included within the definition of
  • prevention or "reduction” of the B-cell mediated immune response is a reduction in by at least 2- fold, with reduction of at least about 2- to 10-fold being useful and reductions of at least about 10- fold being similarly useful.
  • the present invention finds use in situations where a therapeutic protein (including a therapeutic antibody) has not yet been shown to cause a significant immune response. That is, the incorporation of the amino acid substitutions with the Fc domain can be done prior to an immune response being a problem with an administered drug. In this case, the reduction of a B-cell mediated immune response is determined by comparing the response in an animal model, such as the ADA models outlined above.
  • the present invention provides methods of reducing the immune response of immunogens.
  • the present invention provides methods for reducing the B-cell mediated immune response to an immunogen.
  • an "immunogen” is a substance that causes an immune response, in this case an undesirable B-cell mediated immune response, in a patient. That is, the immunogen can be a protein involved in mediating the pathology of a disease. As is outlined herein, in general, immunogens fall into four general categories herein.
  • the immunogen is a therapeutic antibody (e.g. the immunogen is exogenous to the host).
  • the immunogen is a therapeutic protein (again an exogeneous immunogen).
  • the immunogen is an autoantigen, resulting in an immune response to an endogenous molecule, leading to an undesirable autoimmune disease or symptoms.
  • the immunogen is an allergen (again an exogenous molecule to the host), which normally causes an undesirable allergic reaction in some patients.
  • the immunogen is a therapeutic antibody. That is, as described below and known in the art, therapeutic antibodies can take on a number of formats. In the context of this invention, a therapeutic antibody has an antigen-binding domain as well as an Fc domain. Therapeutic antibody structures that no longer possess Fc domains can also be used (e.g. Fabs), but in that case they would be considered "therapeutic proteins" to which a variant Fc domain of the invention would be fused, creating a fusion composition herein.
  • Each tetramer is typically composed of two identical pairs of polypeptide chains, each pair having one "light” (typically having a molecular weight of about 25 kDa) and one "heavy” chain (typically having a molecular weight of about 50-70 kDa).
  • Human light chains are classified as kappa and lambda light chains.
  • Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
  • IgG has several subclasses, including, but not limited to lgG1 , lgG2, lgG3, and lgG4.
  • IgM has subclasses, including, but not limited to, lgM1 and lgM2.
  • isotype as used herein is meant any of the subclasses of immunoglobulins defined by the chemical and antigenic characteristics of their constant regions.
  • the known human immunoglobulin isotypes are lgG1 , lgG2, lgG3, lgG4, lgA1 , lgA2, lgM1 , lgM2, IgD, and IgE.
  • therapeutic antibodies can also comprise hybrids of isotypes and/or subclasses. For example, hybrid lgG1/lgG2 hybrids are described in U.S. Publication No.
  • each chain includes a variable region of about 100 to 1 10 or more amino acids primarily responsible for antigen recognition.
  • variable region three loops are gathered for each of the V domains of the heavy chain and light chain to form an antigen- binding site.
  • Each of the loops is referred to as a complementarity-determining region (hereinafter referred to as a "CDR"), in which the variation in the amino acid sequence is most significant.
  • CDR complementarity-determining region
  • each chain defines a constant region primarily responsible for effector function.
  • Kabat et al. collected numerous primary sequences of the variable regions of heavy chains and light chains. Based on the degree of conservation of the sequences, they classified individual primary sequences into the CDR and the framework and made a list thereof (see SEQUENCES OF IMMUNOLOGICAL INTEREST, 5th edition, NIH publication, No. 91 -3242, E.A. Kabat et al., entirely incorporated by reference).
  • immunoglobulin domains in the heavy chain.
  • immunoglobulin (Ig) domain herein is meant a region of an immunoglobulin having a distinct tertiary structure.
  • the heavy chain domains including, the constant heavy (CH) domains and the hinge domains.
  • the IgG isotypes each have three CH regions. Accordingly, "CH” domains in the context of IgG are as follows: “CH1 " refers to positions 1 18-220 according to the EU index as in Kabat. "CH2" refers to positions 237-340 according to the EU index as in Kabat, and “CH3” refers to positions 341 -447 according to the EU index as in Kabat.
  • Ig domain of the heavy chain is the hinge region.
  • hinge region or “hinge region” or “antibody hinge region” or “immunoglobulin hinge region” herein is meant the flexible polypeptide comprising the amino acids between the first and second constant domains of an antibody.
  • the IgG CH1 domain ends at EU position 220, and the IgG CH2 domain begins at residue EU position 237.
  • the antibody hinge is herein defined to include positions 221 (D221 in lgG1 ) to 236 (G236 in lgG1 ), wherein the numbering is according to the EU index as in Kabat.
  • the lower hinge is included, with the “lower hinge” generally referring to positions 226 or 230.
  • Fc regions Of particular interest in the present invention are the Fc regions. By “Fc” or “Fc region” or
  • Fc domain as used herein is meant the polypeptide comprising the constant region of an antibody excluding the first constant region immunoglobulin domain and in some cases, part of the hinge. Thus Fc refers to the last two constant region immunoglobulin domains of IgA, IgD, and
  • IgG the last three constant region immunoglobulin domains of IgE and IgM, and the flexible hinge
  • Fc may include the J chain.
  • the Fc domain comprises immunoglobulin domains Cy2 and Cy3 (Cy2 and Cy3) and the lower hinge region between Cy1 (Cy1 ) and Cy2 (Cy2).
  • Cy2 and Cy3 immunoglobulin domains Cy2 and Cy3
  • Cy2 and Cy3 immunoglobulin domains Cy2 and Cy3
  • Cy2 and Cy3 immunoglobulin domains Cy2 and Cy3
  • Cy2 and Cy2 and Cy3 the lower hinge region between Cy1 (Cy1 ) and Cy2 (Cy2).
  • IgG heavy chain Fc region is usually defined to include residues C226 or P230 to its carboxyl- terminus, wherein the numbering is according to the EU index as in Kabat.
  • Fc may refer to this region in isolation, or this region in the context of an Fc fusion ("fusion composition" or "fusion construct"), as described below.
  • Fc domains include all or part of an Fc region; that is, N- or C- terminal sequences may be removed from wild-type or variant Fc domains recited herein, as long as binding to FcyRllb is preserved. That is, an Fc domain of the invention retains binding to FcyRllb, with variant Fc domains having binding affinities and/or increased binding to the FcyRllb receptor as outlined herein.
  • Fc polypeptides include antibodies, Fc fusions, isolated Fes, and Fc fragments.
  • the antibodies are full length.
  • full length antibody herein is meant the structure that constitutes the natural biological form of an antibody, including variable and constant regions, including one or more modifications as outlined herein.
  • the antibodies can be a variety of structures, including, but not limited to, antibody fragments, monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as "antibody mimetics"), chimeric antibodies, humanized antibodies, antibody fusions (sometimes referred to as “antibody conjugates”), and fragments of each, respectively.
  • antibody mimetics sometimes referred to herein as "antibody mimetics”
  • chimeric antibodies humanized antibodies
  • antibody fusions sometimes referred to as “antibody conjugates”
  • the antibody is an antibody fragment.
  • Specific antibody fragments include, but are not limited to, (i) the Fab fragment consisting of VL, VH, CL and CH1 domains, (ii) the Fd fragment consisting of the VH and CH1 domains, (iii) the Fv fragment consisting of the VL and VH domains of a single antibody; (iv) the dAb fragment (Ward et al., 1989, Nature 341 :544- 546, entirely incorporated by reference) which consists of a single variable, (v) isolated CDR regions, (vi) F(ab')2 fragments, a bivalent fragment comprising two linked Fab fragments (vii) single chain Fv molecules (scFv), wherein a VH domain and a VL domain are linked by a peptide linker which allows the two domains to associate to form an antigen binding site (Bird et al., 1988, Science 242:423-426, Huston et al
  • the antibody can be a mixture from different species, e.g. a chimeric antibody and/or a humanized antibody.
  • chimeric antibodies and “humanized antibodies” refer to antibodies that combine regions from more than one species.
  • chimeric antibodies traditionally comprise variable region(s) from a mouse (or rat, in some cases) and the constant region(s) from a human.
  • Humanized antibodies generally refer to non-human antibodies that have had the variable-domain framework regions swapped for sequences found in human antibodies.
  • the entire antibody, except the CDRs is encoded by a polynucleotide of human origin or is identical to such an antibody except within its CDRs.
  • the CDRs are grafted into the beta-sheet framework of a human antibody variable region to create an antibody, the specificity of which is determined by the engrafted CDRs.
  • the creation of such antibodies is described in, e.g., WO 92/1 1018, Jones, 1986, Nature 321 :522-525, Verhoeyen et al., 1988, Science 239:1534-1536, all entirely incorporated by reference.
  • the humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region, typically that of a human immunoglobulin, and thus will typically comprise a human Fc region. Humanized antibodies can also be generated using mice with a genetically engineered immune system. Roque et al., 2004, Biotechnol. Prog.
  • Humanization methods include but are not limited to methods described in Jones et al., 1986, Nature 321 :522-525; Riechmann et al., 1988; Nature 332:323-329; Verhoeyen et al., 1988, Science, 239:1534-1536; Queen et al., 1989, Proc Natl Acad Sci, USA 86:10029-33; He et al., 1998, J. Immunol. 160: 1029-1035; Carter et al., 1992, Proc Natl Acad Sci USA 89:4285-9, Presta et al., 1997, Cancer Res.57(20):4593-9; Gorman et al., 1991 , Proc. Natl. Acad. Sci. USA 88:4181 - 4185; O'Connor et al., 1998, Protein Eng 1 1 :321 -8, all entirely incorporated by reference.
  • Humanization or other methods of reducing the immunogenicity of nonhuman antibody variable regions may include resurfacing methods, as described for example in Roguska et al., 1994, Proc. Natl. Acad. Sci. USA 91 :969-973, entirely incorporated by reference.
  • the parent antibody has been affinity matured, as is known in the art. Structure-based methods may be employed for humanization and affinity maturation, for example as described in USSN
  • Selection based methods may be employed to humanize and/or affinity mature antibody variable regions, including but not limited to methods described in Wu et al., 1999, J. Mol. Biol. 294:151-162; Baca et al., 1997, J. Biol. Chem. 272(16):10678-10684; Rosok et al., 1996, J. Biol. Chem. 271 (37): 2261 1-22618; Rader et al., 1998, Proc. Natl. Acad. Sci. USA 95: 8910-8915; Krauss et al., 2003, Protein Engineering 16(10):753-759, all entirely incorporated by reference.
  • the antibodies of the invention multispecific antibody, and notably a bispecific antibody, also sometimes referred to as "diabodies". These are antibodies that bind to two (or more) different antigens. Diabodies can be manufactured in a variety of ways known in the art (Holliger and Winter, 1993, Current Opinion Biotechnol. 4:446-449, entirely incorporated by reference), e.g., prepared chemically or from hybrid hybridomas.
  • the antibody is a minibody.
  • Minibodies are minimized antibody-like proteins comprising a scFv joined to a CH3 domain.
  • Hu et al., 1996, Cancer Res. 56:3055-3061 entirely incorporated by reference.
  • the scFv can be joined to the Fc region, and may include some or the entire hinge region.
  • Covalent modifications of antibodies are included within the scope of this invention, and are generally, but not always, done post-translationally.
  • several types of covalent modifications of the antibody are introduced into the molecule by reacting specific amino acid residues of the antibody with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C-terminal residues.
  • Cysteinyl residues may also be derivatized by reaction with bromotrifluoroacetone, a-bromo-3-(5-imidozoyl)propionic acid, chloroacetyl phosphate, N- alkylmaleimides, 3-nitro-2-pyridyl disulfide, methyl 2-pyridyl disulfide, p-chloromercuribenzoate, 2- chloromercuri-4-nitrophenol, or chloro-7-nitrobenzo-2-oxa-1 ,3-diazole and the like.
  • Histidyl residues are derivatized by reaction with diethylpyrocarbonate at pH 5.5-7.0 because this agent is relatively specific for the histidyl side chain.
  • Para-bromophenacyl bromide also is useful; the reaction is preferably performed in 0.1 M sodium cacodylate at pH 6.0.
  • Lysinyl and amino terminal residues are reacted with succinic or other carboxylic acid anhydrides. Derivatization with these agents has the effect of reversing the charge of the lysinyl residues.
  • Other suitable reagents for derivatizing alpha-amino-containing residues include imidoesters such as methyl picolinimidate; pyridoxal phosphate; pyridoxal; chloroborohydride; trinitrobenzenesulfonic acid; O-methylisourea; 2,4-pentanedione; and transaminase-catalyzed reaction with glyoxylate.
  • Arginyl residues are modified by reaction with one or several conventional reagents, among them phenylglyoxal, 2,3-butanedione, 1 ,2-cyclohexanedione, and ninhydrin. Derivatization of arginine residues requires that the reaction be performed in alkaline conditions because of the high pKa of the guanidine functional group. Furthermore, these reagents may react with the groups of lysine as well as the arginine epsilon-amino group.
  • tyrosyl residues may be made, with particular interest in introducing spectral labels into tyrosyl residues by reaction with aromatic diazonium compounds or tetranitromethane.
  • aromatic diazonium compounds or tetranitromethane Most commonly, N-acetylimidizole and tetranitromethane are used to form O- acetyl tyrosyl species and 3-nitro derivatives, respectively.
  • Tyrosyl residues are iodinated using 1251 or 131 1 to prepare labeled proteins for use in radioimmunoassay, the chloramine T method described above being suitable.
  • aspartyl and glutamyl residues are converted to asparaginyl and glutaminyl residues by reaction with ammonium ions.
  • Derivatization with bifunctional agents is useful for crosslinking antibodies to a water- insoluble support matrix or surface for use in a variety of methods, in addition to methods described below.
  • Commonly used crosslinking agents include, e.g., 1 ,1 -bis(diazoacetyl)-2- phenylethane, glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with 4- azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3,3'- dithiobis (succinimidylpropionate), and bifunctional maleimides such as bis-N-maleimido-1 ,8- octane.
  • Derivatizing agents such as methyl-3-[(p-azidophenyl)dithio]propioimidate yield
  • photoactivatable intermediates that are capable of forming crosslinks in the presence of light.
  • reactive water-insoluble matrices such as cyanogen bromide-activated
  • Glutaminyl and asparaginyl residues are frequently deamidated to the corresponding glutamyl and aspartyl residues, respectively. Alternatively, these residues are deamidated under mildly acidic conditions. Either form of these residues falls within the scope of this invention.
  • labels including fluorescent, enzymatic, magnetic, radioactive, etc. can all be added to the antibodies (as well as the other compositions of the invention).
  • the antibodies comprising variant Fc domains disclosed herein can be modified to include one or more engineered glycoforms.
  • engineered glycoform as used herein is meant a carbohydrate composition that is covalently attached to the antibody, wherein said carbohydrate composition differs chemically from that of a parent antibody.
  • Engineered glycoforms may be useful for a variety of purposes, including but not limited to enhancing or reducing effector function.
  • Engineered glycoforms may be generated by a variety of methods known in the art (Umafia et al., 1999, Nat Biotechnol 17:176-180; Davies et al., 2001 , Biotechnol Bioeng 74:288-294; Shields et al., 2002, J Biol Chem 277:26733-26740; Shinkawa et al., 2003, J Biol Chem 278:3466-3473; US 6,602,684; USSN 10/277,370; USSN 10/1 13,929; PCT WO 00/61739A1 ; PCT WO 01/29246A1 ; PCT WO 02/31 140A1 ; PCT WO 02/30954A1 , all entirely incorporated by reference; (Potelligent® technology [Biowa, Inc., Princeton, NJ]; GlycoMAb® glycosylation engineering technology [Glycart Biotechnology AG, Zurich, Switzerland]).
  • Engineered glycoform typically refers to the different carbohydrate or oligosaccharide; thus an IgG variant, for example an antibody or Fc fusion, can include an engineered glycoform.
  • engineered glycoform may refer to the IgG variant that comprises the different carbohydrate or oligosaccharide.
  • glycosylation patterns can depend on both the sequence of the protein (e.g., the presence or absence of particular glycosylation amino acid residues, discussed below), or the host cell or organism in which the protein is produced.
  • N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue.
  • the tri-peptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain.
  • polypeptide creates a potential glycosylation site.
  • O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose, to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.
  • Addition of glycosylation sites to the antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tri-peptide sequences (for N-linked glycosylation sites). The alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the starting sequence (for O-linked glycosylation sites).
  • the antibody amino acid sequence is preferably altered through changes at the DNA level, particularly by mutating the DNA encoding the target polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids.
  • Another means of increasing the number of carbohydrate moieties on the antibody is by chemical or enzymatic coupling of glycosides to the protein. These procedures are advantageous in that they do not require production of the protein in a host cell that has glycosylation capabilities for N- and O-linked glycosylation.
  • the sugar(s) may be attached to (a) arginine and histidine, (b) free carboxyl groups, (c) free sulfhydryl groups such as those of cysteine, (d) free hydroxyl groups such as those of serine, threonine, or hydroxyproline, (e) aromatic residues such as those of phenylalanine, tyrosine, or tryptophan, or (f) the amide group of glutamine.
  • Removal of carbohydrate moieties present on the starting antibody may be accomplished chemically or enzymatically.
  • Chemical deglycosylation requires exposure of the protein to the compound trifluoromethanesulfonic acid, or an equivalent compound. This treatment results in the cleavage of most or all sugars except the linking sugar (N-acetylglucosamine or N- acetylgalactosamine), while leaving the polypeptide intact.
  • Chemical deglycosylation is described by Hakimuddin et al., 1987, Arch. Biochem. Biophys. 259:52 and by Edge et al., 1981 , Anal. Biochem. 1 18:131 , both entirely incorporated by reference.
  • Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., 1987, Meth. Enzymol. 138:350, entirely incorporated by reference. Glycosylation at potential glycosylation sites may be prevented by the use of the compound tunicamycin as described by Duskin et al., 1982, J. Biol. Chem. 257:3105, entirely incorporated by reference. Tunicamycin blocks the formation of protein-N-glycoside linkages.
  • Another type of covalent modification of the antibody comprises linking the antibody to various nonproteinaceous polymers, including, but not limited to, various polyols such as polyethylene glycol, polypropylene glycol or polyoxyalkylenes, in the manner set forth in, for example, 2005-2006 PEG Catalog from Nektar Therapeutics (available at the Nektar website) US Patents 4,640,835; 4,496,689; 4,301 , 144; 4,670,417; 4,791 ,192 or 4, 179,337, all entirely incorporated by reference.
  • amino acid substitutions may be made in various positions within the antibody to facilitate the addition of polymers such as PEG. See for example, U.S. Publication No. 2005/01 14037A1 , entirely incorporated by reference.
  • Therapeutic Antibodies [87] As will be appreciated by those in the art, the present invention finds use in any number of current or future therapeutic antibodies.
  • any antigen may be targeted by the antibody compositions of the invention, including but not limited to proteins, subunits, domains, motifs, and/or epitopes belonging to the following list of target antigens, which includes both soluble factors such as cytokines and membrane-bound factors, including transmembrane receptors: 17-IA, 4-1 BB, 4Dc, 6-keto-PGF1 a, 8-iso-PGF2a, 8-oxo-dG, A1 Adenosine Receptor, A33, ACE, ACE-2, Activin, Activin A, Activin AB, Activin B, Activin C, Activin RIA, Activin RIA ALK-2, Activin RIB ALK-4, Activin RIIA, Activin RUB, ADAM, ADAM 10, ADAM12, ADAM 15, ADAM17/TACE, ADAM8, ADAM9, ADAMTS, ADAMTS4, ADAMTS5, Addressins
  • BACE Atrial natriuretic factor, av/b3 integrin, Axl, b2M, B7-1 , B7-2, B7-H, B-lymphocyte Stimulator (BlyS), BACE, BACE-1 , Bad, BAFF, BAFF-R, Bag-1 , BAK, Bax, BCA-1 , BCAM, Bel, BCMA, BDNF, b-ECGF, bFGF, BID, Bik, BIM, BLC, BL-CAM, BLK, BMP, BMP-2 BMP-2a, BMP-3 Osteogenin, BMP-4 BMP-2b, BMP-5, BMP-6 Vgr-1 , BMP-7 (OP-1 ), BMP-8 (BMP-8a, OP-2), BMPR, BMPR-IA (ALK-3), BMPR-IB (ALK-6), BRK-2, RPK-1 , BMPR-II (BRK-3), BMPs, b-NGF,
  • HSV gD glycoprotein HSV gD glycoprotein, HGFA, High molecular weight melanoma-associated antigen (HMW-MAA), HIV gp120, HIV NIB gp 120 V3 loop, HLA, HLA-DR, HM1 .24, HMFG PEM, HRG, Hrk, human cardiac myosin, human cytomegalovirus (HCMV), human growth hormone (HGH), HVEM, I-309, IAP, ICAM, ICAM-1 , ICAM-3, ICE, ICOS, IFNg, Ig, IgA receptor, IgE, IGF, IGF binding proteins, IGF-1 R, IGFBP, IGF-I, IGF-II, IL, IL-1 , IL-1 R, IL-2, IL-2R, IL-4, IL-4R, IL-5, IL-5R, IL-6, IL-6R, IL-8, IL-9, IL-10, IL-12, IL-13,
  • TNFRSF4 (OX40 ACT35, TXGP1 R), TNFRSF5 (CD40 p50), TNFRSF6 (Fas Apo-1 , APT1 , CD95), TNFRSF6B (DcR3 M68, TR6), TNFRSF7 (CD27), TNFRSF8 (CD30), TNFRSF9 (4-1 BB CD137, I LA), TNFRSF21 (DR6), TNFRSF22 (DcTRAIL R2 TNFRH2), TNFRST23 (DcTRAIL R1 TNFRH1 ), TNFRSF25 (DR3 Apo-3, LARD, TR-3, TRAMP, WSL-1 ), TNFSF10 (TRAIL Apo-2 Ligand, TL2), TNFSF1 1 (TRANCE/RANK Ligand ODF, OPG Ligand), TNFSF12 (TWEAK Apo-3 Ligand, DR3 Ligand), TNFSF13 (APRIL TALL2), TNFSF13B (BAFF B
  • targets refers not only to specific proteins and biomolecules, but the biochemical pathway or pathways that comprise them.
  • CTLA-4 as a target antigen implies that the ligands and receptors that make up the T cell co-stimulatory pathway, including CTLA-4, B7-1 , B7-2, CD28, and any other undiscovered ligands or receptors that bind these proteins, are also targets.
  • target as used herein refers not only to a specific biomolecule, but the set of proteins that interact with said target and the members of the biochemical pathway to which said target belongs.
  • any of the aforementioned target antigens, the ligands or receptors that bind them, or other members of their corresponding biochemical pathway may be operably linked to the Fc variants of the present invention in order to generate an Fc fusion.
  • an Fc fusion that targets EGFR could be constructed by operably linking an Fc variant to EGF, TGF- b, or any other ligand, discovered or undiscovered, that binds EGFR.
  • an Fc variant of the present invention could be operably linked to EGFR in order to generate an Fc fusion that binds EGF, TGF-b, or any other ligand, discovered or undiscovered, that binds EGFR.
  • any polypeptide whether a ligand, receptor, or some other protein or protein domain, including but not limited to the aforementioned targets and the proteins that compose their corresponding biochemical pathways, may be operably linked to the Fc variants of the present invention to develop an Fc fusion.
  • Suitable antigen depends on the desired application. For anti-cancer treatment it is desirable to have a target whose expression is restricted to the cancerous cells. Some targets that have proven especially amenable to antibody therapy are those with signaling functions. Other therapeutic antibodies exert their effects by blocking signaling of the receptor by inhibiting the binding between a receptor and its cognate ligand. Another mechanism of action of therapeutic antibodies is to cause receptor down regulation. Other antibodies do not work by signaling through their target antigen. In some cases, antibodies directed against infectious disease agents are used.
  • the Fc variants of the present invention are incorporated into an antibody against a cytokine.
  • the Fc variants are fused or conjugated to a cytokine.
  • cytokine as used herein is meant a generic term for proteins released by one cell population that act on another cell as intercellular mediators.
  • cytokines may be fused to antibody to provide an array of desirable properties. Examples of such cytokines are lymphokines, monokines, and traditional polypeptide hormones. Included among the cytokines are growth hormone such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin;
  • glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor-alpha and -beta; mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors such as NGF-beta; platelet-growth factor; transforming growth factors (TGFs) such as TGF-alpha and TGF-beta; insulin-like growth factor-l and -II;
  • FSH follicle stimulating hormone
  • TSH thyroid stimulating hormone
  • LH luteinizing hormone
  • hepatic growth factor such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH)
  • hepatic growth factor
  • erythropoietin EPO
  • osteoinductive factors EPO
  • interferons such as interferon-alpha, beta, and - gamma
  • colony stimulating factors CSFs
  • M-CSF macrophage-CSF
  • GM-CSF granulocyte- macrophage-CSF
  • G-CSF granulocyte-CSF
  • interleukins ILs
  • IL-1 interleukins
  • IL-15 a tumor necrosis factor
  • TNF-alpha or TNF-beta C5a
  • KL kit ligand
  • the term cytokine includes proteins from natural sources or from
  • Cytokines and soluble targets are preferred targets for use with the variants of the present invention.
  • anti-VEGF, anti-CTLA-4, and anti-TNF antibodies, or fragments thereof are particularly good antibodies for the use of Fc variants that increase the FcRn binding.
  • Therapeutics against these targets are frequently involved in the treatment of autoimmune diseases and require multiple injections over long time periods.
  • the Fc polypeptides of the present invention may find use in a range of clinical products and candidates.
  • a number of antibodies that target CD20 may benefit from the Fc polypeptides of the present invention.
  • the Fc polypeptides of the present invention may find use in an antibody that is substantially similar to rituximab (Rituxan®,
  • IDEC/Genentech/Roche see for example US 5,736,137
  • HuMax-CD20 an anti-CD20 currently being developed by Genmab
  • hA20 Immunomedics, Inc.
  • HumaLYM Intracel
  • the Fc polypeptides of the present invention may find use in an antibody that is substantially similar to trastuzumab (Herceptin®, Genentech) (see for example US 5,677, 171 ), a humanized anti-Her2/neu antibody approved to treat breast cancer; pertuzumab (rhuMab-2C4, OmnitargTM), currently being developed by Genentech; an anti-Her2 antibody described in US 4,753,894; cetuximab (Erbitux®, Imclone) (US 4,943,533; PCT WO 96/40210), a chimeric anti-EGFR antibody in clinical trials for a variety of cancers; ABX-EGF (US 6,235,883), currently being developed by Abgenix-lmmunex-Amgen; HuMax-EGFr (USSN 10/172,317), currently being developed by Genmab; 425, EMD55900, EMD62000, and EMD72000 (Merck KGaA) (US 5,558,86
  • the Fc polypeptides of the present invention may find use in alemtuzumab (Campath®, Millenium), a humanized monoclonal antibody currently approved for treatment of B-cell chronic lymphocytic leukemia.
  • the Fc polypeptides of the present invention may find use in a variety of antibodies or Fc fusions that are substantially similar to other clinical products and candidates, including but not limited to muromonab-CD3 (Orthoclone OKT3®), an anti-CD3 antibody developed by Ortho Biotech/Johnson & Johnson, ibritumomab tiuxetan (Zevalin®), an anti-CD20 antibody developed by IDEC/Schering AG, gemtuzumab ozogamicin (Mylotarg®), an anti-CD33 (p67 protein) antibody developed by Celltech/Wyeth, alefacept (Amevive®), an anti-LFA-3 Fc fusion developed by Biogen), abciximab (ReoPro®), developed by Centocor/Lilly, basiliximab (Simulect®), developed by Novartis, palivizumab (Synagis®), developed by Medlmmune, infliximab (Remicade®),
  • AvastinTM (bevacizumab, rhuMAb- VEGF), an anti-VEGF antibody being developed by Genentech, an anti-HER receptor family antibody being developed by Genentech, Anti-Tissue Factor (ATF), an anti-Tissue Factor antibody being developed by Genentech, XolairTM (Omalizumab), an anti-lgE antibody being developed by Genentech, RaptivaTM (Efalizumab), an anti-CD1 1 a antibody being developed by Genentech and Xoma, MLN-02 Antibody (formerly LDP-02), being developed by Genentech and Millenium Pharmaceuticals, HuMax CD4, an anti-CD4 antibody being developed by Genmab, HuMax-IL15, an anti-IL15 antibody being developed by Genmab and Amgen, HuMax-lnflam, being developed by Genmab and Medarex, HuMax-Cancer, an anti-Heparanase I antibody being
  • anti-macrophage migration factor (MIF) antibodies being developed by IDEC Pharmaceuticals, BEC2, an anti-idiotypic antibody being developed by Imclone, IMC-1 C1 1 , an anti-KDR antibody being developed by Imclone, DC101 , an anti-flk-1 antibody being developed by Imclone, anti-VE cadherin antibodies being developed by Imclone, CEA-CideTM (labetuzumab), an anti-carcinoembryonic antigen (CEA) antibody being developed by Immunomedics, LymphoCideTM (Epratuzumab), an anti-CD22 antibody being developed by Immunomedics, AFP-Cide, being developed by Immunomedics, MyelomaCide, being developed by Immunomedics, LkoCide, being developed by Immunomedics, ProstaCide, being developed by Immunomedics, MDX-010, an anti- CTLA4 antibody being developed by Medarex, MDX-060, an anti-
  • compositions of the invention comprise a variant Fc domain (either as part of the variant therapeutic antibody or as a fusion partner in a fusion composition, described herein).
  • variant protein or “protein variant”, or “variant” as used herein is meant a protein that differs from that of a parent protein by virtue of at least one amino acid modification, including insertions, deletions and substitutions, with the latter finding particular use in the present invention.
  • Protein variant may refer to the protein itself, a composition comprising the protein, or the amino sequence that encodes it.
  • the protein variant has at least one amino acid modification compared to the parent protein, e.g.
  • variant protein can refer to the variant protein itself, compositions comprising the protein variant, or the DNA sequence that encodes it.
  • antibody variant or “variant antibody” as used herein is meant an antibody that differs from a parent antibody by virtue of at least one amino acid modification
  • IgG variant or “variant IgG” as used herein is meant an antibody that differs from a parent IgG by virtue of at least one amino acid modification
  • immunoglobulin variant or “variant immunoglobulin” as used herein is meant an immunoglobulin sequence that differs from that of a parent immunoglobulin sequence by virtue of at least one amino acid modification
  • Fc variant or “variant Fc” as used herein is meant a protein comprising a modification in an Fc domain.
  • the Fc variant domains of the present invention are defined according to the amino acid modifications that compose them.
  • S267E or 267E is an Fc variant with the substitution of a glutamic acid at position 267 relative to the parent Fc polypeptide, wherein the numbering is according to the EU index.
  • 267E/328F defines an Fc variant with the substitutions S267E and L328F.
  • the identity of the WT amino acid may be unspecified, in which case the aforementioned variant is referred to as 267E/328F. It is noted that the order in which substitutions are provided is arbitrary, that is to say that, for example,
  • 267E/328F is the same Fc variant as 328F/267E, and so on.
  • numbering is according to the EU index.
  • the EU index or EU index as in Kabat or EU numbering scheme refers to the numbering of the EU antibody (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, hereby entirely incorporated by reference.)
  • the modification can be an addition, deletion, or substitution. Substitutions can include naturally occurring amino acids (which generally finds the most use in the present invention when the compositions of the invention are produced recombinantly) and non-naturally occurring amino acids. Variants may comprise non-natural amino acids. Examples include US 6,586,207; WO 98/48032; WO
  • protein herein is meant at least two covalently attached amino acids, which includes proteins, polypeptides, oligopeptides and peptides.
  • the peptidyl group may comprise naturally occurring amino acids and peptide bonds, or synthetic peptidomimetic structures, i.e. "analogs", such as peptoids (see Simon et al., PNAS USA 89(20):9367 (1992), entirely incorporated by reference).
  • the amino acids may either be naturally occurring or non- naturally occurring; as will be appreciated by those in the art, again with naturally occuring amino acids being preferred when the compositions of the invention are produced recombinantly.
  • homo-phenylalanine, citrulline, and noreleucine are considered amino acids for the purposes of the invention, and both D- and L- (R or S) configured amino acids may be utilized.
  • the variants of the present invention may comprise modifications that include the use of unnatural amino acids incorporated using, for example, the technologies developed by Schultz and colleagues, including but not limited to methods described by Cropp & Shultz, 2004, Trends Genet. 20(12):625-30, Anderson et al., 2004, Proc Natl Acad Sci USA 101 (2):7566-71 , Zhang et al., 2003, 303(5656):371-3, and Chin et al., 2003, Science 301 (5635):964-7, all entirely incorporated by reference.
  • polypeptides may include synthetic derivatization of one or more side chains or termini, glycosylation, PEGylation, circular permutation, cyclization, linkers to other molecules, fusion to proteins or protein domains, and addition of peptide tags or labels, some of which are described below.
  • any amino acid substitutions that increase the binding affinity of the variant Fc domain to the FcyRllb receptor (often referred to herein as "Mb variants").
  • the K D for the human wild-type lgG1 Fc domain is generally in the ⁇ range, as shown below.
  • the K D for the variant Fc domain is generally in the nM range, with K D s of less than about 100 nM finding particular use in some embodiments.
  • the affinity of the Fc variant domain has a K D less than about 100 nM, e.g., less than or equal to about 95 nM, less than or equal to about 90 nM, less than or equal to about 85 nM, less than or equal to about 80 nM, less than or equal to about 75 nM, less than or equal to about 74 nM.
  • the binding affinity of the variant Fc domain to the FcyRllb receptor can be at least about 50 fold, 100 fold, 150 fold, 200 fold, 300 fold, 400 fold or higher greater than the affinity of a human wild type Fc domain, such as those from lgG1 (although other wild type Fc domains are also included).
  • Substitutions to enhance FcyR affinity include substitutions made at one or more of Fc positions selected from the group consisting of 234, 235, 236, 237, 239, 266, 267, 268, 325, 326, 327, 328, and 332, wherein numbering is according to the EU index.
  • amino acid substitutions can be selected independently and optionally independently combined with any other amino acid substitution.
  • subsitutions are made to at least one or more of the nonlimiting following positions to enhance affinity to FcyRllb: 235, 236, 239, 266, 267, 268, and 328.
  • Substitutions for enhancing affinity to FcyRllb include but are not limited to: 234D, 234E, 234W, 235D, 235F, 235R, 235Y, 236D, 236N, 237D, 237N, 239D, 239E, 266M, 267D, 267E, 268D, 268E, 327D, 327E, 328F, 328W, 328Y, and 332E, wherein numbering is according to the EU index. More preferred substitutions for enhancing affinity to FcyRllb include but are not limited to: 235Y, 236D, 239D, 266M, 267E, 268D, 268E, 328F, 328W, and 328Y.
  • Combinations of substitutions for enhancing affinity to FcyRllb include: 234D/267E, 234E/267E, 234F/267E, 234E/328F, 234W/239D, 234W/239E, 234W/267E, 234W/328Y, 235D/267E, 235D/328F, 235F/239D, 235F/267E, 235F/328Y, 235Y/236D, 235Y/239D,
  • combinations of substitutions for enhancing affinity to FcyRllb include, but are not limited to: 235Y/267E, 236D/267E, 239D/268D, 239D/267E, 267E/268D, 267E/268E, and 267E/328F.
  • Substitutions or combinations of substitutions for enhancing affinity to FcyRllb may include but are not limited to: 234F/236N, 234F/236D, 236A/237A, 236S/237A, 235D/239D, 234D/267E, 234E/267E, 234F/267E, 235D/267E, 235F/267E, 235S/267E, 235T/267E, 235Y/267D,
  • substitutions or combinations of substitutions for enhancing affinity to FcyRllb may include but are not limited to: 266D, 234F/236N, 234F/236D, 236A/237A, 236S/237A, 235D/239D, 234D/267E, 234E/267E, 234F/267E, 235D/267E, 235F/267E, 235S/267E, 235T/267E,
  • Substitutions or combinations of substitutions for enhancing affinity to FcyRllb may include but are not limited to: 234N, 235Q, 235R, 235W, 235Y, 236D, 236H, 236I, 236L, 236S, 236Y, 237H, 237L, 239D, 239N, 266I, 266M, 267A, 267D, 267E, 267G, 268D, 268E, 268N, 268Q, 298E, 298L, 298M, 298Q, 326A, 326E, 326W, 327D, 327L, 328E, 328F, 330D, 330H, 330K, 234F/236N, 234F/236D, 235D/239D, 234D/267E, 234E/267E, 234F/267E, 235D/267E, 235F/267E,
  • amino acid substitutions that result in increased binding to the FcRn receptor and/or increased in vivo half life of Fc domains containing such variants are included, including, but not limited to, 308FCYW, 259I, 428L, 434S, 259I/308F, 428L/434S, 259I/308F/428L and 308F/428L.
  • amino acid substitutions include, but are not limited to, 239D/332E and others shown in Figure 41 of 1 1/124,620.
  • Variants can be constructed in the Fc region of any antibody or biotherapeutic Fc fusion (e.g. fusion composition).
  • Figure 8 provides amino acid sequences of the Fc regions of the native human IgG isotypes, as well as the Fc-engineered 267E/328F NbE lgG1 version described in the Examples.
  • the variant Fc domains of the invention may also be linked to therapeutic proteins (which are not antibodies), autoantigens and/or allergens to reduce the immunogenicity of these immunogens.
  • Therapeutic proteins sometimes also referred to as "biologic drugs” that may be variant Fc domain fusion partners for the immunoprotective effect of the variant Fc regions of the invention include but are not limited to: recombinant human growth hormone, gonadotropin-releasing hormone, human chorionic gonadotropin, salmon calcitonin, recombinant human erythropoietin, insulin, GnRH, edenileukin diftitox,adenosine deamidase, megakaryocyte-derived growth factor (MGDF, thrombopoietin), glucocerebrosidase, Alpha-galactosidase, tissue plasminogen activator, Glucagon-like peptide-1 (GLP-1 ), and urokinase, enzymes including Factor VIII, Factor Vila, rhDNase, recombinant tissue plasminogen activator, recombinant streptokinase, recombinant
  • the present invention finds use in the "tolerization" of immunogens, such that undesirable B-cell mediated immune responses are reduced or eliminated.
  • This approach outlined in Figure 9, mimics the inhibitory effects of immune complex by high-affinity coengagement of Fc Rllb and the BCR coreceptor complex on human B cells.
  • a key step in immune response to an autoantigen or allergen is engagement with specific BCR on B cells followed by activation, internatlization, and presentation to T cells. Fusion of the autoantigen or allergen to the IgG Fc region enables interaction with the inhibitory receptor FcyRllb.
  • this strategy is also based on generating a high affinity interaction between the Fc region and FcyRllb, which may enable maximal inhibition of B cell activation by monovalent (nonimmune complexed) autoantigen or allergen.
  • Coupling of FcyRllb -enhanced Fc domains to autoantigen or allergen utilizes the natural inhibitory pathway to inhibit the B cell response to the fusion partner.
  • Enhanced affinity of the protein-Fc fusion for the inhibitory FcyRllb prevents (e.g. reduces) anti-autoantigen or anti-allergen B cells from activation and differentiation into
  • the immunogen is an allergen.
  • allergen herein is meant a substance that produces an inflammatory and/or allergic reaction in some population of patients. Allergens are generally exogeneous to the host or patient; that is, the allergenic substance is not normally found within the host or patient. In some embodiments, the immunogen is an
  • autoantigen a substance, generally endogeneous to the host (patient), that results in undesirable immune reactions. Autoantigens are generally endogeneous to the host or patient; that is, they are found within the patient but the patient is displaying an undesirable immune response to the autoantigen.
  • Autoimmune diseases that may be treated by this approach include allogenic islet graft rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune
  • Addison's disease antineutrophil cytoplasmic autoantibodies (ANCA), autoimmune diseases of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, autoimmune urticaria, Behcet's disease, bullous pemphigoid, cardiomyopathy, Castleman's syndrome, celiac spruce-dermatitis, chronic fatigue immune disfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatrical pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, factor VIII deficiency, fibromyalgia-fibromyositis, glomerulonephritis, Grave's disease,
  • Inflammatory and allergic disorders that may be treated by this approach include acute respiratory distress syndrome (ARDS), acute septic arthritis, adjuvant arthritis, juvenile idiopathic arthritis, allergic encephalomyelitis, allergic rhinitis, allergic vasculitis, allergy, asthma,
  • ARDS acute respiratory distress syndrome
  • acute septic arthritis adjuvant arthritis
  • juvenile idiopathic arthritis juvenile idiopathic arthritis
  • allergic encephalomyelitis allergic encephalomyelitis
  • allergic rhinitis allergic vasculitis
  • allergy asthma
  • any molecule associated with the above disorders may be used as the immunogen to which an immunoprotective Fc domain is fused as described herein.
  • immunoprotective Fc regions of the invention include but are not limited to double-stranded DNA, platelet antigens, myelin protein antigen, Sm antigens in snRNPs, islet cell antigen, Rheumatoid factor, and anticitrullinated protein, citrullinated proteins and peptides such as CCP-1 , CCP-2 (cyclical citrullinated peptides), fibrinogen, fibrin, vimentin, fillaggrin, collagen I and II peptides, alpha-enolase, translation initiation factor 4G1 , perinuclear factor, keratin, Sa (cytoskeletal protein vimentin), components of articular cartilage such as collagen II, IX, and XI, circulating serum proteins such as RFs (IgG, IgM), fibrinogen, plasminogen, ferritin, nuclear components such as RA33/hnRNP A2, Sm, eukaryotic trasnlation elogation factor 1 alpha 1
  • Fc fusion partners for the immunoprotective Fc regions peroxiredoxin-4, ubiquitin carboxyl-terminal hydrolase isozyme L1 , splicing factor arginine/serine- rich 3, histone H2A type 1 , histone 2A, SC35, U1-70 k, SmB/B', PML, topoisomerase I, CENP-B, CENP-C, fibrillarin, UBF, SmD, SmBO/B, ANA, dsDNA, U1 RNP, Sm, Ro, La, ribosomal P, cardiolipin, ssDNA, and ribosomal P (Riemekasten et al., 2005, Rheumatology 44[8]:975-82; lizuka et al., 2010, Lupus 19[6]:717-26).
  • Fc fusion partners for the immunoprotective Fc regions: myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), myelin associated glycoprotein (MAG), proteolipid protein (PLP), cyclic nucleotide phosphodiesterase (CNP), and neurofascin (Schmidt 1999, Multiple sclerosis 5[3]:147-60).
  • MBP myelin basic protein
  • MOG myelin oligodendrocyte glycoprotein
  • MAG myelin associated glycoprotein
  • PGP proteolipid protein
  • CNP cyclic nucleotide phosphodiesterase
  • Fc fusion partners for the immunoprotective Fc regions insulin/proinsulin, glutamic acid decarboxylase (GAD), protein tyrosine phosphatase-like proteins IA-2 and ⁇ -2 ⁇ (Christie 1996, European journal of clinical investigation 26[10]:827-38).
  • Fc fusion partner for the immunoprotective Fc regions: acetylcholine receptor (Sheng et al., 2009, Muscle & nerve 40[2]:279-86).
  • Examples of common allergen proteins implicated in allergy and asthma that may be Fc fusion partners for the immunoprotective Fc regions of the invention include but are not limited to (PDB references to structures or homology models are in parentheses): Grass group 2 (1 BMW, 1 WHO, 1 WHP), Grass group 1 , Grass group 3, Mite group 2 (1A9V, 1AHK, 1AHM), Serine proteases (example: 1 DPO, trypsin), Mite group 3, Mite group 6, Mite group 9, Soybean Kunitz-type trypsin inhibitor (1AVW), Ole e 1 , Grass group 1 1 , Fruits group 2: thaumatin (1 AUN), Vicilin: peanut Ara h 1 (1 CAW, 1 DGR, 1 DGW), Tree group 1 (1 BTV, 1 BV1 ), Lipocalin, Milk ⁇ -lac
  • immunoprotective Fc regions are: Bla g 1 (cockroach), Can f 1 (dog), Der f 1 (Dermatophagoides farinae), Der p 1 (Dermatophagoides pteronyssinus), Fel d 1 (cat), Alt A1 and Alt A2 (Alternaria alternata), and MUP (mouse) (Arbes et al., 2005, The Journal of allergy and clinical immunology 1 16[2]:377-83; Salo et al., 2008, The Journal of allergy and clinical immunology 121 [3]:678-684 e2).
  • Some preferred food allergens that may be Fc fusion partners for the immunoprotective Fc regions of the invention include but are not limited to: major fish allergen parvalbumin, the cow's milk allergens casein and 3Lg, peanut allergens including Ara hi , Ara h2, and Ara h3, and the nsLTPs and Bet v 1 homologs found in a variety of plant foods (Breiteneder et al., 2005, The Journal of allergy and clinical immunology 1 15[1 ]:14-23; quiz 24).
  • An exemplary autoantigen for use in the immunoprotection mechanism of the invention is myelin oligodendrocyte glycoprotein (MOG).
  • MOG is a glycoprotein of the myelin sheath that has been intensively studied as an autoantigen in demyelinating diseases such as multiple sclerosis (MS) (Lalive, 2008, Swiss Med Wkly 138[47-48]:692-707).
  • MS multiple sclerosis
  • MOG may be coupled to a variant Fc domain as outlined herein to reduce immunogenicity and thus treat the disease, in this case MS.
  • the present invention provides compositions comprising a first fusion protein comprising the autoantigen or allergen and a second fusion protein comprising a variant Fc domain as described above.
  • first and second are not meant to confer an orientation of the sequences with respect to the N- and C- terminal orientation of the two components.
  • the immunogen can be connected at its C-terminus to the N-terminus of the variant Fc domain, or at its N-terminus to the C-terminus of the variant Fc domain.
  • the former is the configuration of the constructs shown in Figure 10.
  • the fusion partners may be linked directly or indirectly through the use of a linker.
  • a direct linkage is generally where the N- and C-termini are covalently attached, and are generally constructed by aligning the coding regions of the first and second domains into a single nucleic acid that is expressed, as is more fully outlined herein.
  • linkers may find use in the present invention to covalently link Fc variant domains to the fusion partner (e.g. the immunogen) to form a fusion composition.
  • linker sequence e.g. the immunogen
  • spacer tethering sequence
  • grammatical equivalents thereof herein is meant a molecule or group of molecules (such as a monomer or polymer) that connects two molecules and often serves to place the two molecules in a preferred configuration.
  • a number of strategies may be used to covalently link molecules together. These include, but are not limited to polypeptide linkages between N- and C-termini of proteins or protein domains, linkage via disulfide bonds, and linkage via chemical cross-linking reagents. In one aspect of this
  • the linker is a peptide bond, generated by recombinant techniques or peptide synthesis. Choosing a suitable linker for a specific case where two polypeptide chains are to be connected depends on various parameters, including but not limited to the nature of the two polypeptide chains (e.g., whether they naturally oligomerize), the distance between the N- and the C-termini to be connected if known, and/or the stability of the linker towards proteolysis and oxidation. Furthermore, the linker may contain amino acid residues that provide flexibility. Thus, the linker peptide may predominantly include the following amino acid residues: Gly, Ser, Ala, or Thr.
  • the linker peptide should have a length that is adequate to link two molecules in such a way that they assume the correct conformation relative to one another so that they retain the desired activity. Suitable lengths for this purpose include at least one and not more than 50 amino acid residues. Preferably, the linker is from about 1 to 30 amino acids in length, with linkers of 1 to 20 amino acids in length being most preferred. In addition, the amino acid residues selected for inclusion in the linker peptide should exhibit properties that do not interfere significantly with the activity of the other fusion domains.
  • linker peptide on the whole should not exhibit a charge that would be inconsistent with the activity of the polypeptide, or interfere with internal folding, or form bonds or other interactions with amino acid residues in one or more of the monomers that would seriously impede the binding of receptor monomer domains.
  • Useful linkers include glycine-serine polymers (including, for example, (GS)n, (GSGGS)n SEQ ID NO:XX, (GGGGS)n SEQ ID NO:XX, and (GGGS)n SEQ ID NO:XX, where n is an integer of at least one), glycine-alanine polymers, alanine-serine polymers, and other flexible linkers such as the tether for the shaker potassium channel, and a large variety of other flexible linkers, as will be appreciated by those in the art. Glycine-serine polymers are preferred since both of these amino acids are relatively unstructured, and therefore may be able to serve as a neutral tether between components.
  • linker is not immunogenic when administered in a human patient.
  • linkers may be chosen such that they have low immunogenicity or are thought to have low immunogenicity.
  • a linker may be chosen that exists naturally in a human.
  • the linker has the sequence of the hinge region of an antibody, that is the sequence that links the antibody Fab and Fc regions; alternatively the linker has a sequence that comprises part of the hinge region, or a sequence that is substantially similar to the hinge region of an antibody.
  • Another way of obtaining a suitable linker is by optimizing a simple linker, e.g., (Gly4Ser)n SEQ ID NO:XX, through random mutagenesis.
  • a suitable polypeptide linker is defined, additional linker polypeptides can be created to select amino acids that more optimally interact with the domains being linked.
  • Other types of linkers that may be used in the present invention include artificial polypeptide linkers and inteins.
  • disulfide bonds are designed to link the two molecules.
  • linkers are chemical cross-linking agents.
  • bifunctional protein coupling agents including but not limited to N- succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), succinimidyl-4-(N- maleimidomethyl)cyclohexane-1-carboxylate, iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis(p- azidobenzoyl)hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)- ethylenediamine), diisocyanates (such as tolyene 2,6-di
  • SPDP N- succinimidyl-3-(
  • a ricin immunotoxin can be prepared as described in Vitetta et al., 1971 , Science 238:1098.
  • Chemical linkers may enable chelation of an isotope.
  • Carbon-14-labeled 1 -isothiocyanatobenzyl-3- methyldiethylene triaminepentaacetic acid is an exemplary chelating agent for conjugation of radionucleotide to the antibody (see PCT WO 94/1 1026).
  • the linker may be cleavable, facilitating release of the cytotoxic drug in the cell.
  • an acid-labile linker for example, an acid-labile linker, peptidase-sensitive linker, dimethyl linker or disulfide-containing linker (Chari et al., 1992, Cancer Research 52: 127-131 ) may be used.
  • a variety of nonproteinaceous polymers including but not limited to polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol, may find use as linkers, that is may find use to link the Fc variants of the present invention to a fusion or conjugate partner to generate an Fc fusion, or to link the Fc variants of the present invention to a conjugate.
  • compositions of the invention including therapeutic antibodies with variant Fc domains and the Fc fusion compositions comprising an immunogen such as an autoantigen or an allergen, are made recombinantly using nucleic acids encoding the compositions as is well known in the art.
  • nucleic acids encoding the compositions as is well known in the art.
  • the composition is a traditional therapeutic antibody, generally two nucleic acids, one encoding the heavy chain and one encoding the light chain, are introduced into a host cell (generally but not exclusively mammalian cells), and the host cells are grown under conditions whereby the antibodies are produced.
  • Fusion compositions of the invention are generally made by constructing nucleic acids that encode the fusion (with or without protein linkers) as is well known in the art. In the case where the fusion compositions are chemically linked, separate nucleic acids encoding each domain may be made, introduced into host cells (either the same host cell or different ones) and grown under conditions where the proteins are expressed.
  • nucleic acids encoding the compositions of the invention may include other nucleic acid sequences including promoters and other regulatory sequences.
  • compositions of the invention are then purified if required as is well known in the art.
  • compositions of the invention are administered to a patient to ameliorate, prevent or treat a disorder or disease.
  • a "patient” for the purposes includes humans and other animals, preferably mammals and most preferably humans.
  • disorder or “disease” herein are meant a disorder that may be ameliorated by the administration of a pharmaceutical composition comprising a composition of the invention.
  • the composition of the invention is a therapeutic antibody containing a variant Fc domain
  • the disorder can be an antibody related disorder.
  • Antibody related disorders include but are not limited to autoimmune diseases, immunological diseases, infectious diseases, inflammatory diseases, neurological diseases, and oncological and neoplastic diseases including cancer.
  • cancer and “cancerous” herein refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • examples of cancer include but are not limited to carcinoma, lymphoma, blastoma, sarcoma (including liposarcoma), neuroendocrine tumors, mesothelioma, schwanoma, meningioma, adenocarcinoma, melanoma, and leukemia and lymphoid malignancies.
  • the compositions of the invention is the only therapeutically active agent administered to a patient.
  • the compositions are administered in combination with one or more other therapeutic agents, including but not limited to cytotoxic agents, chemotherapeutic agents, cytokines, growth inhibitory agents, anti-hormonal agents, kinase inhibitors, anti-angiogenic agents, cardioprotectants, or other therapeutic agents.
  • cytotoxic agents including but not limited to cytotoxic agents, chemotherapeutic agents, cytokines, growth inhibitory agents, anti-hormonal agents, kinase inhibitors, anti-angiogenic agents, cardioprotectants, or other therapeutic agents.
  • compositions of the invention may be administered concomitantly with one or more other therapeutic regimens.
  • a composition of the invention useful in cancer e.g. a therapeutic antibody
  • chemotherapy including other therapeutic antibodies
  • radiation therapy or both chemotherapy and radiation therapy.
  • a variety of other therapeutic agents may find use for administration with the
  • compositions of the invention including any number of other drugs, including, but not limited to, antibodies, small molecule drugs and other biologies.
  • compositions are contemplated wherein a composition of the invention and one or more pharmaceutical carriers are formulated.
  • Formulations of the IgG variants are prepared for storage by mixing the IgG having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed., 1980, entirely incorporated by reference), in the form of lyophilized formulations or aqueous solutions.
  • the formulations to be used for in vivo administration are preferably sterile. This is readily accomplished by filtration through sterile filtration membranes or other methods.
  • the IgG variants and other therapeutically active agents disclosed herein may also be formulated as immunoliposomes, and/or entrapped in microcapsules.
  • the concentration of the composition in the formulation may vary from about 0.1 to 100% by weight. In a preferred embodiment, the concentration of the composition of the invention is in the range of 0.003 to 1.0 molar.
  • a therapeutically effective dose of the composition is administered.
  • therapeutically effective dose herein is meant a dose that produces the effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques. Dosages may range from 0.01 to 100 mg/kg of body weight or greater, for example 0.01 , 0.1 , 1 .0, 10, or 50 mg/kg of body weight, with 1 to 10mg/kg being preferred.
  • compositions preferably in the form of a sterile aqueous solution, may be done in a variety of ways, including, but not limited to, orally,
  • subcutaneously intravenously, parenterally, intranasally, intraotically, intraocularly, rectally, vaginally, transdermally, topically (e.g., gels, salves, lotions, creams, etc.), intraperitoneally, intramuscularly, intrapulmonary (e.g., AERx® inhalable technology commercially available from Aradigm, or Inhance® pulmonary delivery system commercially available from Nektar
  • Example 1 Immunoprotection to reduce immunoqencity of biotherapeutics
  • This example describes the utilization of the FcyRllb-mediated inhibitory mechanism to reduce the immune response to a therapeutic protein.
  • Our novel approach illustrated in Figure 1 , mimics the inhibitory effects of immune complex by high-affinity coengagement of FcyRllb and the BCR coreceptor complex on human B cells.
  • a key step in immune response to an adminstered protein is engagement with anti-drug specific BCR on B cells followed by activation, internalization, and presentation to T cells.
  • Fusion of the therapeutic protein to the IgG Fc region enables interaction with the inhibitory receptor FcyRllb.
  • native IgG's bind FcyRllb with weak (uM) affinity
  • FcyRllb-mediated inhibition occurs in response only to immune complexed but not monomeric IgG Fc.
  • FcyRI lb-enhanced (llbE) Fc domains to therapeutic proteins utilizes the natural inhibitory pathway to inhibit the B cell response to the fusion partner.
  • Enhanced affinity of the protein-Fc fusion for the inhibitory FcyRllb will prevent anti-therapeutic B cells from activation and differentiation into immunoglobulin-producing plasma cells.
  • the Fc domain was engineered to create a biologic with high affinity for FcyRllb that mimics the suppressive effects of cognate immune complex on activated B cells (USSN).
  • B cells are important in adaptive immunity because BCR-antigen complex internalization is the first step in antigen presentation. Because FcyRllb coengagement inhibits BCR-dependent antigen internalization and processing, the activities of the llbE variants presented here may also suppress T cell-mediated adaptive immunity.
  • the fusions of the invention thus suppress differentiation, survival, and proliferation only of B cell populations possessing BCRs specific for epitopes of the original (non-modified) drug. This strategy may selectively eliminate only drug-reactive B cells, and thus mitigate potential immunogenicity concerns arising from the clinical use of therapeutic proteins.
  • llbE Fc regions have therapeutic applications by selectively eliminating only drug-reactive B cells, and thus mitigate potential immunogenicity concerns arising from the clinical use of therapeutic proteins.
  • the exemplary test system for the immunoprotection approach outlined herein was the anti-TNFa (anti-TNF) antibody adalimumab (marketed as the drug Humira®).
  • Humira is known to elicit significant immunogenicity in humans.
  • MTX methotrexate
  • MTX methotrexate
  • MTX methotrexate
  • Plates were coated with adalimumab lgG1 antibody, and then blocked with SuperBlock (Pierce) and washed with buffer. Cyno serum samples were added in 5- fold dilutions, as well as recombinant TNFa (R&D Systems) as a controls, and plates were incubated at room temperature for 1 hour. Plates were washed, and anti-adalimumab antibody was detected by adding europium-labeled adaliumumab. Plates were incubated at room temperature for 1 hour, washed, DELFIA Enhancement Solution (Perkin Elmer) was added, and samples were incubated at room temperature for 15 minutes in the dark.
  • DELFIA Enhancement Solution Perkin Elmer
  • Time-resolved flluorescence was read using an Envision plate reader (Perkin Elmer).
  • the results in Figure 2 show that adalimumab lgG1 elicited strong immune response in both monkeys despite B cell depletion using rituximab.
  • S267E and L328F substitutions were introduced into adalimumab lgG1 in the pTT5 vector using site-directed mutagenesis (QuikChange, Stratagene, Cedar Creek, TX). Heavy and light chain constructs were cotransfected into HEK293E cells for expression, and antibodies were purified using protein A affinity chromatography (Pierce Biotechnology, Rockford, IL). Binding to human FcyRllb and TNFa antigen were measured using surface plasmon resonance (SPR) based technology (Biacore). SPR measurements were performed using a Biacore 3000 instrument (Biacore, Piscataway, NJ).
  • SPR surface plasmon resonance
  • a protein A/G (Pierce Biotechnology) CM5 biosensor chip (Biacore) was generated using a standard primary amine coupling protocol. All measurements were performed using HBS-EP buffer (10 mM HEPES pH 7.4, 0.15 M NaCI, 3 mM EDTA, 0.005% vol/vol surfactant P20, Biacore). Antibodies at 20 nM or 50 nM in HBS-EP buffer were immobilized on the protein A/G surface, and then recombinant human FcyRllb (R&D Systems) or TNFa (R&D Systems) was injected in a concentration series. After each cycle, the surface was regenerated by injecting glycine buffer (10 mM, pH 1 .5).
  • mice Five mice were given a single intravenous 2 mg/kg dose, and 25-50 ul blood samples were collected via retro-orbital sinus/plexus (OSP) at times 1 hr and days 1 , 2, 4, 7, 9, 1 1 , and 14 post-injection.
  • Anti-adalimumab antibody was detected using the ADA assay described above. Results are shown in Figure 6. Consistent with the previous studies, the lgG1 version of adalimumab showed 100% immune response. In contrast, the llbE version of adalimumab engineered for high affinity to FcyRllb showed a substantial reduction in immunogenicity. Mean ADA response on day 14 was 56640 for lgG1 and 5877 for llbE. Thus the llbE Fc region resulted in a 90% (10-fold) reduction in ADA response.
  • Anti- adalimumab antibody was detected using the ADA assay described above. The results are shown in Figure 7. As previously observed, adalimumab lgG1 resulted in a strong immune response in the hCD32b+ tg mice. Again, Fc-engineered adalimumumab llbE (267E/328F) showed a reduction in the level of immunogenicity in the hCD32b+ tg mice. Mean ADA response on day 24 was 218478 for lgG1 and 92092 for llbE. Thus the llbE Fc region resulted in a 58% (2.4-fold) reduction in ADA response.
  • mice lacking the human FcyRllb transgene hCD32b- tg mice
  • adalimumab llbE did not reduce immunogenicity.
  • variants herein, and in particular 267E/328F can be transferred to other therapeutic antibodies and exhibit the same effects.
  • Fc variants can be "transferred” to different antibodies, including antibodies with different Fv regions and different isotypes and subclasses of Igs, and retain their function. See for example USSN 12/156, 183, filed May 30, 2008, entitled “Methods and Compositions for Inhibiting CD32b Expressing cells", and USSN 12/562,088, filed Sep. 17, 2009, entitled “Novel Compositions and Methods for Treating IgE-Mediated Disorders", herein incorporated expressly by reference.
  • MOG myelin oligodendrocyte glycoprotein
  • Binding to the human inhibitory receptor FcyRllb, the human activating receptor FcyRllla, and an antibody recognizing human MOG were measured using surface plasmon resonance. SPR measurements were performed using a Biacore 3000 instrument (Biacore, Piscataway, NJ). A protein A G (Pierce Biotechnology) CM5 biosensor chip (Biacore) was generated using a standard primary amine coupling protocol. All fusion proteins were diluted in HBS-EP buffer to 100 nM and immobilized on protein A followed by injection of FcyRllb, FcyRllla, or anti-MOG antibody.
  • Anti- MOG antibody is a rat lgG2b which does not bind to protein A, and thus does not interference with the binding experiment. Data were processed by zeroing time and response before the injection of analyte and by subtracting appropriate nonspecific signals (response of reference channel and injection of running buffer).
  • lymphocyte Ca2+ responses a role for Lyn sequestration in extinguishing negative regulation. J Biol Chem 276:44820-44827.

Abstract

L'invention concerne des fractions thérapeutiques présentant une réponse immunogène réduite, utilisées en particulier à des fins thérapeutiques.
PCT/US2011/023813 2010-02-04 2011-02-04 Immunoprotection de fractions thérapeutiques avec des régions fc améliorées WO2011097527A2 (fr)

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